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Grosu S, Fabritius MP, Winkelmann M, Puhr-Westerheide D, Ingenerf M, Maurus S, Graser A, Schulz C, Knösel T, Cyran CC, Ricke J, Kazmierczak PM, Ingrisch M, Wesp P. Effect of artificial intelligence-aided differentiation of adenomatous and non-adenomatous colorectal polyps at CT colonography on radiologists' therapy management. Eur Radiol 2025; 35:4091-4099. [PMID: 39862248 DOI: 10.1007/s00330-025-11371-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2024] [Revised: 12/01/2024] [Accepted: 12/22/2024] [Indexed: 01/27/2025]
Abstract
OBJECTIVES Adenomatous colorectal polyps require endoscopic resection, as opposed to non-adenomatous hyperplastic colorectal polyps. This study aims to evaluate the effect of artificial intelligence (AI)-assisted differentiation of adenomatous and non-adenomatous colorectal polyps at CT colonography on radiologists' therapy management. MATERIALS AND METHODS Five board-certified radiologists evaluated CT colonography images with colorectal polyps of all sizes and morphologies retrospectively and decided whether the depicted polyps required endoscopic resection. After a primary unassisted reading based on current guidelines, a second reading with access to the classification of a radiomics-based random-forest AI-model labelling each polyp as "non-adenomatous" or "adenomatous" was performed. Performance was evaluated using polyp histopathology as the reference standard. RESULTS 77 polyps in 59 patients comprising 118 polyp image series (47% supine position, 53% prone position) were evaluated unassisted and AI-assisted by five independent board-certified radiologists, resulting in a total of 1180 readings (subsequent polypectomy: yes or no). AI-assisted readings had higher accuracy (76% +/- 1% vs. 84% +/- 1%), sensitivity (78% +/- 6% vs. 85% +/- 1%), and specificity (73% +/- 8% vs. 82% +/- 2%) in selecting polyps eligible for polypectomy (p < 0.001). Inter-reader agreement was improved in the AI-assisted readings (Fleiss' kappa 0.69 vs. 0.92). CONCLUSION AI-based characterisation of colorectal polyps at CT colonography as a second reader might enable a more precise selection of polyps eligible for subsequent endoscopic resection. However, further studies are needed to confirm this finding and histopathologic polyp evaluation is still mandatory. KEY POINTS Question This is the first study evaluating the impact of AI-based polyp classification in CT colonography on radiologists' therapy management. Findings Compared with unassisted reading, AI-assisted reading had higher accuracy, sensitivity, and specificity in selecting polyps eligible for polypectomy. Clinical relevance Integrating an AI tool for colorectal polyp classification in CT colonography could further improve radiologists' therapy recommendations.
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Affiliation(s)
- Sergio Grosu
- Department of Radiology, LMU University Hospital, LMU Munich, Marchioninistraße 15, 81377, Munich, Germany.
| | - Matthias P Fabritius
- Department of Radiology, LMU University Hospital, LMU Munich, Marchioninistraße 15, 81377, Munich, Germany
| | - Michael Winkelmann
- Department of Radiology, LMU University Hospital, LMU Munich, Marchioninistraße 15, 81377, Munich, Germany
| | - Daniel Puhr-Westerheide
- Department of Radiology, LMU University Hospital, LMU Munich, Marchioninistraße 15, 81377, Munich, Germany
| | - Maria Ingenerf
- Department of Radiology, LMU University Hospital, LMU Munich, Marchioninistraße 15, 81377, Munich, Germany
| | - Stefan Maurus
- Department of Radiology, LMU University Hospital, LMU Munich, Marchioninistraße 15, 81377, Munich, Germany
- Department for Diagnostic and Interventional Radiology and Neuroradiology, Klinikum Kempten, Robert-Weixler-Straße 50, 87439, Kempten, Germany
| | - Anno Graser
- Gemeinschaftspraxis Radiologie München, Burgstraße 7, 80331, Munich, Germany
| | - Christian Schulz
- Department of Medicine II, LMU University Hospital, LMU Munich, Marchioninistraße 15, 81377, Munich, Germany
| | - Thomas Knösel
- Department of Pathology, LMU University Hospital, LMU Munich, Marchioninistraße 15, 81377, Munich, Germany
| | - Clemens C Cyran
- Department of Radiology, LMU University Hospital, LMU Munich, Marchioninistraße 15, 81377, Munich, Germany
| | - Jens Ricke
- Department of Radiology, LMU University Hospital, LMU Munich, Marchioninistraße 15, 81377, Munich, Germany
| | - Philipp M Kazmierczak
- Department of Radiology, LMU University Hospital, LMU Munich, Marchioninistraße 15, 81377, Munich, Germany
| | - Michael Ingrisch
- Department of Radiology, LMU University Hospital, LMU Munich, Marchioninistraße 15, 81377, Munich, Germany
- Munich Center for Machine Learning (MCML), Geschwister-Scholl-Platz 1, 80539, Munich, Germany
| | - Philipp Wesp
- Department of Radiology, LMU University Hospital, LMU Munich, Marchioninistraße 15, 81377, Munich, Germany
- Munich Center for Machine Learning (MCML), Geschwister-Scholl-Platz 1, 80539, Munich, Germany
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Qi GX, Zhao RX, Gao C, Ma ZY, Wang S, Xu J. Recent advances and challenges in colorectal cancer: From molecular research to treatment. World J Gastroenterol 2025; 31:106964. [DOI: 10.3748/wjg.v31.i21.106964] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/11/2025] [Revised: 04/22/2025] [Accepted: 05/26/2025] [Indexed: 06/06/2025] Open
Abstract
Colorectal cancer (CRC) ranks among the top causes of cancer-related fatalities globally. Recent progress in genomics, proteomics, and bioinformatics has greatly improved our comprehension of the molecular underpinnings of CRC, paving the way for targeted therapies and immunotherapies. Nonetheless, obstacles such as tumor heterogeneity and drug resistance persist, hindering advancements in treatment efficacy. In this context, the integration of artificial intelligence (AI) and organoid technology presents promising new avenues. AI can analyze genetic and clinical data to forecast disease risk, prognosis, and treatment responses, thereby expediting drug development and tailoring treatment plans. Organoids replicate the genetic traits and biological behaviors of tumors, acting as platforms for drug testing and the formulation of personalized treatment approaches. Despite notable strides in CRC research and treatment - from genetic insights to therapeutic innovations - numerous challenges endure, including the intricate tumor microenvironment, tumor heterogeneity, adverse effects of immunotherapies, issues related to AI data quality and privacy, and the need for standardization in organoid culture. Future initiatives should concentrate on clarifying the pathogenesis of CRC, refining AI algorithms and organoid models, and creating more effective therapeutic strategies to alleviate the global impact of CRC.
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Affiliation(s)
- Gao-Xiu Qi
- Department of Pathology, Qingdao Central Hospital, University of Health and Rehabilitation Sciences (Qingdao Central Medical Group), Qingdao 266042, Shandong Province, China
| | - Rui-Xia Zhao
- Department of Pathology, Qingdao Central Hospital, University of Health and Rehabilitation Sciences (Qingdao Central Medical Group), Qingdao 266042, Shandong Province, China
| | - Chen Gao
- Department of Pathology, Qingdao Central Hospital, University of Health and Rehabilitation Sciences (Qingdao Central Medical Group), Qingdao 266042, Shandong Province, China
| | - Zeng-Yan Ma
- Department of Pathology, Qingdao Central Hospital, University of Health and Rehabilitation Sciences (Qingdao Central Medical Group), Qingdao 266042, Shandong Province, China
| | - Shang Wang
- Department of Pathology, School of Basic Medicine, Qingdao University, Qingdao 266071, Shandong Province, China
| | - Jing Xu
- Department of Pathology, Qingdao Central Hospital, University of Health and Rehabilitation Sciences (Qingdao Central Medical Group), Qingdao 266042, Shandong Province, China
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Kahn CL, Petersen MM, Kleif J, Mansvelders MSE, Rasmussen M, Jørgensen LN, Vilandt J, Seidelin JB, Jaensch C, Bondeven P, Gotschalck KA, Løve US, Andersen B, Christensen IJ, LaPoint LC, Therkildsen C. Circulating Tumor DNA in Addition to Fecal Immunochemical Test in a Dual-Test Colorectal Cancer Screening Approach. Clin Colorectal Cancer 2025; 24:310-319.e1. [PMID: 40204621 DOI: 10.1016/j.clcc.2025.03.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2024] [Revised: 02/03/2025] [Accepted: 03/07/2025] [Indexed: 04/11/2025]
Abstract
BACKGROUND Early detection is paramount when reducing incidence and mortality of colorectal cancer (CRC). Current population-based screening programs primarily use fecal immunochemical test (FIT) to allocate individuals for colonoscopy although low specificity challenges colonoscopy capacities. We aimed to assess the potential of circulating tumor (ct)DNA markers for early CRC detection in a dual-test CRC screening approach among FIT positive individuals. METHODS Plasma samples from 774 FIT positive (≥100 ng Hemoglobin/mL) individuals from the Danish CRC screening program were analyzed for hypermethylated DNA in the genes Branched Chain Amino-acid Transaminase 1 (BCAT1), Ikaros-Family Zinc Finger transcription 1 (IKZF1), and Interferon Regulator Factor 4 (IRF4). Multivariate logistic regression models were generated adding the ctDNA markers and age to the FIT value. The dual-test approach was benchmarked to FIT at specific thresholds. RESULTS The dual-test approach improved CRC detection compared to the FIT alone (AUC of 87.2 [95% CI, 82.9-91.4] vs AUC of 72.5 [95% CI, 67.0-77.9]). This was also seen when adding advanced adenomas to the outcome resulting in AUCs of 71.8 [95% CI, 67.8-75.8] for the dual-test approach compared to 65.5 [95% CI, 61.3-69.7] for the FIT model alone. Benchmarking the dual-test approach at FIT cut-offs between 100 and 600 ng Hb/mL showed a potential for either reducing the colonoscopy requirement by up to 56% or increasing CRC detection by up to 28%. CONCLUSIONS As increasing FIT cutoff will decrease CRC detection rate, application of the ctDNA panel can increase the sensitivity and specificity in a dual-test approach among asymptomatic individuals.
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Affiliation(s)
| | - Mathias M Petersen
- Gastro Unit, Hvidovre Hospital, Hvidovre, Denmark; Institute for Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
| | - Jakob Kleif
- Gastro Unit, Hvidovre Hospital, Hvidovre, Denmark; Institute for Clinical Medicine, University of Copenhagen, Copenhagen, Denmark; Department of Surgery, Nordsjællands Hospital, Hillerød, Denmark
| | | | - Morten Rasmussen
- Institute for Clinical Medicine, University of Copenhagen, Copenhagen, Denmark; Digestive Disease Center, Bispebjerg Hospital, Copenhagen, Denmark
| | - Lars N Jørgensen
- Institute for Clinical Medicine, University of Copenhagen, Copenhagen, Denmark; Digestive Disease Center, Bispebjerg Hospital, Copenhagen, Denmark
| | - Jesper Vilandt
- Department of Surgery, Nordsjællands Hospital, Hillerød, Denmark
| | - Jakob B Seidelin
- Gastro Unit, Section for Gastroenterology, Herlev Hospital, Herlev, Denmark
| | - Claudia Jaensch
- Endocrine Laboratory, Department of Clinical Chemistry, Amsterdam UMC, AMC & VUMC, Amsterdam, The Netherlands
| | - Peter Bondeven
- Department of Surgery, Randers Hospital, Randers, Denmark
| | - Kåre A Gotschalck
- Department of Surgery, Horsens Hospital, Horsens, Denmark; Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
| | - Uffe S Løve
- Department of Surgery, Viborg Hospital, Viborg, Denmark; Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
| | - Berit Andersen
- Department of Public Health Programmes and University Research Clinic for Cancer Screening, Randers Regional Hospital, Randers, Denmark; Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
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Crecca E, Di Giuseppe G, Camplone C, Vigiano Benedetti V, Melaiu O, Mezza T, Cencioni C, Spallotta F. The multifaceted role of agents counteracting metabolic syndrome: A new hope for gastrointestinal cancer therapy. Pharmacol Ther 2025; 270:108847. [PMID: 40216262 DOI: 10.1016/j.pharmthera.2025.108847] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2024] [Revised: 01/27/2025] [Accepted: 04/03/2025] [Indexed: 04/24/2025]
Abstract
Metabolic syndrome (MetS) is defined by the presence of at least three of five clinical parameters including abdominal obesity, insulin resistance, elevated triglycerides, reduced high-density lipoprotein (HDL) and hypertension. Major features describing MetS have been recognized risk factors for cancer onset, with an alarming impact on gastrointestinal (GI) tumors. Intriguingly, therapeutic administration of drugs to improve glycemic control and dyslipidemia (including metformin, statins) has been shown to have a preventive role in the development and in prognosis improvement of several cancer types. Overall, these observations highlight the key role of altered metabolism prevalently in cancer risk development and unveil anti-MetS agent repurposing potential beyond their conventional pharmacological action. The objective of this review is to summarize the current knowledge about the antitumor activity of anti-diabetic and anti-lipemic agents in GI cancer onset and progression. Here, pre-clinical evidence of their therapeutic potential and of their integration in novel compelling therapeutic strategies will be discussed. Possible clinical outcomes of these novel therapeutic combined protocols specifically dedicated to GI cancer patients will be put under the spotlight. In the future, these novel therapeutic options should be considered to improve conventional chemotherapy response and prognosis of this group of patients.
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Affiliation(s)
- Elena Crecca
- Institute of System Analysis and Informatics "Antonio Ruberti", National Research Council (IASI-CNR), 00185 Rome, Italy
| | - Gianfranco Di Giuseppe
- Endocrinology and Diabetology Unit, Fondazione Policlinico Universitario Gemelli IRCCS, Rome, Italy; Department of Translational Medicine, Catholic University of the Sacred Heart, 00168 Rome, Italy
| | - Claudia Camplone
- Department of Biology and Biotechnologies "Charles Darwin", Sapienza University, 00185 Rome, Italy; Istituto Pasteur Italia-Fondazione Cenci Bolognetti, Sapienza University, 00185 Rome, Italy
| | | | - Ombretta Melaiu
- Department of Clinical Sciences and Translational Medicine, University of Rome "Tor Vergata", Rome, Italy
| | - Teresa Mezza
- Department of Translational Medicine, Catholic University of the Sacred Heart, 00168 Rome, Italy; Pancreas Unit, CEMAD Digestive Diseases Center, Internal Medicine and Gastroenterology Unit, Fondazione Policlinico Universitario Gemelli IRCCS, Rome, Italy
| | - Chiara Cencioni
- Institute of System Analysis and Informatics "Antonio Ruberti", National Research Council (IASI-CNR), 00185 Rome, Italy.
| | - Francesco Spallotta
- Department of Biology and Biotechnologies "Charles Darwin", Sapienza University, 00185 Rome, Italy; Istituto Pasteur Italia-Fondazione Cenci Bolognetti, Sapienza University, 00185 Rome, Italy.
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Wang K, Zhou S, Wang H, Zhang X, Cheng W, Sun Y, Ding C, Guan W. The influence of microsatellite status on tertiary lymphoid structures and lymph node metastasis in colorectal cancer. Clin Transl Oncol 2025:10.1007/s12094-025-03946-6. [PMID: 40418304 DOI: 10.1007/s12094-025-03946-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2025] [Accepted: 04/26/2025] [Indexed: 05/27/2025]
Abstract
BACKGROUND Microsatellite stability influences the prognosis of patients with colorectal cancer (CRC). However, there are few studies on the relationship between microsatellite stability and lymph node metastasis (LNM) in CRC. OBJECTIVE This study aims to elucidate the relationship between microsatellite stability and LNM in CRC and to investigate potential underlying mechanisms. METHODS A retrospective analysis was performed on a cohort of 309 CRC patients, who were categorized into microsatellite instability (MSI) and microsatellite stability (MSS) groups based on their microsatellite status. Clinical and pathological indicators were collected, and differences between the two groups were assessed. The tertiary lymphoid structures (TLS) in both groups were examined using immunohistochemistry and immunofluorescence to compare differences in density, maturity, and the ratio of CD8+T cells. Establishing the relationship between microsatellite stability, TLS characteristics, and lymph node metastasis. RESULTS The TNM staging for patients in the MSI group was significantly earlier compared to those in the MSS group. Subsequent analysis of pathological indicators demonstrated that the MSI group exhibited a significantly lower incidence of lymph node metastases (31.4% vs. 47%, P=0.005), while no statistically significant differences were observed in other pathological indicators (P>0.05). Examination of CRC tissue sections revealed that the MSI group possessed a greater number and maturity of tertiary lymphoid structures, as well as a higher proportion of CD8+T cells. CONCLUSION MSI may decrease the incidence of LNM in CRC, potentially as a result of the activation of local anti-tumor immune responses facilitated by MSI.
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Affiliation(s)
- Kai Wang
- Department of General Surgery, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing, China
| | - Shizhen Zhou
- Department of General Surgery, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
| | - Hao Wang
- Department of General Surgery, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing, China
| | - Xufei Zhang
- Department of General Surgery, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing, China
| | - Wei Cheng
- Department of General Surgery, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing, China
| | - Yan Sun
- Department of Anesthesiology, Nanjing Drum Tower Hospital, The Affiliated Hospital Medical School, Nanjing University, Nanjing, China
| | - Chao Ding
- Department of General Surgery, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing, China.
| | - Wenxian Guan
- Department of General Surgery, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing, China.
- Department of General Surgery, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China.
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Goto N, Agudo J, Yilmaz ÖH. Early immune evasion in colorectal cancer: interplay between stem cells and the tumor microenvironment. Trends Cancer 2025:S2405-8033(25)00112-8. [PMID: 40382216 DOI: 10.1016/j.trecan.2025.04.016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2025] [Revised: 04/23/2025] [Accepted: 04/24/2025] [Indexed: 05/20/2025]
Abstract
Most colorectal cancers (CRCs) are characterized by a low mutational burden and an immune-cold microenvironment, limiting the efficacy of immune checkpoint blockade (ICB) therapies. While advanced tumors exhibit diverse immune evasion mechanisms, emerging evidence suggests that aspects of immune escape arise much earlier, within precancerous lesions. In this review, we discuss how early driver mutations and epigenetic alterations contribute to the establishment of an immunosuppressive microenvironment in CRC. We also highlight the dynamic crosstalk between cancer cells, stromal niche cells, and immune cells driving immune evasion and liver metastasis. A deeper understanding of these early events may guide the development of more effective preventive and therapeutic strategies for CRC.
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Affiliation(s)
- Norihiro Goto
- Joan and Sanford I. Weill Department of Medicine, Division of Gastroenterology & Hepatology, Weill Cornell Medicine, Cornell University, New York, NY 10021, USA; Jill Roberts Institute for Research in Inflammatory Bowel Disease, Weill Cornell Medicine, Cornell University, New York, NY 10021, USA.
| | - Judith Agudo
- Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Immunology, Harvard Medical School, Boston, MA 02215, USA; Ludwig Center at Harvard, Boston, MA 02215, USA; Parker Institute for Cancer Immunotherapy at Dana-Farber Cancer Institute, Boston, MA 02215, USA; New York Stem Cell Foundation, New York, NY 10019, USA
| | - Ömer H Yilmaz
- Department of Biology, The David H. Koch Institute for Integrative Cancer Research at MIT, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA 02142, USA; Department of Pathology, Beth Israel Deaconess Hospital and Harvard Medical School, Boston, MA 02114, USA; Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
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Liao JN, Ni WJ, Wu PH, Yang YD, Yang Y, Long W, Xie MZ, Zhu XZ, Xie FH, Leng XM. Switching from messenger RNAs to noncoding RNAs, METTL3 is a novel colorectal cancer diagnosis and treatment target. World J Gastrointest Oncol 2025; 17:104076. [DOI: 10.4251/wjgo.v17.i5.104076] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/09/2024] [Revised: 03/10/2025] [Accepted: 04/03/2025] [Indexed: 05/15/2025] Open
Abstract
N6-methyladenosine (m6A) modification, one of the most prevalent RNA epigenetic modifications in eukaryotes, constitutes over 60% of all RNA methylation modifications. This dynamic modification regulates RNA processing, maturation, nucleocytoplasmic transport, translation efficiency, phase separation, and stability, thereby linking its dysregulation to diverse physiological and pathological processes. METTL3, a core catalytic component of the methyltransferase complex responsible for m6A deposition, is frequently dysregulated in diseases, including colorectal cancer (CRC). Although METTL3’s involvement in CRC pathogenesis has been documented, its precise molecular mechanisms and functional roles remain incompletely understood. METTL3 mediates CRC progression-encompassing proliferation, invasion, drug resistance, and metabolic reprogramming-through m6A-dependent modulation of both coding RNAs and noncoding RNAs. Its regulatory effects are primarily attributed to interactions with key signaling pathways at multiple stages of CRC development. Emerging evidence highlights METTL3 as a promising biomarker for CRC diagnosis and prognosis, as well as a potential therapeutic target. By synthesizing recent advances in METTL3 research within CRC, this review provides critical insights into novel strategies for clinical diagnosis and targeted therapy.
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Affiliation(s)
- Jun-Nan Liao
- The First Affiliated Hospital of Gannan Medical University, Gannan Medical University, Ganzhou 341000, Jiangxi Province, China
| | - Wen-Juan Ni
- School of Basic Medicine, Gannan Medical University, Ganzhou 341000, Jiangxi Province, China
| | - Ping-Hui Wu
- The First Affiliated Hospital of Gannan Medical University, Gannan Medical University, Ganzhou 341000, Jiangxi Province, China
| | - Ya-Dong Yang
- The First Affiliated Hospital of Gannan Medical University, Gannan Medical University, Ganzhou 341000, Jiangxi Province, China
| | - Ying Yang
- School of Basic Medicine, Gannan Medical University, Ganzhou 341000, Jiangxi Province, China
| | - Wen Long
- School of Basic Medicine, Gannan Medical University, Ganzhou 341000, Jiangxi Province, China
| | - Mei-Zhen Xie
- School of Basic Medicine, Gannan Medical University, Ganzhou 341000, Jiangxi Province, China
| | - Xiu-Zhi Zhu
- School of Basic Medicine, Gannan Medical University, Ganzhou 341000, Jiangxi Province, China
| | - Fu-Hua Xie
- School of Basic Medicine, Gannan Medical University, Ganzhou 341000, Jiangxi Province, China
| | - Xiao-Min Leng
- School of Basic Medicine, Gannan Medical University, Ganzhou 341000, Jiangxi Province, China
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Huang S, Liu S, Tan F, Chen H, Chen G. Construction and validation of a risk nomogram model for colorectal sessile serrated lesions. J Int Med Res 2025; 53:3000605251337577. [PMID: 40357909 PMCID: PMC12075987 DOI: 10.1177/03000605251337577] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2024] [Accepted: 04/09/2025] [Indexed: 05/15/2025] Open
Abstract
ObjectiveThis study aimed to explore the risk factors for colorectal sessile serrated lesions and construct a risk nomogram model.MethodsPatients were enrolled retrospectively from the Affiliated Xuzhou Municipal Hospital of Xuzhou Medical University from January 2019 to September 2023 and randomized to the training and validation sets at a ratio of 7:3. The predictors for constructing the nomogram model were screened via univariate analysis and multivariate logistic regression analysis. Subsequently, the performance of the model was evaluated.ResultsMultivariate logistic regression analysis revealed that age, history of smoking, history of alcohol consumption, and triglyceride-glucose index were independent risk factors for colorectal sessile serrated lesions (p < 0.05). The area under the curve values of the nomogram model in the training and validation sets were 0.715 (95% confidence interval: 0.676-0.753) and 0.742 (95% confidence interval: 0.669-0.815), respectively. The calibration curves showed good homogeneity between the predicted and actual values. Decision curve analysis showed that this nomogram model can achieve positive clinical benefits.ConclusionsAge, history of smoking, history of alcohol consumption, and triglyceride-glucose index are independent predictors of colorectal sessile serrated lesions. This nomogram model may predict the risk of colorectal sessile serrated lesions.
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Affiliation(s)
| | | | - Fang Tan
- The Affiliated Xuzhou Municipal Hospital of Xuzhou Medical University, China
| | - Hu Chen
- The Affiliated Xuzhou Municipal Hospital of Xuzhou Medical University, China
| | - Guangxia Chen
- The Affiliated Xuzhou Municipal Hospital of Xuzhou Medical University, China
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Teixeira N, Baião A, Dias S, Sarmento B. The progress and challenges in modeling colorectal cancer and the impact on novel drug discovery. Expert Opin Drug Discov 2025; 20:565-574. [PMID: 39282980 DOI: 10.1080/17460441.2024.2404238] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2024] [Accepted: 09/10/2024] [Indexed: 05/03/2025]
Abstract
INTRODUCTION Colorectal cancer (CRC) remains one of the leading causes of cancer-related morbidity and mortality worldwide. This disease is complex and heterogeneous, influenced by a variety of genetic, epigenetic, and environmental factors that drive CRC initiation and progression. Despite advances in therapeutic strategies, the five-year survival rate for metastatic CRC is alarmingly low. Traditional two-dimensional (2D) cell culture systems have been the foundation of cancer research, but their inability to replicate the complex tumor microenvironment (TME) limits their effectiveness. AREAS COVERED This paper explores the evolution of CRC models, starting with the limitations of traditional 2D cell culture systems and the significant advancements offered by 3D models. Additionally, it highlights 3D bioprinting and on-chip CRC models, which have enhanced the ability to mimic in vivo conditions. EXPERT OPINION The transition to advanced 3D models represents a pivotal shift in CRC research, offering considerable improvements over the established 2D models. These models hold promise for the development of patient-specific models that better mimic in vivo conditions. However, the inherent complexity of CRC continues to pose challenges in developing models that can fully capture the disease's multifaceted nature. This complexity and high costs associated with these technologies, along with the need for standardized protocols, pose significant challenges to their widespread adoption.
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Affiliation(s)
- Natália Teixeira
- i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal
- INEB - Instituto de Engenharia Biomédica, Universidade do Porto, Porto, Portugal
- ICBAS - Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, Porto, Portugal
| | - Ana Baião
- i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal
- INEB - Instituto de Engenharia Biomédica, Universidade do Porto, Porto, Portugal
- ICBAS - Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, Porto, Portugal
| | - Sofia Dias
- i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal
- INEB - Instituto de Engenharia Biomédica, Universidade do Porto, Porto, Portugal
- ICBAS - Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, Porto, Portugal
| | - Bruno Sarmento
- i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal
- INEB - Instituto de Engenharia Biomédica, Universidade do Porto, Porto, Portugal
- CESPU - IUCS - Instituto Universitário de Ciências da Saúde, Gandra, Portugal
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Mehanna MG, El-Halawany AM, Al-Abd AM, Alqurashi MM, Bukhari HA, Kazmi I, Al-Qahtani SD, Bawadood AS, Anwar F, Al-Abbasi FA. 6-Paradol enhances sorafenib's effects against colorectal cancer and promotes active metabolite formation. Pathol Res Pract 2025; 269:155876. [PMID: 40086339 DOI: 10.1016/j.prp.2025.155876] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/04/2024] [Revised: 01/03/2025] [Accepted: 02/27/2025] [Indexed: 03/16/2025]
Abstract
AIM This research aimed to investigate the effect of 6-Paradol on sorafenib cytotoxicity in colorectal cancer (CRC) cell lines (HT-29, HCT-116, LS-174T, CaCo-2) through its effects on cellular processes. BACKGROUND CRC, which ranks as the third most prevalent cancer, arises in the colon or rectum due to a multifaceted interplay of dietary, lifestyle, genetic, and age-related factors. Sorafenib (multikinase inhibitor), a drug targeting multiple cancer signals, shows promise against liver, thyroid, and kidney tumors but faces resistance in CRC. 6-Paradol (Zingiberaceae), a natural compound, offers the potential for overcoming this resistance. OBJECTIVE The current study investigates whether 6-paradol potentiates sorafenib's anti-cancer activity in CRC cells by promoting increased drug entrapment, uptake, and metabolism. METHOD Sulpharodamine B assay, caspase-3 activity, PARP cleavage, cell cycle distribution analysis, and P-gp efflux activity were assessed for Cytotoxicity using CRC cell lines (HT-29, HCT-116, LS-174T, CaCo-2). RESULT Sorafenib showed potent cytotoxicity across CRC cell lines (IC50: 2.0-11.1 µM). Notably, 6-Paradol synergistically enhanced its effect in HT-29 and HCT-116 cells, reducing IC50 from 338 ± 55.7 to 107 ± 5.3 µM, respectively. 6-Paradol synergized with sorafenib, reducing HCT-116 cell proliferation from from 14.25 ± 0.62 to 20.7 ± 0 fg/cell and Paradol didn't show any significant change in c-PARP concentration which equaled 289.82 ± 27.32 pg/cell, suggesting enhanced cytotoxicity. 6-Paradol exposure resulted in a concentration-dependent (1-100 µM) increase in intracellular p-gp accumulation in CaCo-2, HCT-116, and HT-29. Co-incubation with 6-paradol significantly enhanced sorafenib cellular internalization within CaCo-2 cells, resulting in a concomitant decrease in its extracellular concentration from 1491 ± 132 ng/ml to 216 ± 39 ng/ml. 6-Paradol increased sorafenib intracellular accumulation ranges from 239 ± 16 to 327 ± 34 pg/cell, respectively in HCT-116 cells. 6-Paradol significantly increased the intracellular conversion of sorafenib to its active N-oxide metabolite and facilitated its retention within the CaCo-2 cell compartment. CONCLUSION In conclusion, 6-Paradol marked elevation in sorafenib's cytotoxic profile by influencing its cellular uptake and metabolism. Future research should expand in vitro studies to diverse cell lines, conducting in vivo elucidating underlying mechanisms and rigorously evaluating safety and toxicity.
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Affiliation(s)
- Mohamed G Mehanna
- Department of Biochemistry, Faculty of Sciences, King Abdulaziz University, Jeddah 21589, Saudi Arabia.
| | - Ali M El-Halawany
- Pharmacognosy Department, Faculty of Pharmacy, Cairo University, Kasr-El-Ainy Street, Cairo 11562, Egypt.
| | - Ahmed M Al-Abd
- Pharmacology Department, Medical Research Institute, National Research Centre, Dokki, Cairo 12622, Egypt.
| | - May M Alqurashi
- Department of Biochemistry, Faculty of Sciences, King Abdulaziz University, Jeddah 21589, Saudi Arabia.
| | - Hussam A Bukhari
- Department of Pathology, Faculty of Medicine, King Abdulaziz University, Jeddah 21589, Saudi Arabia; King Abdulaziz University Hospital, King Abdulaziz University, Jeddah 21589, Saudi Arabia.
| | - Imran Kazmi
- Department of Biochemistry, Faculty of Sciences, King Abdulaziz University, Jeddah 21589, Saudi Arabia.
| | - Salwa D Al-Qahtani
- Department of Medical Laboratory Sciences, College of Applied Medical Sciences, Majmaah University, Al Majmaah 11952, Saudi Arabia.
| | - Azizah Salim Bawadood
- Basic Medical Sciences Department, College of Medicine, Prince Sattam Bin Abdulaziz University, Al-Kharj, Saudi Arabia.
| | - Firoz Anwar
- Department of Biochemistry, Faculty of Sciences, King Abdulaziz University, Jeddah 21589, Saudi Arabia.
| | - Fahad A Al-Abbasi
- Department of Biochemistry, Faculty of Sciences, King Abdulaziz University, Jeddah 21589, Saudi Arabia.
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11
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Neumann J. [Colon polyps-nomenclature, histology, and molecular pathology]. PATHOLOGIE (HEIDELBERG, GERMANY) 2025; 46:171-178. [PMID: 40237801 DOI: 10.1007/s00292-025-01438-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Accepted: 02/21/2024] [Indexed: 04/18/2025]
Abstract
Polyps are macroscopically visible protrusions of the mucosa in hollow organs. In the colon, epithelial neoplasms deriving from the mucosa dominate. These can be classified based on their morphology into classic and serrated adenomas and show different degrees of epithelial dysplasia. The histological subtypes show various molecular alterations and can be assigned to different pathways of carcinogenesis. These must be separated from hamartomatous polyps of the colon mucosa, which can occur sporadically or as part of hereditary syndromes.
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Affiliation(s)
- Jens Neumann
- Pathologisches Institut, Medizinische Fakultät, Ludwig-Maximilians-Universität München, Thalkirchner Straße 36, 80337, München, Deutschland.
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12
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Meng B, Ma Y, Wang Y, Zhou M, He C. Dual-Time-Point 18F-FDG PET/CT imaging in the diagnosis of colorectal carcinoma or advanced adenoma in patients with fixed focal colorectal 18F-FDG uptake. BMC Cancer 2025; 25:755. [PMID: 40264039 PMCID: PMC12012953 DOI: 10.1186/s12885-025-14129-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2024] [Accepted: 04/09/2025] [Indexed: 04/24/2025] Open
Abstract
BACKGROUND Fixed focal fluorine 18 fluorodeoxyglucose (18F-FDG) uptake in colorectal areas is commonly seen in PET/CT scan and may indicates malignant tumor. This study aims to investigate the diagnostic efficacy of dual-time-point 18F-FDG PET/CT in detecting colorectal carcinoma or advanced adenoma in patients with fixed focal colorectal 18F-FDG uptake. METHODS A retrospective analysis was conducted on patients who underwent dual-time-point 18F-FDG PET/CT scans between January 2019 and December 2023. Patients showing fixed focal colorectal 18F-FDG uptake in both early and delayed scans, and subsequently undergoing colonoscopy within one month, were included in the study. Advanced adenoma was defined as an adenoma larger than 10 mm in diameter and/or with villous histology and/or presenting with high-grade dysplasia. The maximum standardized uptake value (SUV) in the early and delayed scans, as well as the retention index (RI), were compared between colorectal carcinoma/advanced adenomas and non-advanced lesions. Predictive factors for colorectal carcinoma/advanced adenoma were identified by uni- and multivariable analysis. RESULTS A total of 122 patients were enrolled in this study. A total of 141 lesions was studied, 80 (56.7%) of which were diagnosed as colorectal carcinoma or advanced adenoma. When compared with non-advanced lesions, colorectal carcinoma/advanced adenoma had higher SUVmax in delayed scan (25.1 ± 14.2 vs. 14.5 ± 7.5, P<0.001), and higher RI (32.9%±25.4% vs. 7.8%±28.4%, P<0.001) in dual-time-point PET/CT. SUVmax in delayed scan (odds ratio [OR],1.084; 95% confidence interval [CI]: 1.037, 1.134; P<0.001) and RI (OR, 20.120; 95% CI: 4.068, 99.516; P<0.001) were identified as independent predictors for colorectal carcinoma/advanced adenoma by multivariable logistic regression analysis. When combining the SUVmax in the delayed scan with the retention index, the area under the receiver operating characteristic (ROC) curve achieved 0.801, and the sensitivity and specificity for predicting colorectal carcinoma/advanced adenoma were found to be 65.0% and 80.3%, respectively. Based on the threshold values of SUVmax in the delayed scan and RI, we observed prediction rates of 13.9% (5 out of 36), 58.6% (34 out of 58), and 87.2% (41 out of 47) for colorectal carcinoma/advanced adenoma in the low-, moderate-, and high-risk subgroups, respectively. CONCLUSIONS Dual-time-point PET/CT aids in distinguishing between colorectal cancer/advanced adenoma and non-advanced lesions in fixed focal FDG uptake. Higher SUVmax in delayed scan and higher RI are predictive factors for colorectal carcinoma/advanced adenoma.
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Affiliation(s)
- Baosheng Meng
- Department of Nuclear Medicine, The Third Affiliated Hospital of Soochow University, Changzhou, 213003, Jiangsu, China
- Changzhou Key Laboratory of Molecular Imaging, Changzhou, 213003, Jiangsu, China
| | - Yuanyuan Ma
- Department of Nuclear Medicine, The Third Affiliated Hospital of Soochow University, Changzhou, 213003, Jiangsu, China
- Changzhou Key Laboratory of Molecular Imaging, Changzhou, 213003, Jiangsu, China
| | - Yuetao Wang
- Department of Nuclear Medicine, The Third Affiliated Hospital of Soochow University, Changzhou, 213003, Jiangsu, China
- Changzhou Key Laboratory of Molecular Imaging, Changzhou, 213003, Jiangsu, China
| | - Mingge Zhou
- Department of Nuclear Medicine, The Third Affiliated Hospital of Soochow University, Changzhou, 213003, Jiangsu, China.
- Changzhou Key Laboratory of Molecular Imaging, Changzhou, 213003, Jiangsu, China.
| | - Chen He
- Department of Nuclear Medicine, The Third Affiliated Hospital of Soochow University, Changzhou, 213003, Jiangsu, China.
- Changzhou Key Laboratory of Molecular Imaging, Changzhou, 213003, Jiangsu, China.
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13
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Linhares SM, Schultz KS, Mongiu AK. Computer aided polyp detection has limited clinical efficacy. BMJ 2025; 389:r732. [PMID: 40246307 DOI: 10.1136/bmj.r732] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 04/19/2025]
Affiliation(s)
- Samantha M Linhares
- Division of Colon & Rectal Surgery, Department of Surgery, Yale School of Medicine, New Haven, CT 06519, USA
| | - Kurt S Schultz
- Division of Colon & Rectal Surgery, Department of Surgery, Yale School of Medicine, New Haven, CT 06519, USA
| | - Anne K Mongiu
- Division of Colon & Rectal Surgery, Department of Surgery, Yale School of Medicine, New Haven, CT 06519, USA
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14
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Han B, Zhang Y, Feng X, Yang J, Wang B, Fang J, Wang Z, Zhu J, Niu G, Guo Y. The power of microbes: the key role of gut microbiota in the initiation and progression of colorectal cancer. Front Oncol 2025; 15:1563886. [PMID: 40297806 PMCID: PMC12034544 DOI: 10.3389/fonc.2025.1563886] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2025] [Accepted: 03/24/2025] [Indexed: 04/30/2025] Open
Abstract
Colorectal cancer (CRC) is ranked as the third most prevalent malignancy and is a leading cause of cancer-related mortality globally, significantly affecting the health and longevity of middle-aged individuals and the elderly. The primary risk factors for CRC are mainly due to unhealthy dietary habits and lifestyle choices, and they have been shown to profoundly influence the composition of the gut microbiota. Given that dietary patterns are critical determinants of gut microbial diversity, a compelling association exists between gut microbiota and the pathogenesis of CRC. Recent research has increasingly focused on the intricate interplay between gut microbiota and CRC, exploring its role in disease initiation, progression, and the modulation of host immune responses. Investigations have demonstrated that certain specific microbial communities can promote inflammation, disrupt metabolic pathways, and produce carcinogenic compounds, thereby contributing to the development of CRC. Conversely, a diverse and balanced gut microbiome may confer protective effects against cancer through mechanisms such as the production of short-chain fatty acids and the enhancement of intestinal barrier integrity. This article provides a comprehensive overview of the characteristics of the gut microbial community and its complex relationship with CRC. It highlights potential mechanisms through which gut microbiota may influence CRC pathogenesis, including chronic inflammation, toxins, metabolites, epigenetic dysregulation, and immune regulatory dysfunction. Additionally, this review summarizes innovative strategies for CRC prevention and treatment, emphasizing the therapeutic potential of probiotics and natural plant extracts. By elucidating these connections, this work aims to enhance the understanding of the gut microbiome's role in CRC.
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Affiliation(s)
- Bo Han
- Department of General Surgery, 63650 Military Hospital, Urumqi, China
| | - Yongfeng Zhang
- Department of General Surgery, 63650 Military Hospital, Urumqi, China
| | - Xue Feng
- Department of Cardiology, 63650 Military Hospital, Urumqi, China
| | - Jun Yang
- Department of General Surgery, 63650 Military Hospital, Urumqi, China
| | - Baolin Wang
- Department of General Surgery, 63650 Military Hospital, Urumqi, China
| | - Jiang Fang
- Department of General Surgery, 63650 Military Hospital, Urumqi, China
| | - Zhigang Wang
- Department of General Surgery, 63650 Military Hospital, Urumqi, China
| | - Jun Zhu
- Department of General Surgery, 63650 Military Hospital, Urumqi, China
| | - Ge Niu
- Department of General Surgery, 63650 Military Hospital, Urumqi, China
| | - Youxiang Guo
- Department of General Surgery, 63650 Military Hospital, Urumqi, China
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15
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Li H, Shan C, Zhu Y, Yao X, Lin L, Zhang X, Qian Y, Wang Y, Xu J, Zhang Y, Li H, Zhao L, Chen K. Helminth-induced immune modulation in colorectal cancer: exploring therapeutic applications. Front Immunol 2025; 16:1484686. [PMID: 40297577 PMCID: PMC12034720 DOI: 10.3389/fimmu.2025.1484686] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2024] [Accepted: 03/24/2025] [Indexed: 04/30/2025] Open
Abstract
Colorectal cancer is one of the most lethal tumors, posing a financial and healthcare burden. This study investigates how helminths and pre-existing diseases such as colitis, obesity, diabetes, and gut microbiota issues influence colon cancer development and prognosis. The immune system's protective immunosuppressive response to helminth invasion minimizes inflammation-induced cell damage and DNA mutations, lowering the risk of colorectal cancer precursor lesions. Helminth infection-mediated immunosuppression can hasten colorectal cancer growth and metastasis, which is detrimental to patient outcomes. Some helminth derivatives can activate immune cells to attack cancer cells, making them potentially useful as colorectal cancer vaccines or therapies. This review also covers gene editing approaches. We discovered that using CRISPR/Cas9 to inhibit live helminths modulates miRNA, which limits tumor growth. We propose more multicenter studies into helminth therapy's long-term effects and immune regulation pathways. We hope to treat colorectal cancer patients with helminth therapy and conventional cancer treatments in an integrative setting.
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Affiliation(s)
- Hongyu Li
- Key Laboratory of Artificial Organs and Computational Medicine of Zhejiang Province, Shulan International Medical College, Zhejiang Shuren University, Hangzhou, China
- Ocean College, Beibu Gulf University, Qinzhou, China
| | - Chaojun Shan
- Key Laboratory of Artificial Organs and Computational Medicine of Zhejiang Province, Shulan International Medical College, Zhejiang Shuren University, Hangzhou, China
| | - Yunhuan Zhu
- Key Laboratory of Artificial Organs and Computational Medicine of Zhejiang Province, Shulan International Medical College, Zhejiang Shuren University, Hangzhou, China
| | - Xiaodong Yao
- School of Marxism, Hangzhou Medical College, Hangzhou, Zhejiang, China
| | - Lijun Lin
- School of Basic Medicine and Forensic Medicine, Hangzhou Medical College, Hangzhou, China
| | - Xiaofen Zhang
- Key Laboratory of Artificial Organs and Computational Medicine of Zhejiang Province, Shulan International Medical College, Zhejiang Shuren University, Hangzhou, China
| | - Yuncheng Qian
- Key Laboratory of Artificial Organs and Computational Medicine of Zhejiang Province, Shulan International Medical College, Zhejiang Shuren University, Hangzhou, China
| | - Yuqing Wang
- Key Laboratory of Artificial Organs and Computational Medicine of Zhejiang Province, Shulan International Medical College, Zhejiang Shuren University, Hangzhou, China
| | - Jialu Xu
- Key Laboratory of Artificial Organs and Computational Medicine of Zhejiang Province, Shulan International Medical College, Zhejiang Shuren University, Hangzhou, China
| | - Yijie Zhang
- Key Laboratory of Artificial Organs and Computational Medicine of Zhejiang Province, Shulan International Medical College, Zhejiang Shuren University, Hangzhou, China
| | - Hairun Li
- Key Laboratory of Artificial Organs and Computational Medicine of Zhejiang Province, Shulan International Medical College, Zhejiang Shuren University, Hangzhou, China
| | - Ling Zhao
- Key Laboratory of Artificial Organs and Computational Medicine of Zhejiang Province, Shulan International Medical College, Zhejiang Shuren University, Hangzhou, China
| | - Keda Chen
- Key Laboratory of Artificial Organs and Computational Medicine of Zhejiang Province, Shulan International Medical College, Zhejiang Shuren University, Hangzhou, China
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16
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Lin J, Yin Y, Cao J, Zou B, Han K, Chen Y, Li S, Huang C, Chen J, Lv Y, Xu S, Xie D, Wang F. Nudix Hydrolase 13 Impairs the Initiation of Colorectal Cancer by Inhibiting PKM1 ADP-Ribosylation. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2025; 12:e2410058. [PMID: 39921866 PMCID: PMC11967829 DOI: 10.1002/advs.202410058] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/21/2024] [Revised: 01/06/2025] [Indexed: 02/10/2025]
Abstract
Metabolic dysregulation has been implicated as a key factor in colorectal cancer (CRC) initiation, however, the underlying driving forces and mechanisms remain poorly understood. Herein, transcriptome profiling of paired early-stage CRCs and adenomas identifies Nudix hydrolase 13 (NUDT13) as a critical suppressor. Elevated NUDT13 expression impedes the proliferation of CRC cells under hypoxic conditions and markedly inhibits CRC initiation by upregulating PKM1. Mechanistically, NUDT13 directly binds and stabilizes PKM1 protein by reducing its poly ADP-ribosylation (PARylation), which is catalyzed by PARP1 at E275/D281/E282/E285/D296, thereby inducing an oxidative phosphorylation (OXPHOS) phenotype in CRC cells. Moreover, spatiotemporal knockout of Nudt13 enhances intestinal tumorigenesis in mice, which can be significantly suppressed by PARP1 inhibitor Olaparib. Notably, residues E245/E248/E249 within the Nudix box motif of NUDT13 are essential for PKM1 PARylation, and a mimic peptide derived from this motif is sufficient to stabilize PKM1 protein and robustly inhibit CRC tumorigenesis. Collectively, this study reveals a previously unknown PARylation-dependent mechanism that regulates PKM1 protein stability and switches the metabolic pathway of CRC cells, providing a promising target for CRC treatment.
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Affiliation(s)
- Jinlong Lin
- State Key Laboratory of Oncology in South ChinaGuangdong Provincial Clinical Research Center for CancerSun Yat‐sen University Cancer CenterGuangzhou510060P. R. China
- Department of Thoracic SurgerySun Yat‐sen University Cancer CenterGuangzhou510060P. R. China
| | - Yixin Yin
- State Key Laboratory of Oncology in South ChinaGuangdong Provincial Clinical Research Center for CancerSun Yat‐sen University Cancer CenterGuangzhou510060P. R. China
- Department of AnesthesiologySun Yat‐sen University Cancer CenterGuangzhou510060P. R. China
| | - Jinghua Cao
- State Key Laboratory of Oncology in South ChinaGuangdong Provincial Clinical Research Center for CancerSun Yat‐sen University Cancer CenterGuangzhou510060P. R. China
| | - Bingxu Zou
- State Key Laboratory of Oncology in South ChinaGuangdong Provincial Clinical Research Center for CancerSun Yat‐sen University Cancer CenterGuangzhou510060P. R. China
| | - Kai Han
- Department of Colorectal SurgerySun Yat‐sen University Cancer CenterGuangzhou510060P. R. China
| | - Yufan Chen
- Department of EndoscopySun Yat‐sen University Cancer CenterGuangzhou510060P. R. China
| | - Siyu Li
- State Key Laboratory of Oncology in South ChinaGuangdong Provincial Clinical Research Center for CancerSun Yat‐sen University Cancer CenterGuangzhou510060P. R. China
| | - Cijun Huang
- State Key Laboratory of Oncology in South ChinaGuangdong Provincial Clinical Research Center for CancerSun Yat‐sen University Cancer CenterGuangzhou510060P. R. China
| | - Jiewei Chen
- Department of PathologySun Yat‐sen University Cancer CenterGuangzhou510060P. R. China
| | - Yongrui Lv
- State Key Laboratory of Oncology in South ChinaGuangdong Provincial Clinical Research Center for CancerSun Yat‐sen University Cancer CenterGuangzhou510060P. R. China
| | - Shuidan Xu
- State Key Laboratory of Oncology in South ChinaGuangdong Provincial Clinical Research Center for CancerSun Yat‐sen University Cancer CenterGuangzhou510060P. R. China
| | - Dan Xie
- State Key Laboratory of Oncology in South ChinaGuangdong Provincial Clinical Research Center for CancerSun Yat‐sen University Cancer CenterGuangzhou510060P. R. China
- Department of PathologySun Yat‐sen University Cancer CenterGuangzhou510060P. R. China
| | - Fengwei Wang
- State Key Laboratory of Oncology in South ChinaGuangdong Provincial Clinical Research Center for CancerSun Yat‐sen University Cancer CenterGuangzhou510060P. R. China
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17
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Sultan S, Shung DL, Kolb JM, Foroutan F, Hassan C, Kahi CJ, Liang PS, Levin TR, Siddique SM, Lebwohl B. AGA Living Clinical Practice Guideline on Computer-Aided Detection-Assisted Colonoscopy. Gastroenterology 2025; 168:691-700. [PMID: 40121061 DOI: 10.1053/j.gastro.2025.01.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 03/25/2025]
Abstract
BACKGROUND & AIMS This American Gastroenterological Association (AGA) guideline is intended to provide an overview of the evidence and support endoscopists and patients on the use of computer-aided detection (CADe) systems for the detection of colorectal polyps during colonoscopy. METHODS A multidisciplinary panel of content experts and guideline methodologists used the Grading of Recommendations Assessment, Development and Evaluation framework and relied on the following sources of evidence: (1) a systematic review examining the desirable and undesirable effects (ie, benefits and harms) of CADe-assisted colonoscopy, (2) a microsimulation study estimating the effects of CADe on longer-term patient-important outcomes, (3) a systematic search of evidence evaluating the values and preferences of patients undergoing colonoscopy, and (4) a systematic review of studies evaluating health care providers' trust in artificial intelligence technology in gastroenterology. RESULTS The panel reached the conclusion that no recommendation could be made for or against the use of CADe-assisted colonoscopy in light of very low certainty of evidence for the critical outcomes, desirable and undesirable (11 fewer colorectal cancers per 10,000 individuals and 2 fewer colorectal cancer deaths per 10,000 individuals), increased burden of more intensive surveillance colonoscopies (635 more per 10,000 individuals), and cost and resource implications. The panel acknowledged the 8% (95% CI, 6%-10%) increase in adenoma detection rate and 2% (95% CI, 0%-4%) increase in advanced adenoma and/or sessile serrated lesion detection rate. CONCLUSIONS This guideline highlights the close tradeoff between desirable and undesirable effects and the limitations in the current evidence to support a recommendation. The panel acknowledged the potential for CADe to continually improve as an iterative artificial intelligence application. Ongoing publications providing evidence for critical outcomes will help inform a future recommendation.
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Affiliation(s)
- Shahnaz Sultan
- Division of Gastroenterology, Hepatology, and Nutrition, University of Minnesota, Minneapolis, Minnesota; Minneapolis Veterans Affairs Healthcare System, Minneapolis, Minnesota
| | - Dennis L Shung
- Department of Medicine, Section of Digestive Diseases, Yale School of Medicine, New Haven, Connecticut
| | - Jennifer M Kolb
- Vatche and Tamar Manoukian Division of Digestive Diseases, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, California; Division of Gastroenterology, Hepatology and Parenteral Nutrition, Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, California
| | - Farid Foroutan
- MAGIC Evidence Ecosystem Foundation, Oslo, Norway; Ted Rogers Centre for Heart Research, University Health Network, Toronto, Ontario, Canada
| | - Cesare Hassan
- IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy; Department of Biomedical Sciences, Humanitas University, Milan, Italy
| | - Charles J Kahi
- Department of Gastroenterology, Indiana University Medical Center, Indianapolis, Indiana
| | - Peter S Liang
- Department of Medicine, Division of Gastroenterology and Hepatology, NYU Langone Health, New York, New York; Department of Medicine, Veterans Affairs New York Harbor Health Care System, New York, New York
| | - Theodore R Levin
- Division of Research, Kaiser Permanente Northern California, Pleasanton, California; Department of Gastroenterology, Kaiser Permanente Walnut Creek, Walnut Creek, California
| | - Shazia Mehmood Siddique
- Division of Gastroenterology, University of Pennsylvania, Philadelphia, Pennsylvania; Leonard Davis Institute of Health Economics, University of Pennsylvania, Philadelphia, Pennsylvania; Center for Healthcare Improvement and Patient Safety, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Benjamin Lebwohl
- Department of Medicine, Columbia University Irving Medical Center, New York, New York; Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, New York
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Tsai KY, Wei PL, Lee CC, Zumbi CN, Prince GMSH, Batzorig U, Huang CY, Chang YJ. Solute Carrier Family 35 A2 (SLC35A2) Promotes Tumor Progression through MYC-Mediated Pathways in Colorectal Cancer. Int J Med Sci 2025; 22:1992-2009. [PMID: 40303483 PMCID: PMC12035830 DOI: 10.7150/ijms.109767] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/02/2025] [Accepted: 03/13/2025] [Indexed: 05/02/2025] Open
Abstract
Colorectal cancer (CRC) is one of the most prevalent cancers, posing a significant threat to human life. Although therapeutic approaches for advanced-stage patients have improved in recent years, there is still room for enhancing treatment response. Recent evidence suggests that dysregulation of nucleotide sugar transporters (NSTs) is associated with the development and progression of tumors. Therefore, this study aims to explore the potential therapeutic and prognostic implications of the solute carrier family 35 A (SLC35A) members in CRC. To achieve this, we performed integrative bioinformatics analysis using various publicly available databases, including GENT2, TCGA, UALCAN, cBioPortal, Kaplan-Meier plotter, The ROC plotter, GDSC, TISIDB, and TIMER. We compared gene expression profiles between CRC tumors and adjacent normal tissues, revealing that only SLC35A2 exhibited significant upregulation in tumors, while the other family members were downregulated. Additionally, higher SLC35A2 expression was found in microsatellite stable (MSS) colorectal tumors. Further analysis of TCGA and GEO datasets showed that patients with high SLC35A2 expression experienced poorer relapse-free survival. Next, we conducted gene set enrichment analysis (GSEA), and the results indicated that the upregulation of SLC35A2 is linked to cellular metabolism pathways, such as MYC Targets V2, Steroid Biosynthesis, Pentose Phosphate Pathway, and TCA Cycle. Furthermore, our CRC cell models revealed the tumor-promoting role of SLC35A2 and discovered that the upregulation of SLC35A2 is associated with chemoresistance against irinotecan. Additionally, we observed a negative correlation between SLC35A2 expression and the infiltration of immune cells, particularly cytotoxic CD8+ T cells and B cells. This suggests the immunomodulatory role of SLC35A2. In summary, SLC35A2 is abnormally upregulated in CRC, and patients with high SLC35A2 expression tend to have poor relapse-free survival. This may be due to its involvement in regulating cancer cell metabolic reprogramming, promoting tumor progression, modulating the immune landscape, and influencing treatment response. Consequently, SLC35A2 could serve as a significant prognostic factor and a potential therapeutic target in CRC.
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Affiliation(s)
- Kuei-Yen Tsai
- Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan
- Department of Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan
- Division of General Surgery, Department of Surgery, Shuang Ho Hospital, Taipei Medical University, New Taipei City 235041, Taiwan
| | - Po-Li Wei
- Department of Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan
- Division of Colorectal Surgery, Department of Surgery, Taipei Medical University Hospital, Taipei Medical University, Taipei 11031, Taiwan
- Cancer Research Center and Translational Laboratory, Department of Medical Research, Taipei Medical University Hospital, Taipei Medical University, Taipei 11031, Taiwan
- Graduate Institute of Cancer Biology and Drug Discovery, Taipei Medical University, Taipei 11031, Taiwan
| | - Cheng-Chin Lee
- Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan
| | - Crystal Ngofi Zumbi
- Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan
| | | | - Uyanga Batzorig
- Department of Dermatology, University of California, San Diego, La Jolla, CA 92093, USA
| | - Chien-Yu Huang
- School of Medicine, National Tsing Hua University, Hsinchu 300044, Taiwan
- Institute of Molecular and Cellular Biology, National Tsing Hua University 300044, Hsinchu, Taiwan
- Department of Pathology, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan
| | - Yu-Jia Chang
- Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan
- Cancer Research Center and Translational Laboratory, Department of Medical Research, Taipei Medical University Hospital, Taipei Medical University, Taipei 11031, Taiwan
- Department of Pathology, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan
- Cell Physiology and Molecular Image Research Center, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan
- Graduate Institue of Medical Sciences, National Defense Medical Center, Taipei 114201, Taiwan
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19
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Meyer CE, Vukelic N, Mariadason JM, Kipp AP. Connecting concentrations of copper, selenium, and zinc with transcriptomic and proteomic data of well-characterized human colorectal cancer cell lines. J Trace Elem Med Biol 2025; 89:127638. [PMID: 40179449 DOI: 10.1016/j.jtemb.2025.127638] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/12/2024] [Revised: 02/18/2025] [Accepted: 03/26/2025] [Indexed: 04/05/2025]
Abstract
BACKGROUND Colorectal cancer (CRC) incidence is associated with lower circulating selenium and zinc and elevated copper concentrations. Moreover, copper and selenium accumulate within tumor tissue, indicating a disturbed homeostasis of these essential trace elements in CRC. OBJECTIVE This study aimed to identify associations between CRC characteristics (based on genomic, transcriptomic and proteomic data) and trace element concentrations. METHODS The concentrations of copper, selenium, and zinc were measured in 83 human CRC cell lines and correlated with transcript and protein expression levels to identify trace element-related gene signatures. By using publicly available gene expression data from The Cancer Genome Atlas we investigated the association between those signatures with the survival probability of CRC patients. RESULTS The CRC cell lines differed in their copper (fold change 7.3), selenium (fold change 6), and zinc (fold change 2.6) concentrations. The concentrations were not associated with genetic or cellular characteristics, except for lower copper concentrations in KRAS mutant cells. Expression levels of known copper- and zinc-related proteins correlated significantly with the respective trace element concentrations, serving as a proxy for trace element concentrations in tumors, and with patient survival. This was not the case for selenium and selenoproteins. In addition, an unbiased approach identified novel high and low copper- and zinc-related gene expression signatures significantly associated with patient's outcome. CONCLUSION Herein we identify gene signatures associated with intracellular copper and zinc concentrations in CRC cell lines. Extrapolating these signatures to primary colorectal tumors revealed that they can inform outcome of CRC patients.
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Affiliation(s)
- Caroline E Meyer
- Department of Nutritional Physiology, Friedrich Schiller University Jena, Jena, Germany
| | - Natalia Vukelic
- Olivia Newton-John Cancer Research Institute, Melbourne, Australia
| | | | - Anna P Kipp
- Department of Nutritional Physiology, Friedrich Schiller University Jena, Jena, Germany.
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20
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Mirea CS, Schenker M, Petre-Mandache B, Cucu MG, Camen GC, Vîlcea ID, Albu BC, Obleagă CV, Ciorbagiu MC, Streață I, Pleșea RM, Riza AL, Burada F. GAS5 rs145204276 Ins/Del Polymorphism Is Associated with CRC Susceptibility in a Romanian Population. Int J Mol Sci 2025; 26:3078. [PMID: 40243746 PMCID: PMC11988689 DOI: 10.3390/ijms26073078] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2025] [Revised: 03/18/2025] [Accepted: 03/24/2025] [Indexed: 04/18/2025] Open
Abstract
Colorectal cancer (CRC) is a leading cause of cancer-related morbidity and mortality, influenced by both genetic and epigenetic factors. Long non-coding RNAs (lncRNAs) such as GAS5 and CASC8 have been implicated in cancer susceptibility. This study aimed to assess the association of GAS5 rs145204276 ins/del and CASC8 rs10505477 A>G polymorphisms with CRC risk in a Romanian population. A case-control study was conducted, including 156 CRC patients and 195 healthy controls. Genotyping for GAS5 and CASC8 polymorphisms was performed using real-time PCR, and the association with CRC risk was evaluated using logistic regression to calculate odds ratios (OR) and 95% confidence intervals (CI). The carriers of GAS5 rs145204276 del allele was significantly associated with increased CRC risk (OR: 2.13, 95% CI: 1.24-3.63, p = 0.005) in a dominant model. In the subgroup analysis, the association of GAS5 rs145204276 ins/del polymorphism was restricted to distal colon cancer cases (OR: 2.98, 95% CI: 1.57-5.66, p = 0.001), advanced tumor stages (III + IV) (OR: 2.54, 95% CI: 1.31-4.91, p = 0.007), and poorly differentiated tumors (G3) (OR: 3.98, 95% CI: 1.49-10.59, p = 0.009). No significant correlation was found for the CASC8 rs10505477 A>G polymorphism. GAS5 rs145204276 polymorphism may influence CRC susceptibility, particularly in distal tumors and advanced stages. However, CASC8 rs10505477 polymorphism showed no association with CRC risk in this Romanian cohort.
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Affiliation(s)
- Cecil Sorin Mirea
- Department of Surgery, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania; (C.S.M.); (I.D.V.); (C.V.O.); (M.C.C.)
- Department of Surgery, Emergency Clinical County Hospital, 200642 Craiova, Romania;
| | - Michael Schenker
- Department of Oncology, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania;
| | - Bianca Petre-Mandache
- Doctoral School, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
| | - Mihai-Gabriel Cucu
- Laboratory of Human Genomics, University of Medicine and Pharmacy of Craiova, 200638 Craiova, Romania; (I.S.); (R.M.P.); (A.-L.R.); (F.B.)
- Regional Centre of Medical Genetics Dolj, Emergency Clinical County Hospital Craiova, 200642 Craiova, Romania
| | - Georgiana-Cristiana Camen
- Department of Radiology and Medical Imaging, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania;
| | - Ionică Daniel Vîlcea
- Department of Surgery, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania; (C.S.M.); (I.D.V.); (C.V.O.); (M.C.C.)
- Department of Surgery, Emergency Clinical County Hospital, 200642 Craiova, Romania;
| | - Bogdan Cristian Albu
- Department of Surgery, Emergency Clinical County Hospital, 200642 Craiova, Romania;
- Doctoral School, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
| | - Cosmin Vasile Obleagă
- Department of Surgery, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania; (C.S.M.); (I.D.V.); (C.V.O.); (M.C.C.)
- Department of Surgery, Emergency Clinical County Hospital, 200642 Craiova, Romania;
| | - Mihai Călin Ciorbagiu
- Department of Surgery, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania; (C.S.M.); (I.D.V.); (C.V.O.); (M.C.C.)
- Department of Surgery, Emergency Clinical County Hospital, 200642 Craiova, Romania;
| | - Ioana Streață
- Laboratory of Human Genomics, University of Medicine and Pharmacy of Craiova, 200638 Craiova, Romania; (I.S.); (R.M.P.); (A.-L.R.); (F.B.)
- Regional Centre of Medical Genetics Dolj, Emergency Clinical County Hospital Craiova, 200642 Craiova, Romania
| | - Răzvan Mihail Pleșea
- Laboratory of Human Genomics, University of Medicine and Pharmacy of Craiova, 200638 Craiova, Romania; (I.S.); (R.M.P.); (A.-L.R.); (F.B.)
- Regional Centre of Medical Genetics Dolj, Emergency Clinical County Hospital Craiova, 200642 Craiova, Romania
| | - Anca-Lelia Riza
- Laboratory of Human Genomics, University of Medicine and Pharmacy of Craiova, 200638 Craiova, Romania; (I.S.); (R.M.P.); (A.-L.R.); (F.B.)
- Regional Centre of Medical Genetics Dolj, Emergency Clinical County Hospital Craiova, 200642 Craiova, Romania
| | - Florin Burada
- Laboratory of Human Genomics, University of Medicine and Pharmacy of Craiova, 200638 Craiova, Romania; (I.S.); (R.M.P.); (A.-L.R.); (F.B.)
- Regional Centre of Medical Genetics Dolj, Emergency Clinical County Hospital Craiova, 200642 Craiova, Romania
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21
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Neira M, Mena C, Torres K, Simón L. The Potential Benefits of Curcumin-Enriched Diets for Adults with Colorectal Cancer: A Systematic Review. Antioxidants (Basel) 2025; 14:388. [PMID: 40298630 PMCID: PMC12024020 DOI: 10.3390/antiox14040388] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2025] [Revised: 03/20/2025] [Accepted: 03/22/2025] [Indexed: 04/30/2025] Open
Abstract
Colorectal cancer (CRC) is the second leading cause of cancer-related deaths worldwide. Conventional treatments such as chemotherapy and radiotherapy are often associated with severe side effects and limited effectiveness. Curcumin, a polyphenol derived from Curcuma longa, has demonstrated anti-inflammatory and anticancer properties. A systematic review of the recent scientific literature followed PRISMA guidelines to evaluate the benefits of a curcumin-enriched diet for adults with colorectal cancer. Articles published between 2018 and 2024 were retrieved from PubMed, SciELO, Google Scholar, and Scopus. Studies meeting the inclusion criteria focused on curcumin, adults, and colorectal cancer outcomes. The administration of curcumin-containing products was associated with improved survival rates, enhanced quality of life, tumor reduction, and anti-inflammatory effects. A curcumin-enriched diet shows potential as an effective adjunct therapy for CRC patients, though its limited bioavailability and potential side effects, such as gastrointestinal discomfort, pose challenges. Addressing these limitations through larger cohorts, extended study durations, and improved formulations to enhance bioavailability is essential. Such efforts could enable the development of personalized dietary recommendations for CRC management.
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Affiliation(s)
| | | | - Keila Torres
- Escuela de Nutrición y Dietética, Universidad Finis Terrae, Santiago 7501015, Chile; (M.N.); (C.M.)
| | - Layla Simón
- Escuela de Nutrición y Dietética, Universidad Finis Terrae, Santiago 7501015, Chile; (M.N.); (C.M.)
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22
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Silinskaite U, Valciukiene J, Jakubauskas M, Poskus T. The Immune Environment in Colorectal Adenoma: A Systematic Review. Biomedicines 2025; 13:699. [PMID: 40149674 PMCID: PMC11940254 DOI: 10.3390/biomedicines13030699] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2025] [Accepted: 02/28/2025] [Indexed: 03/29/2025] Open
Abstract
Background/Objectives: Research on colorectal adenoma is significantly less comprehensive compared to studies on colorectal carcinoma. Although colorectal adenoma is a precursor of the majority of sporadic colorectal cancers, not all adenomas develop into carcinomas. The complex interaction of immune responses in the premalignant tumor microenvironment might be a factor for that. Methods: In this systematic review, we aim to provide a thorough analysis of the current research examining the immune infiltration patterns in sporadic colorectal adenoma tissues in the context of immune cell-based, cytokine-based, and other immunological factor-related changes along the conventional adenoma-carcinoma sequence. The articles included in the review extend up to December 2024 in PubMed and Web of Science databases. Results: Most included studies have shown significant differences in immune cell counts, densities, and cytokine expression levels associated with premalignant colorectal lesions (and/or colorectal cancer). No consensus on the immune-related tendencies concerning CD4+T cells and CD8+T cells was reached. Decreasing expression of mDCs and plasma and naïve B cells were detected along the ACS. The increased density of tissue eosinophils in the adenoma tissue dramatically diminishes after the transition to carcinoma. As the adenoma progresses, the increasing expression of IL-1α, IL-4, IL-6, IL-8, IL-10, IL-17A, IL-21, IL-23, IL-33, and TGF-β and decreasing levels of IL-12A, IL-18, IFN-γ, and TNFα cytokines in the invasive carcinoma stage is being detected. The over-expression of COX-2, PD-1/PD-L1, CTLA-4, and ICOS/ICOSLG in the colorectal adenomatous and cancerous tissues was also observed. Conclusions: Further studies are needed for a better understanding of the whole picture of colorectal adenoma-associated immunity and its impact on precancerous lesion's potential to progress.
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23
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Ladeira Bernardes A, Albuquerque Pereira MDF, Xisto Campos I, Ávila L, Dos Santos Cruz BC, Duarte Villas Mishima M, Maciel Dos Santos Dias M, de Oliveira Mendes TA, Gouveia Peluzio MDC. Oral intake of Hibiscus sabdariffa L. increased c-Myc and caspase-3 gene expression and altered microbial population in colon of BALB/c mice induced to preneoplastic lesions. Eur J Nutr 2025; 64:109. [PMID: 40042671 DOI: 10.1007/s00394-025-03622-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2024] [Accepted: 02/17/2025] [Indexed: 04/17/2025]
Abstract
BACKGROUND Colorectal carcinogenesis induces changes in the colon, such as the appearance of aberrant crypt foci (ACF). This process is influenced by genetic and environmental factors, such as diet. Hibiscus sabdariffa L. is a considerable source of phenolic compounds, such as anthocyanins, and dietary fibers that may exert anti-inflammatory, antioxidant and prebiotic properties, attenuating the appearance of ACFs. OBJECTIVES To investigate whether supplementation with 5% or 10% of dehydrated calyces of Hibiscus sabadariffa (DHSC) influences the composition of the intestinal microbiota and the expression of genes related to colorectal carcinogenesis in BALB/c mice. METHODS The in vivo experiment lasted 12 weeks and the animals were divided into 3 experimental groups: the control group and the supplemented groups (5% or 10% DCHS) and induced pre-neoplastic lesions with the drug Dimethylhydrazine. Serum aspartate aminotransferase and alanine aminotransferase markers, liver cytokine profile, gut microbiota composition and tumor protein 53, cellular myelocytomatosis oncogene, caspase-3 and Proliferating Cell Nuclear Antigen gene expression were determined. RESULTS Supplementation with 5% or 10% of DCHS altered the composition of the intestinal microbiota, increasing the abundance of the families Lachnospiraceae, Ruminococcaceae, Clostridiaceae and of the genus Clostridum, important producers of butyrate. Furthermore, 5% and 10% DCHS supplementation increased caspase-3 and c-Myc expression, respectively, which may suggest apoptotic events. CONCLUSIONS Therefore, the effects of DHSC, rich in anthocyanins and dietary fiber, on the composition of the intestinal microbiota and on the expression of genes associated with cell apoptosis may contribute to reducing the risk of developing preneoplastic lesions.
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Affiliation(s)
- Andressa Ladeira Bernardes
- Department of Nutrition and Health, Universidade Federal de Viçosa, Campus Universitário da, Viçosa, Minas Gerais, CEP:36570-900, Brazil.
| | | | - Iasmim Xisto Campos
- Department of Nutrition and Health, Universidade Federal de Viçosa, Campus Universitário da, Viçosa, Minas Gerais, CEP:36570-900, Brazil
| | - Larissa Ávila
- Department of Biochemistry and Molecular Biology, Universidade Federal de Viçosa, Viçosa, Minas Gerais, 36570-900, Brazil
| | - Bruna Cristina Dos Santos Cruz
- Department of Nutrition and Health, Universidade Federal de Viçosa, Campus Universitário da, Viçosa, Minas Gerais, CEP:36570-900, Brazil
| | - Marcella Duarte Villas Mishima
- Department of Nutrition and Health, Universidade Federal de Viçosa, Campus Universitário da, Viçosa, Minas Gerais, CEP:36570-900, Brazil
| | - Manoela Maciel Dos Santos Dias
- Department of Nutrition and Health, Universidade Federal de Viçosa, Campus Universitário da, Viçosa, Minas Gerais, CEP:36570-900, Brazil
| | | | - Maria do Carmo Gouveia Peluzio
- Department of Nutrition and Health, Universidade Federal de Viçosa, Campus Universitário da, Viçosa, Minas Gerais, CEP:36570-900, Brazil
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24
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Zengin Kurt B, Özmen Ö, Öztürk Civelek D, Şenol H, Sonmez F. Exploring anticancer properties of new triazole-linked benzenesulfonamide derivatives against colorectal carcinoma: Synthesis, cytotoxicity, and in silico insights. Bioorg Med Chem 2025; 119:118060. [PMID: 39793404 DOI: 10.1016/j.bmc.2025.118060] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2024] [Revised: 12/10/2024] [Accepted: 01/01/2025] [Indexed: 01/13/2025]
Abstract
This study reports the design, synthesis, and characterization of a novel series of benzene sulfonamide-triazole hybrid derivatives, to evaluate their anticancer potential against colorectal cancer. The synthesized compounds were characterized using NMR and HRMS spectroscopic techniques. In vitro cytotoxicity assessments revealed that compounds 5g and 5j exhibited significant anticancer effects. 5g showed the highest potency in the DLD-1 cell line (IC50 = 11.84 µM), while 5j demonstrated robust activity in the HT-29 cell line (IC50 = 9.35 µM). Apoptotic analysis indicated that compound 5g effectively induced early and total apoptosis, surpassing the chemotherapeutic agent 5-fluorouracil (5-FU), highlighting its therapeutic potential. Molecular docking studies showed strong binding interactions with key proteins involved in colorectal cancer progression, such as TGFβ2 and VEGFR1. 5j displayed a high binding affinity for TGFβ2 (MM-GBSA ΔG = -92.52 kcal/mol) and 5g showed promising interactions with VEGFR1 (ΔG = -70.63 kcal/mol). Molecular dynamics simulations confirmed the stability of the ligand-protein complexes, indicating potential as targeted therapeutic agents. Compounds 5g and 5j demonstrate significant promise for further development in colorectal cancer treatment.
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Affiliation(s)
- Belma Zengin Kurt
- Bezmialem Vakif University, Faculty of Pharmacy, Department of Pharmaceutical Chemistry, 34093 Istanbul, Turkiye.
| | - Özge Özmen
- Bezmialem Vakif University, Faculty of Pharmacy, 34093 Istanbul, Turkiye; Kartal Dr. Lutfi Kirdar City Hospital, 34865 Istanbul, Turkiye
| | - Dilek Öztürk Civelek
- Bezmialem Vakif University, Faculty of Pharmacy, Department of Pharmacology, 34093 Istanbul, Turkiye
| | - Halil Şenol
- Bezmialem Vakif University, Faculty of Pharmacy, Department of Pharmaceutical Chemistry, 34093 Istanbul, Turkiye
| | - Fatih Sonmez
- Sakarya University of Applied Sciences, Pamukova Vocational School, 54055 Sakarya, Turkiye
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25
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Li J, Pan J, Wang L, Ji G, Dang Y. Colorectal Cancer: Pathogenesis and Targeted Therapy. MedComm (Beijing) 2025; 6:e70127. [PMID: 40060193 PMCID: PMC11885891 DOI: 10.1002/mco2.70127] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2024] [Revised: 02/12/2025] [Accepted: 02/13/2025] [Indexed: 04/29/2025] Open
Abstract
Colorectal cancer (CRC) ranks among the most prevalent malignant neoplasms globally. A growing body of evidence underscores the pivotal roles of genetic alterations and dysregulated epigenetic modifications in the pathogenesis of CRC. In recent years, the reprogramming of tumor cell metabolism has been increasingly acknowledged as a hallmark of cancer. Substantial evidence suggests a crosstalk between tumor cell metabolic reprogramming and epigenetic modifications, highlighting a complex interplay between metabolism and the epigenetic genome that warrants further investigation. Biomarkers associated with the pathogenesis and metabolic characteristics of CRC hold significant clinical implications. Nevertheless, elucidating the genetic, epigenetic, and metabolic landscapes of CRC continues to pose considerable challenges. Here, we attempt to summarize the key genes driving the onset and progression of CRC and the related epigenetic regulators, clarify the roles of gene expression and signaling pathways in tumor metabolism regulation, and explore the potential crosstalk between epigenetic events and tumor metabolic reprogramming, providing a comprehensive mechanistic explanation for the malignant progression of CRC. Finally, by integrating reliable targets from genetics, epigenetics, and metabolic processes that hold promise for translation into clinical practice, we aim to offer more strategies to overcome the bottlenecks in CRC treatment.
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Affiliation(s)
- Jingyuan Li
- Institute of Digestive DiseasesChina‐Canada Center of Research for Digestive DiseasesLonghua HospitalShanghai University of Traditional Chinese MedicineShanghaiChina
- State Key Laboratory of Integration and Innovation of Classic Formula and Modern Chinese Medicine (Shanghai University of Traditional Chinese Medicine)ShanghaiChina
| | - Jiashu Pan
- Institute of Digestive DiseasesChina‐Canada Center of Research for Digestive DiseasesLonghua HospitalShanghai University of Traditional Chinese MedicineShanghaiChina
- State Key Laboratory of Integration and Innovation of Classic Formula and Modern Chinese Medicine (Shanghai University of Traditional Chinese Medicine)ShanghaiChina
| | - Lisheng Wang
- Department of BiochemistryMicrobiology and ImmunologyFaculty of MedicineUniversity of OttawaOttawaOntarioCanada
- China‐Canada Centre of Research for Digestive DiseasesUniversity of OttawaOttawaOntarioCanada
| | - Guang Ji
- Institute of Digestive DiseasesChina‐Canada Center of Research for Digestive DiseasesLonghua HospitalShanghai University of Traditional Chinese MedicineShanghaiChina
- State Key Laboratory of Integration and Innovation of Classic Formula and Modern Chinese Medicine (Shanghai University of Traditional Chinese Medicine)ShanghaiChina
| | - Yanqi Dang
- Institute of Digestive DiseasesChina‐Canada Center of Research for Digestive DiseasesLonghua HospitalShanghai University of Traditional Chinese MedicineShanghaiChina
- State Key Laboratory of Integration and Innovation of Classic Formula and Modern Chinese Medicine (Shanghai University of Traditional Chinese Medicine)ShanghaiChina
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26
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Rong Y, Zhang G, Ye W, Qi L, Hao X, Li X, Zhang W, Chao Y, Gu S. Uncovering the Effects and Molecular Mechanisms of Shaoyao Decoction Against Colorectal Cancer Using Network Pharmacology Analysis Coupled With Experimental Validation and Gut Microbiota Analysis. Cancer Med 2025; 14:e70813. [PMID: 40119640 PMCID: PMC11928771 DOI: 10.1002/cam4.70813] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2024] [Revised: 03/12/2025] [Accepted: 03/13/2025] [Indexed: 03/24/2025] Open
Abstract
BACKGROUND Chronic gut inflammation and dysbiosis contribute significantly to colorectal cancer (CRC) development. Shaoyao decoction (SYD) is a well-established Chinese medicine prescription. Besides ameliorating CRC via anti-inflammatory effects, SYD modulates gut microbiota (GM) to improve inflammatory responses in ulcerative colitis (UC). However, whether and how SYD suppresses CRC by regulating GM remains largely unknown. METHODS SD rats were orally administered SYD for 7 days to obtain medicated serum. We utilized liquid chromatography-mass spectrometry (LC-MS) analysis, GeneCards, DisGeNET, and SwissTargetPrediction databases to analyze blank and SYD-medicated rat serum, comparing the findings with those of SYD aqueous extract in previous studies to identify SYD circulating compounds/components with predictable target genes. Using network pharmacology, the potential active compounds and corresponding hub genes associated with modulating GM to suppress CRC were selected for molecular docking. In vivo experiments, a CRC transplantation tumor model was established in BALB/c mice using CT26 cells, with SYD gavage for 14 days. To investigate the mechanism of SYD-regulated GM against CRC, HE and IHC staining, Western blotting, and 16S rRNA sequencing were employed. RESULTS LC-MS identified 26 SYD compounds with computationally predicted target genes. Network pharmacology prioritized 13 compounds targeting 8 inflammation/immunity-related genes (IL-17/TNF pathways), validated by molecular docking. In vivo experiments, SYD dose-dependently suppressed tumor growth (p < 0.05, medium/high doses), as confirmed by HE staining and IHC analysis of Ki-67. Notably, SYD potentially delayed CRC liver metastasis and alleviated hepatic injury in tumor-bearing mice. Western blotting demonstrated SYD's inhibition of the IL-17/TNF/NF-κB axis, aligning with computational predictions. 16S rRNA sequencing revealed SYD-enriched Akkermansia and GM structural shifts, mechanistically linking microbiota remodeling to anti-tumor efficacy. CONCLUSIONS SYD combats CRC via dual modulation of IL-17/TNF/NF-κB signaling and GM ecosystems (e.g., Akkermansia enrichment). This microbiota-immune crosstalk positions SYD as a potential adjunct to conventional therapies, particularly for CRC patients with dysbiosis.
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Affiliation(s)
- Yaojun Rong
- Shenzhen Bao'an Traditional Chinese Medicine Hospital, Guangzhou University of Chinese MedicineShenzhenGuangdongChina
| | - Guiyu Zhang
- Shenzhen Bao'an Traditional Chinese Medicine Hospital, Guangzhou University of Chinese MedicineShenzhenGuangdongChina
| | - Wenhao Ye
- The Seventh Clinical Medical College of Guangzhou University of Chinese MedicineShenzhenGuangdongChina
| | - Linhua Qi
- Shenzhen Bao'an Traditional Chinese Medicine Hospital, Guangzhou University of Chinese MedicineShenzhenGuangdongChina
| | - Xiaojiang Hao
- Shenzhen Bao'an Traditional Chinese Medicine Hospital, Guangzhou University of Chinese MedicineShenzhenGuangdongChina
| | - Xiaolin Li
- Shenzhen Bao'an Traditional Chinese Medicine Hospital, Guangzhou University of Chinese MedicineShenzhenGuangdongChina
| | - Wuhong Zhang
- Shenzhen Bao'an Traditional Chinese Medicine Hospital, Guangzhou University of Chinese MedicineShenzhenGuangdongChina
| | - Yangfa Chao
- Shenzhen Bao'an Traditional Chinese Medicine Hospital, Guangzhou University of Chinese MedicineShenzhenGuangdongChina
| | - Shaodong Gu
- Shenzhen Bao'an Traditional Chinese Medicine Hospital, Guangzhou University of Chinese MedicineShenzhenGuangdongChina
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Peng L, Zhang X, Zhu Y, Shi L, Ai K, Huang G, Ma W, Wei Z, Wang L, Ma Y, Wang L. T2WI and ADC radiomics combined with a nomogram based on clinicopathologic features to quantitatively predict microsatellite instability in colorectal cancer. Acad Radiol 2025; 32:1431-1450. [PMID: 39490321 DOI: 10.1016/j.acra.2024.10.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2024] [Revised: 10/02/2024] [Accepted: 10/09/2024] [Indexed: 11/05/2024]
Abstract
RATIONALE AND OBJECTIVES Microsatellite instability (MSI) stratification can guide the clinical management of patients with colorectal cancer (CRC). This study aimed to establish a radiomics model for predicting the MSI status of patients with CRC before treatment. MATERIALS AND METHODS This retrospective study was performed on 366 patients diagnosed with CRC who underwent preoperative magnetic resonance imaging (MRI) and immunohistochemical staining between February 2016 and September 2023. The participants were divided randomly into training and testing cohorts in a 7:3 ratio. The tumor volume of interest (VOI) was manually delineated on T2-weighted imaging (T2WI) and apparent diffusion coefficient (ADC) sequences using 3D Slicer software, and radiomics features were extracted. Feature selection was performed using the least absolute shrinkage and selection operator method. A radiomics nomogram was developed using multiple logistic regression, and the predictive performance of the models was evaluated and compared using receiver operating characteristic curves. The calibration curve, clinical decision curve analysis (DCA) and clinical impact curve (CIC) were used to evaluate the clinical application value of the model. RESULTS The radiomics normogram combined with history of chronic enteritis, tumor location, MR-reported inflammatory response, D2-40, carcinoembryonic antigen, tumor protein 53, and monocyte was an excellent predictive tool. The area under the curve for the training and testing cohorts were 0.927 and 0.984, respectively. The DCA and CIC demonstrated favorable clinical application and net benefit. CONCLUSIONS A radiomics nomogram based on T2WI and ADC sequences and clinicopathologic features can effectively and noninvasively predict the MSI status in CRC. This approach helps clinicians in stratifying CRC patients and making clinical decisions for personalized treatment.
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Affiliation(s)
- Leping Peng
- Gansu University of Chinese Medicine, Lanzhou 730000, China
| | - Xiuling Zhang
- Gansu University of Chinese Medicine, Lanzhou 730000, China
| | - Yuanhui Zhu
- Department of Radiology, Gansu Provincial Hospital, Lanzhou 730000, China
| | - Liuyan Shi
- Department of Radiology, Gansu Provincial Hospital, Lanzhou 730000, China
| | - Kai Ai
- Department of Clinical and Technical Support, Philips Healthcare, Xi'an 710065, China
| | - Gang Huang
- Department of Radiology, Gansu Provincial Hospital, Lanzhou 730000, China
| | - Wenting Ma
- Department of Radiology, Gansu Provincial Hospital, Lanzhou 730000, China
| | - Zhaokun Wei
- Department of Radiology, Gansu Provincial Hospital, Lanzhou 730000, China
| | - Ling Wang
- Department of Pathology, Gansu Provincial Hospital, Lanzhou 730000, China
| | - Yaqiong Ma
- Department of Radiology, Gansu Provincial Hospital, Lanzhou 730000, China
| | - Lili Wang
- Department of Radiology, Gansu Provincial Hospital, Lanzhou 730000, China.
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Emile SH, Horesh N, Strassmann V, Garoufalia Z, Gefen R, Zhou P, Wexner SD. A National Cancer Database Analysis of the Characteristics and Outcome of Colon Cancer According to Type of Preexisting Adenoma. Clin Colorectal Cancer 2025; 24:56-63. [PMID: 39443244 DOI: 10.1016/j.clcc.2024.09.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2024] [Revised: 09/23/2024] [Accepted: 09/24/2024] [Indexed: 10/25/2024]
Abstract
BACKGROUND The vast majority of colon cancers occur in pre-existing adenomas. Little is known about the impact of adenoma type on behavior and outcome of subsequent carcinomas. The present study aimed to assess characteristics, behavior, and outcome of colon adenocarcinoma based on histologic type of pre-existing adenoma. METHODS US-National Cancer Database was searched between 2005 and 2019 for patients with colonic adenocarcinoma with known adenoma type who underwent colectomy. Patients were divided into 3 groups according to type of adenoma in which carcinoma developed: tubular adenoma (TA), villous adenoma (VA), and tubulovillous adenoma (TVA)-associated carcinomas. The main outcome of the study was 5-year overall survival (OS). RESULTS 66,854 patients were included. 79.3% of carcinomas originated from TVA, 10.2% from VA, and 0.5% from TA. Patients with adenocarcinoma in VA were more often female whereas carcinomas in TA affected patients of Asian race more often. Approximately one-third of carcinomas in villous and tubulovillous adenomas were in the cecum whereas one-third of carcinomas in tubular adenomas were in the sigmoid colon. More TA-associated carcinomas were of clinical T1-2 stage (30.2% vs. 20.8%; P < .001), clinical N0 stage (69% vs. 62.2%, P < .001), and high grade (15.9% vs. 11.5%, P < .001) compared to VA-associated carcinomas. Patients with TA-associated carcinomas had longer mean OS than patients with VA and TVA-associated carcinomas (130.1 vs. 116.9 vs. 123.5 months, P < .0001). CONCLUSIONS Adenocarcinomas that arose in TA had more T1-2 stage and N0 stage, higher grade, and longer OS than did adenocarcinomas that arose in VA and TVA.
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Affiliation(s)
- Sameh Hany Emile
- Ellen Leifer Shulman and Steven Shulman Digestive Disease Center, Cleveland Clinic Florida, Weston, FL; Colorectal Surgery Unit, General Surgery Department, Mansoura University Hospitals, Mansoura, Egypt
| | - Nir Horesh
- Ellen Leifer Shulman and Steven Shulman Digestive Disease Center, Cleveland Clinic Florida, Weston, FL
| | - Victor Strassmann
- Ellen Leifer Shulman and Steven Shulman Digestive Disease Center, Cleveland Clinic Florida, Weston, FL
| | - Zoe Garoufalia
- Ellen Leifer Shulman and Steven Shulman Digestive Disease Center, Cleveland Clinic Florida, Weston, FL
| | - Rachel Gefen
- Ellen Leifer Shulman and Steven Shulman Digestive Disease Center, Cleveland Clinic Florida, Weston, FL; Department of General Surgery, Hadassah Medical Organization and Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel
| | - Peige Zhou
- Georgia Colon and Rectal Surgical Associates, Northside Hospital, Atlanta, GA
| | - Steven D Wexner
- Ellen Leifer Shulman and Steven Shulman Digestive Disease Center, Cleveland Clinic Florida, Weston, FL.
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Vaghasiya MD, Sain A, Mendapara JV, Khamrai D, Naskar D, Kumari P. Thiazepine-Based Hybrids as Promising Anti-Colon Cancer Agents: Design, Synthesis, Computational and In Vitro Screening. Chem Biodivers 2025; 22:e202401550. [PMID: 39413279 DOI: 10.1002/cbdv.202401550] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2024] [Revised: 09/20/2024] [Accepted: 10/15/2024] [Indexed: 10/18/2024]
Abstract
Novel thiazepine-based hybrids (9 a-d) were designed and synthesized to create lead molecules with exceptional anti-colon cancer efficacy. Analytical methods, including IR, NMR, and HR-MS, characterized the synthesized compounds. The in vitro colorectal study was carried out to compare the biological activity of newly developed compounds with the computational data. The tested compounds induced cytotoxicity in HT-29 cells for both 24 h and 48 h in a dose-dependent manner. However, compound 9 a induced cytotoxicity at much higher concentrations compared to the rest of the compounds. 9 b and 9 c caused 50 % cell death (compared to the untreated cells) at a dose of ~50 μM and 40 μM in case of 24-hour exposure, respectively. On the contrary, for 48 h exposure, both 9 b and 9 c induced 50 % cell death concerning untreated cells at a dose of around ~20 μM, whereas 9 d exhibited 50 % cell death at 5 μM in the case of 48 h exposure. In silico ADMET was also carried out to understand the pharmacokinetics and safety profiles of the drug candidates. We found some of the critical targets of these compounds, which eventually will be integral to exploring the mechanistic actions of these compounds in colon cancer.
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Affiliation(s)
- Mahesh D Vaghasiya
- Department of Chemistry, S.V. National Institute of Technology, Surat, Gujarat, 395007, India
| | - Arindam Sain
- Department of Biotechnology, Maulana Abul Kalam Azad University of Technology, Haringhata, Nadia, West Bengal, 741249, India
| | - Jigarkumar V Mendapara
- Department of Chemistry, S.V. National Institute of Technology, Surat, Gujarat, 395007, India
| | - Dipshikha Khamrai
- Department of Biotechnology, Maulana Abul Kalam Azad University of Technology, Haringhata, Nadia, West Bengal, 741249, India
| | - Debdut Naskar
- Department of Biotechnology, Maulana Abul Kalam Azad University of Technology, Haringhata, Nadia, West Bengal, 741249, India
| | - Premlata Kumari
- Department of Chemistry, S.V. National Institute of Technology, Surat, Gujarat, 395007, India
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30
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Jin L, Jin HY, Kim Y, Cho NY, Bae JM, Kim JH, Han SW, Kim TY, Kang GH. Clinicopathological and molecular features of genome-stable colorectal cancers. Histol Histopathol 2025; 40:381-388. [PMID: 38993017 DOI: 10.14670/hh-18-785] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/13/2024]
Abstract
Colorectal cancers (CRCs) are traditionally divided into those with either chromosomal instability (CIN) or microsatellite instability (MSI). By utilizing TCGA data, the Laird team found a subset of CRCs, namely, genome-stable CRCs (GS CRCs), which lack both CIN and MSI. Although the molecular features of GS CRCs have been described in detail, the clinicopathological features are not well defined. A total of 437 CRCs were analyzed for copy number variation (CNV) statuses in eight genes (ARID1A, EGFR, FGFR1, KDM5B, MYBL2, MYC, SALL4, and SETDB1) using droplet-digital PCR. CRCs that showed CNV in ≤ one gene and no MSI were defined as GS-like CRCs. Clinicopathological and molecular features of GS-like CRCs were compared with those of CIN-like CRCs. GS-like CRCs comprised 4.6% of CRCs and showed a predilection toward the proximal colon, lower nuclear optical density, KRAS mutation, PIK3CA mutation, and aberrant expression of KRT7. Survival analysis showed no significant difference between the three subgroups. Through our study, the GS-like subtype was found to comprise a minor proportion of CRCs and have proclivity toward a proximal bowel location, hypochromatic tumor nuclei, aberrant KRT7 expression, and a high frequency of KRAS and PIK3CA mutations.
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Affiliation(s)
- Lingyan Jin
- Department of Pathology, Seoul National University College of Medicine, Seoul, Korea
- Laboratory of Epigenetics, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Hye-Yeong Jin
- Department of Pathology, Seoul National University College of Medicine, Seoul, Korea
- Laboratory of Epigenetics, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Younghoon Kim
- Laboratory of Epigenetics, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea
- Department of Hospital Pathology, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Nam-Yun Cho
- Laboratory of Epigenetics, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Jeong Mo Bae
- Department of Pathology, Seoul National University College of Medicine, Seoul, Korea
- Laboratory of Epigenetics, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Jung Ho Kim
- Department of Pathology, Seoul National University College of Medicine, Seoul, Korea
| | - Sae-Won Han
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea
| | - Tae-You Kim
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea
| | - Gyeong Hoon Kang
- Laboratory of Epigenetics, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea
- Department of Pathology, Seoul National University College of Medicine, Seoul, Korea.
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31
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Liu Z, Li Y, Wang S, Wang Y, Sui M, Liu J, Chen P, Wang J, Zhang Y, Dang C, Hou P. Genome-wide CRISPR screening identifies PHF8 as an effective therapeutic target for KRAS- or BRAF-mutant colorectal cancers. J Exp Clin Cancer Res 2025; 44:70. [PMID: 40001243 PMCID: PMC11853609 DOI: 10.1186/s13046-025-03338-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2024] [Accepted: 02/17/2025] [Indexed: 02/27/2025] Open
Abstract
BACKGROUND Mutations in KRAS and BRAF genes are prevalent in colorectal cancer (CRC), which strikingly promote tumorigenesis and lead to poor response to a variety of treatments including immunotherapy by activating the MAPK/ERK pathway. Thus, there is an urgent need to discover effective therapeutic targets and strategies. METHODS CRISPR-Cas9 lentiviral knockout library was used to screen the suppressors of anti-PD1 immunotherapy. Bioinformatic analysis was used to analyze the correlation between PHF8 expression and immune indicators in CRC. In vitro and in vivo experiments were utilized to determine the effects of PHF8 on the immune indexes and malignant phenotypes of CRC cells. qRT-PCR, western blotting, immunohistochemical (IHC) staining, and chromatin immunoprecipitation (ChIP)-qPCR assays were used to determine the regulatory effects of PHF8 on PD-L1, KRAS, BRAF, and c-Myc and the regulatory effect c-Myc/miR-22-3p signaling axis on PHF8 expression in CRC cells. RESULTS This study identified histone lysine demethylase PHF8 as a negative regulator for the efficacy of anti-PD1 therapy and found that it was highly expressed in CRCs and strongly associated with poor patient survival. Functional studies showed that PHF8 played an oncogenic role in KRAS- or BRAF-mutant CRC cells, but not in wild-type ones. Mechanistically, PHF8 up-regulated the expression of PD-L1, KRAS, BRAF, and c-Myc by increasing the levels of transcriptional activation marks H3K4me3 and H3K27ac and decreasing the levels of transcriptional repression mark H3K9me2 within their promoter regions, promoting immune escape and tumor progression. Besides, our data also demonstrated that PHF8 was up-regulated by the c-Myc/miR-22-3p signaling axis to form a positive feedback loop. Targeting PHF8 substantially improved the efficacy of anti-PD1 therapy and inhibited the malignant phenotypes of KRAS- or BRAF-mutant CRC cells. CONCLUSION Our data demonstrate that PHF8 may be an effective therapeutic target for KRAS- or BRAF-mutant CRCs.
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Affiliation(s)
- Zhao Liu
- Department of Endocrinology and International Joint Research Center for Tumor Precision Medicine of Shaanxi Province, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, P.R. China
- Department of Surgical Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, P.R. China
| | - Yiqi Li
- Department of General Practice, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, 310016, P.R. China
| | - Simeng Wang
- Department of Endocrinology and International Joint Research Center for Tumor Precision Medicine of Shaanxi Province, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, P.R. China
| | - Yubo Wang
- Department of Endocrinology and International Joint Research Center for Tumor Precision Medicine of Shaanxi Province, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, P.R. China
| | - Mengjun Sui
- Department of Endocrinology and International Joint Research Center for Tumor Precision Medicine of Shaanxi Province, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, P.R. China
| | - Jiaxin Liu
- Department of Vascular Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, P.R. China
| | - Pu Chen
- Department of Endocrinology and International Joint Research Center for Tumor Precision Medicine of Shaanxi Province, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, P.R. China
| | - Jianling Wang
- Department of Endocrinology and International Joint Research Center for Tumor Precision Medicine of Shaanxi Province, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, P.R. China
| | - Yuchen Zhang
- Department of Nuclear Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, P.R. China
| | - Chengxue Dang
- Department of Surgical Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, P.R. China.
| | - Peng Hou
- Department of Endocrinology and International Joint Research Center for Tumor Precision Medicine of Shaanxi Province, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, P.R. China.
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Li W, Wang N, Ye H, Chen M. Correlation Between Skeletal Muscle Mass and Different Pathological Types of Colorectal Polyp in Chinese Asymptomatic Population. Int J Gen Med 2025; 18:927-938. [PMID: 39995636 PMCID: PMC11849526 DOI: 10.2147/ijgm.s503137] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2024] [Accepted: 02/13/2025] [Indexed: 02/26/2025] Open
Abstract
Background Low relative muscle mass was identified to be related to ascending risk of pre-cancerous polyps (adenoma) in recent cohort study. Our study aimed to dig out the correlation between muscle mass and different pathological types of colorectal polyps in Chinese asymptomatic population. Methods In all, 5923 adults were included. The effects of low skeletal muscle mass index (SMI) on colorectal polyp occurrence, including different pathological types, and the effects modification of age and BMI were analyzed using univariate and multivariate logistic regression. Results Lower SMI was connected with the lower occurrence of colorectal polyp (OR: 0.810, 95% CI: 0.683~0.960, p=0.015). Considering different pathological types of colorectal polyps, lower SMI was associated with lower occurrence of inflammatory polyp (OR: 0.633, 95% CI: 0.434~0.898, p=0.013), rather than conventional adenoma and serrated polyp (all p>0.05). Besides, SMI was positively related to the occurrence of 2 pathological types of colorectal polyp in males: inflammatory polyp (OR: 1.237, 95% CI: 1.058~1.444, p=0.007) and serrated polyp (OR: 1.288, 95% CI: 1.143~1.456, p<0.001). The interaction effect of BMI and SMI on occurrence of inflammatory polyp after adjusting age and smoking status was significant (p=0.015). For individuals with low SMI (compared with the normal SMI group), the incidence of inflammatory polyp was reduced from 8.95% to 3.50% in the low BMI quartile (Q1) in the adjusted model (OR of 0.332, 95% CI: 0.005-0.061, p<0.001). It was noticeable for males rather than females that individuals with colorectal polyps had higher levels of SMI (p=0.003). In addition, individuals with inflammatory polyps as well as serrated polyps possessed higher levels of SMI in males (all p<0.05). Conclusion Generally, especially in Chinese asymptomatic males, low SMI kept independent effect on the presence of inflammatory polyp and serrated polyp, rather than conventional adenoma.
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Affiliation(s)
- Wenya Li
- Ultrasound Department, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, People’s Republic of China
| | - Na Wang
- Healthcare Center, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, People’s Republic of China
| | - Huajun Ye
- Gastroenterology Department, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, People’s Republic of China
| | - Mengjun Chen
- Gastroenterology Department, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, People’s Republic of China
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Camandona A, Gagliardi A, Licheri N, Tarallo S, Francescato G, Budinska E, Carnogurska M, Zwinsová B, Martinoglio B, Franchitti L, Gallo G, Cutrupi S, De Bortoli M, Pardini B, Naccarati A, Ferrero G. Multiple regulatory events contribute to a widespread circular RNA downregulation in precancer and early stage of colorectal cancer development. Biomark Res 2025; 13:30. [PMID: 39980011 PMCID: PMC11844049 DOI: 10.1186/s40364-025-00744-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2024] [Accepted: 02/11/2025] [Indexed: 02/22/2025] Open
Abstract
BACKGROUND Early detection of colorectal cancer (CRC) significantly improves its management and patients' survival. Circular RNAs (circRNAs) are peculiar covalently closed transcripts involved in gene expression modulation whose dysregulation has been extensively reported in CRC cells. However, little is known about their alterations in the early phases of colorectal carcinogenesis. METHODS In this study, we performed an integrative analysis of circRNA profiles in RNA-sequencing (RNA-Seq) data of 96 colorectal cancers, 27 adenomas, and matched adjacent mucosa tissues. We also investigated the levels of cognate linear transcripts and those of regulating RNA-binding proteins (RBPs). Levels of circRNA-interacting microRNAs (miRNAs) were explored by integrating data of small RNA-Seq performed on the same samples. RESULTS Our results revealed a significant dysregulation of 34 circRNAs (paired adj. p < 0.05), almost exclusively downregulated in tumor tissues and, prevalently, in early disease stages. This downregulation was associated with decreased expression of circRNA host genes and those encoding for RBPs involved in circRNA biogenesis, including NOVA1, RBMS3, and MBNL1. Guilt-by-association analysis showed that dysregulated circRNAs correlated with increased predicted activity of cell proliferation, DNA repair, and c-Myc signaling pathways. Functional analysis showed interactions among dysregulated circRNAs, RBPs, and miRNAs, which were supported by significant correlations among their expression levels. Findings were validated in independent cohorts and public datasets, and the downregulation of circLPAR1(2,3) and circLINC00632(5) was validated by ddPCR. CONCLUSIONS These results support that multiple altered regulatory mechanisms may contribute to the reduction of circRNA levels that characterize early colorectal carcinogenesis.
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Affiliation(s)
- Alessandro Camandona
- Department of Clinical and Biological Sciences, University of Torino, Turin, 10100, Italy
| | - Amedeo Gagliardi
- Italian Institute for Genomic Medicine (IIGM), c/o IRCCS Candiolo, Turin, 10060, Italy
- Candiolo Cancer Institute, FPO IRCCS, Candiolo, Turin, 10060, Italy
| | - Nicola Licheri
- Department of Clinical and Biological Sciences, University of Torino, Turin, 10100, Italy
| | - Sonia Tarallo
- Italian Institute for Genomic Medicine (IIGM), c/o IRCCS Candiolo, Turin, 10060, Italy
- Candiolo Cancer Institute, FPO IRCCS, Candiolo, Turin, 10060, Italy
| | - Giulia Francescato
- Department of Clinical and Biological Sciences, University of Torino, Turin, 10100, Italy
- Italian Institute for Genomic Medicine (IIGM), c/o IRCCS Candiolo, Turin, 10060, Italy
| | - Eva Budinska
- RECETOX, Faculty of Science, Masaryk University, Brno, 61137, Czech Republic
| | - Martina Carnogurska
- RECETOX, Faculty of Science, Masaryk University, Brno, 61137, Czech Republic
| | - Barbora Zwinsová
- RECETOX, Faculty of Science, Masaryk University, Brno, 61137, Czech Republic
- Institute of Biostatistics and Analyses, Faculty of Medicine, Masaryk University, Brno, 62500, Czech Republic
| | | | - Lorenzo Franchitti
- Department of Clinical and Biological Sciences, University of Torino, Turin, 10100, Italy
| | - Gaetano Gallo
- Department of Surgery, "La Sapienza" University of Rome, Rome, 00161, Italy
- Department of Colorectal Surgery, Clinica S. Rita, Vercelli, 13100, Italy
| | - Santina Cutrupi
- Department of Clinical and Biological Sciences, University of Torino, Turin, 10100, Italy
| | - Michele De Bortoli
- Department of Clinical and Biological Sciences, University of Torino, Turin, 10100, Italy
| | - Barbara Pardini
- Italian Institute for Genomic Medicine (IIGM), c/o IRCCS Candiolo, Turin, 10060, Italy
- Candiolo Cancer Institute, FPO IRCCS, Candiolo, Turin, 10060, Italy
| | - Alessio Naccarati
- Italian Institute for Genomic Medicine (IIGM), c/o IRCCS Candiolo, Turin, 10060, Italy
- Candiolo Cancer Institute, FPO IRCCS, Candiolo, Turin, 10060, Italy
| | - Giulio Ferrero
- Department of Clinical and Biological Sciences, University of Torino, Turin, 10100, Italy.
- Italian Institute for Genomic Medicine (IIGM), c/o IRCCS Candiolo, Turin, 10060, Italy.
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Xiao C, Wu H, Long J, You F, Li X. Olink Profiling of Intestinal Tissue Identifies Novel Biomarkers For Colorectal Cancer. J Proteome Res 2025; 24:599-611. [PMID: 39757570 PMCID: PMC11812010 DOI: 10.1021/acs.jproteome.4c00728] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2024] [Revised: 12/09/2024] [Accepted: 12/25/2024] [Indexed: 01/07/2025]
Abstract
Comprehensive protein profiling in intestinal tissues provides detailed information about the pathogenesis of colorectal cancer (CRC). This study quantified the expression levels of 92 oncology-related proteins in tumors, paired para-carcinoma tissues, and remote normal tissues from a cohort of 52 CRC patients utilizing the Olink technology. The proteomic profile of normal tissues closely resembled that of para-carcinoma tissues while distinctly differing from that of tumors. Among the 68 differentially expressed proteins (DEPs) identified between the tumor and normal tissues, WISP-1, ESM-1, and TFPI-2 showed the most pronounced alterations and exhibited relatively strong correlations. These markers also presented the highest AUC values for distinguishing between tissue types. Bioinformatic analysis of the DEPs revealed that the plasma membrane and the PI3K-AKT signaling pathway were among the most enriched GO terms and KEGG pathways. Furthermore, although TFPI-2 is typically recognized as a tumor suppressor, both Olink and enzyme linked immunosorbent assay (ELISA) analyses have demonstrated that its expression is significantly elevated in tumors compared with paired normal tissues. To the best of our knowledge, this is the first study to profile the proteome of intestinal tissue using the Olink technology. This work offers valuable insights into potential biomarkers and therapeutic targets for CRC, complementing the Olink profiling of circulating proteins.
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Affiliation(s)
- Chong Xiao
- TCM
Regulating Metabolic Diseases Key Laboratory of Sichuan Province, Hospital of Chengdu University of Traditional Chinese
Medicine, Chengdu 610075, Sichuan, China
- Oncology
Teaching and Research Department, Chengdu
University of Traditional Chinese Medicine, Chengdu 610075, Sichuan, China
| | - Hao Wu
- TCM
Regulating Metabolic Diseases Key Laboratory of Sichuan Province, Hospital of Chengdu University of Traditional Chinese
Medicine, Chengdu 610075, Sichuan, China
| | - Jing Long
- TCM
Regulating Metabolic Diseases Key Laboratory of Sichuan Province, Hospital of Chengdu University of Traditional Chinese
Medicine, Chengdu 610075, Sichuan, China
| | - Fengming You
- TCM
Regulating Metabolic Diseases Key Laboratory of Sichuan Province, Hospital of Chengdu University of Traditional Chinese
Medicine, Chengdu 610075, Sichuan, China
- Institute
of Oncology, Chengdu University of Traditional
Chinese Medicine, Chengdu 610075, Sichuan, China
| | - Xueke Li
- TCM
Regulating Metabolic Diseases Key Laboratory of Sichuan Province, Hospital of Chengdu University of Traditional Chinese
Medicine, Chengdu 610075, Sichuan, China
- Oncology
Teaching and Research Department, Chengdu
University of Traditional Chinese Medicine, Chengdu 610075, Sichuan, China
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35
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Liu Z, Liu Q, Zeng A, Song L. Regulatory function of endoplasmic reticulum stress in colorectal cancer: Mechanism, facts, and perspectives. Int Immunopharmacol 2025; 147:114024. [PMID: 39764998 DOI: 10.1016/j.intimp.2025.114024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2024] [Revised: 12/30/2024] [Accepted: 01/03/2025] [Indexed: 01/29/2025]
Abstract
Colorectal cancer (CRC) is an exceedingly common and profoundly impactful malignancy of the digestive system, posing a grave threat to human health. Endoplasmic reticulum stress (ERS) is an intracellular biological reaction that mobilizes the unfolded protein response (UPR) to tackling dysregulation in protein homeostasis. This process subtly modulates the cell to either restore normal cellular function or steer it towards apoptosis. The high metabolic demands of CRC cells sculpt a rigorous tumor microenvironment (TME), compelling CRC cells to experience ERS. Adaptive responses induced by mild ERS furnish the necessary conditions for the survival of CRC cells, whereas the cell death mechanisms triggered by sustained ERS could be considered a prospective strategy for cancer therapy. Considering the complex regulation of ERS in cancer development, this article offers a comprehensive review of the molecular mechanisms through which ERS influences CRC fate. It provides crucial insights for exploring the role of ERS in the occurrence and progression of CRC, laying a new theoretical foundation for devising precise therapeutic strategies targeting ERS. Furthermore, by synthesizing extensive clinical and preclinical studies, we delve into therapeutic strategies targeting ERS, including the potential of targeting ERS in immunotherapy, the utilization of native compounds, advancements in proteasome inhibitors, and the potential synergies of these strategies with traditional chemotherapy agents and emerging therapeutic approaches.
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Affiliation(s)
- Zihan Liu
- School of Medical and Life Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Qiong Liu
- School of Medical and Life Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Anqi Zeng
- Translational Chinese Medicine Key Laboratory of Sichuan Province, Sichuan Academy of Chinese Medicine Sciences, Sichuan Institute for Translational Chinese Medicine, Chengdu, Sichuan 610041, China.
| | - Linjiang Song
- School of Medical and Life Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, China.
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Hunter E, Alshaker H, Weston C, Issa M, Bautista S, Gebregzabhar A, Virdi A, Dring A, Powell R, Green J, Lal R, Velchuru V, Aryal K, Bin Abu Hassan MR, Meng GT, Patel JS, Mohamed Gani SP, Lim CR, Guiel T, Akoulitchev A, Pchejetski D. A New Blood-Based Epigenetic Diagnostic Biomarker Test (EpiSwitch ®® NST) with High Sensitivity and Positive Predictive Value for Colorectal Cancer and Precancerous Polyps. Cancers (Basel) 2025; 17:521. [PMID: 39941889 PMCID: PMC11816175 DOI: 10.3390/cancers17030521] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2024] [Revised: 01/25/2025] [Accepted: 02/02/2025] [Indexed: 02/16/2025] Open
Abstract
BACKGROUND/OBJECTIVES Colorectal cancer (CRC) arises from the epithelial lining of the colon or rectum, often following a progression from benign adenomatous polyps to malignant carcinoma. Screening modalities such as colonoscopy, faecal immunochemical tests (FIT), and FIT-DNA are critical for early detection and prevention, but non-invasive methods lack sensitivity to polyps and early CRC. Chromosome conformations (CCs) are potent epigenetic regulators of gene expression. We have previously developed an epigenetic assay, EpiSwitch®®, that employs an algorithmic-based CCs analysis. Using EpiSwitch®® technology, we have shown the presence of cancer-specific CCs in peripheral blood mononuclear cells (PBMCs) and primary tumours of patients with melanoma and prostate cancer. EpiSwitch®®-based commercial tests are now available to diagnose prostate cancer with 94% accuracy (PSE test) and response to immune checkpoint inhibitors across 14 cancers with 85% accuracy (CiRT test). Methods/Results/Conclusions: Using blood samples collected from n = 171 patients with CRC, n = 44 patients with colorectal polyps and n = 110 patients with a 'clear' colonoscopy we performed whole Genome DNA screening for CCs correlating to CRC diagnosis. Our findings suggest the presence of two eight-marker CC signatures (EpiSwitch®® NST) in whole blood that allow diagnosis of CRC and precancerous polyps, respectively. Independent validation cohort testing demonstrated high accuracy in identifying colorectal polyps and early versus late stages of CRC with an exceptionally high sensitivity of 79-90% and a high positive prediction value of 60-84%. Linking the top diagnostic CCs to nearby genes, we have built pathways maps that likely underline processes contributing to the pathology of polyp and CRC progression, including TGFβ, cMYC, Rho GTPase, ROS, TNFa/NFκB, and APC.
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Affiliation(s)
- Ewan Hunter
- Oxford BioDynamics Plc., Oxford OX4 2WB, UK (A.A.)
| | - Heba Alshaker
- Norwich Medical School, University of East Anglia, Norwich NR4 7TJ, UK
| | | | - Mutaz Issa
- Oxford BioDynamics Plc., Oxford OX4 2WB, UK (A.A.)
| | | | | | - Anya Virdi
- Oxford BioDynamics Plc., Oxford OX4 2WB, UK (A.A.)
| | - Ann Dring
- Oxford BioDynamics Plc., Oxford OX4 2WB, UK (A.A.)
| | - Ryan Powell
- Oxford BioDynamics Plc., Oxford OX4 2WB, UK (A.A.)
| | - Jayne Green
- Oxford BioDynamics Plc., Oxford OX4 2WB, UK (A.A.)
| | - Roshan Lal
- James Paget University Hospitals NHS Trust, Great Yarmouth NR31 6LA, UK
| | - Vamsi Velchuru
- James Paget University Hospitals NHS Trust, Great Yarmouth NR31 6LA, UK
| | - Kamal Aryal
- James Paget University Hospitals NHS Trust, Great Yarmouth NR31 6LA, UK
| | | | - Goh Tiong Meng
- Island Hospital Penang, Jalan Macalister, George Town 10450, Malaysia
| | - Janisha Suriakant Patel
- Penang Reference Laboratory, Oxford BioDynamics Plc., Jalan Tanjung Tokong, George Town 10470, Malaysia
| | | | - Chun Ren Lim
- Penang Reference Laboratory, Oxford BioDynamics Plc., Jalan Tanjung Tokong, George Town 10470, Malaysia
| | - Thomas Guiel
- Oxford BioDynamics Inc., Frederick, MD 21703, USA
| | | | - Dmitri Pchejetski
- Norwich Medical School, University of East Anglia, Norwich NR4 7TJ, UK
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Lei X, Zhang L, Liu Y, Sun H, Yan J, Liu S. ZNF26-Associated Genes as Prognostic Signatures in Colorectal Cancer with Broad Therapeutic Implications. J Appl Genet 2025; 66:141-153. [PMID: 38568413 DOI: 10.1007/s13353-024-00854-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2023] [Revised: 03/08/2024] [Accepted: 03/11/2024] [Indexed: 01/25/2025]
Abstract
The identification of biomarkers correlated with colorectal cancer (CRC) prognosis holds substantial importance from both clinical and scientific perspectives. Zinc finger protein 26 (ZNF26) has not been previously investigated or documented in solid tumors; thus, further research is necessary to ascertain its prognostic value in CRC. Gene expression profiles and clinicopathological data were acquired from The Cancer Genome Atlas (TCGA) database. Subsequently, expression correlation was assessed utilizing the TCGA CRC cohort. The prognostic value of ZNF26 was evaluated through Kaplan-Meier (KM) and ROC curve analyses. Following this, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were conducted to perform enrichment analysis between high- and low-ZNF26 expression groups. The association between immune cells, immune checkpoint genes, and ZNF26 expression levels was examined. Lastly, the research findings were further validated using CRC tissue samples. The results revealed that, in comparison to healthy controls, CRC significantly reduced ZNF26 expression. Elevated ZNF26 expression was associated with poorer overall survival in CRC patients. Additionally, high ZNF26 expression exhibited an inverse relationship with the immunological score and immune checkpoint gene expression in CRC patients. The findings from the TCGA data analysis were corroborated by the PCR results obtained from CRC tissue samples. ZNF26 is markedly upregulated in colorectal cancer tissues, potentially serving as a biomarker for CRC.
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Affiliation(s)
- Xue Lei
- Department of Clinical Specialty of Integrated Traditional Chinese and Western Medicine, Graduate School, Heilongjiang University of Chinese Medicine, Harbin, 150040, Heilongjiang Province, People's Republic of China
| | - Lijia Zhang
- Ethics Committee Office, First Affiliated Hospital, Heilongjiang University of Chinese Medicine, Harbin, 150040, Heilongjiang Province, People's Republic of China
| | - Ye Liu
- Department of Intensive Care Unit, First Affiliated Hospital, Heilongjiang University of Chinese Medicine, Harbin, 150040, Heilongjiang Province, People's Republic of China
| | - Heng Sun
- Department of Oncology, First Affiliated Hospital, Heilongjiang University of Chinese Medicine, Harbin, 150040, Heilongjiang Province, People's Republic of China
| | - Jun Yan
- Department of Oncology, First Affiliated Hospital, Heilongjiang University of Chinese Medicine, Harbin, 150040, Heilongjiang Province, People's Republic of China
| | - Songjiang Liu
- Department of Oncology, First Affiliated Hospital, Heilongjiang University of Chinese Medicine, Harbin, 150040, Heilongjiang Province, People's Republic of China.
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Zou J, Shi X, Wu Z, Zuo S, Tang X, Zhou H, Huang Y. MRTX1133 attenuates KRAS G12D mutated-colorectal cancer progression through activating ferroptosis activity via METTL14/LINC02159/FOXC2 axis. Transl Oncol 2025; 52:102235. [PMID: 39657309 PMCID: PMC11683245 DOI: 10.1016/j.tranon.2024.102235] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2024] [Revised: 11/30/2024] [Accepted: 12/07/2024] [Indexed: 12/12/2024] Open
Abstract
Colorectal cancer (CRC) ranks as the third most commonly diagnosed cancer and the second leading cause of cancer-related deaths worldwide. Studies have shown that CRC patients with KRAS mutations, especially KRASG12D, have an increased risk of metastasis. Emerging evidence indicates that long non-coding RNAs (lncRNAs) are crucial in the carcinogenesis and progression of various cancers, regulating multiple biological processes but the link between KRASG12D mutations and lncRNAs in CRC remains unclear. Therefore, this study was designed to identify a novel lncRNA involved in KRASG12D-mutated CRC and to elucidate its molecular mechanisms. The analysis of differentially expressed lncRNAs in the GSE201412 dataset revealed that LINC02159 was significantly upregulated following treatment with the KRASG12D inhibitor MTRX1133 Data from the GTEx database indicated that LINC02159 is highly expressed in CRC tumour tissues and is associated with better patient outcomes. In vitro and in vivo experiments suggest that LINC02159 acts as a tumour suppressor in CRC progression. Specifically, LINC02159 knockdown negated the inhibitory effects of MRTX1133 on tumourigenesis and its promotive effect on ferroptosis in KRASG12D-mutated CRC cells. LINC02159 expression is regulated by METTL14, with METTL14 knockdown decreasing m6A methylation of LINC02159, leading to its increased expression in CRC cells. Additionally, LINC02159 stabilised FOXC2 expression through de-ubiquitination. Rescue experiments further clarified that the METTL14/LINC02159/FOXC2 signalling axis is crucial for the inhibitory effects of MRTX1133 in KRASG12D-mutated CRC. Our study provides novel insights into the therapeutic potential of MRTX1133 in treating KRASG12D-mutated CRC by identifying a METTL14/LINC02159/FOXC2 signalling axis that mediates drug response. Our findings highlight the importance of understanding the molecular mechanisms of lncRNAs in cancer to develop effective targeted therapies.
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Affiliation(s)
- Junwei Zou
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital of Wannan Medical College, Wuhu, Anhui, China
| | - Xiuhua Shi
- Department of Radiotherapy & Oncology, The No.2 People's Hospital of Wuhu City, Wuhu, Anhui, China
| | - Zhaoying Wu
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital of Wannan Medical College, Wuhu, Anhui, China
| | - Siyuan Zuo
- School of Clinical Medicine, Wannan Medical College, Wuhu, Anhui, China
| | - Xiaolei Tang
- Center for Translational Medicine, The Second Affiliated Hospital of Wannan Medical College, Wuhu, Anhui, China
| | - Hailang Zhou
- Department of Gastroenterology, Lianshui People's Hospital of kangda college Affiliated to Nanjing Medical University, Huai'an, Jiangsu, China.
| | - Yong Huang
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital of Wannan Medical College, Wuhu, Anhui, China.
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Coelho D, Estêvão D, Oliveira MJ, Sarmento B. Radioresistance in rectal cancer: can nanoparticles turn the tide? Mol Cancer 2025; 24:35. [PMID: 39885557 PMCID: PMC11784129 DOI: 10.1186/s12943-025-02232-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2024] [Accepted: 01/14/2025] [Indexed: 02/01/2025] Open
Abstract
Rectal cancer accounts for over 35% of the worldwide colorectal cancer burden representing a distinctive subset of cancers from those arising in the colon. Colorectal cancers exhibit a continuum of traits that differ with their location in the large intestine. Due to anatomical and molecular differences, rectal cancer is treated differently from colon cancer, with neoadjuvant chemoradiotherapy playing a pivotal role in the control of the locally advanced disease. However, radioresistance remains a major obstacle often correlated with poor prognosis. Multifunctional nanomedicines offer a promising approach to improve radiotherapy response rates, as well as to increase the intratumoral concentration of chemotherapeutic agents, such as 5-Fluorouracil. Here, we revise the main molecular differences between rectal and colon tumors, exploring the complex orchestration beyond rectal cancer radioresistance and the most promising nanomedicines reported in the literature to improve neoadjuvant therapy response rates.
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Affiliation(s)
- Diogo Coelho
- i3S - Instituto de Investigação e Inovação em Saúde, Universidade Do Porto, Rua Alfredo Allen 208, Porto, 4200‑135, Portugal
- INEB - Instituto de Engenharia Biomédica, Universidade Do Porto, Rua Alfredo Allen 208, Porto, 4200‑135, Portugal
- IUCS - Instituto Universitário de Ciências da Saúde, CESPU, Rua Central de Gandra 1317, Gandra, 4585-116, Portugal
| | - Diogo Estêvão
- i3S - Instituto de Investigação e Inovação em Saúde, Universidade Do Porto, Rua Alfredo Allen 208, Porto, 4200‑135, Portugal
- INEB - Instituto de Engenharia Biomédica, Universidade Do Porto, Rua Alfredo Allen 208, Porto, 4200‑135, Portugal
- Laboratory of Experimental Cancer Research, Department of Human Structure and Repair, Cancer Research Institute, Ghent University, Ghent, Belgium
- ICBAS - Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, Rua Jorge Viterbo Ferreira, Porto, 4200-319, Portugal
| | - Maria José Oliveira
- i3S - Instituto de Investigação e Inovação em Saúde, Universidade Do Porto, Rua Alfredo Allen 208, Porto, 4200‑135, Portugal
- INEB - Instituto de Engenharia Biomédica, Universidade Do Porto, Rua Alfredo Allen 208, Porto, 4200‑135, Portugal
- ICBAS - Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, Rua Jorge Viterbo Ferreira, Porto, 4200-319, Portugal
| | - Bruno Sarmento
- i3S - Instituto de Investigação e Inovação em Saúde, Universidade Do Porto, Rua Alfredo Allen 208, Porto, 4200‑135, Portugal.
- INEB - Instituto de Engenharia Biomédica, Universidade Do Porto, Rua Alfredo Allen 208, Porto, 4200‑135, Portugal.
- IUCS - Instituto Universitário de Ciências da Saúde, CESPU, Rua Central de Gandra 1317, Gandra, 4585-116, Portugal.
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Singer M, Valerin J, Zhang Z, Zhang Z, Dayyani F, Yaghmai V, Choi A, Imagawa D, Abi-Jaoudeh N. Promising Cellular Immunotherapy for Colorectal Cancer Using Classical Dendritic Cells and Natural Killer T Cells. Cells 2025; 14:166. [PMID: 39936958 PMCID: PMC11817869 DOI: 10.3390/cells14030166] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2024] [Revised: 01/15/2025] [Accepted: 01/20/2025] [Indexed: 02/13/2025] Open
Abstract
Colorectal cancer (CRC) remains one of the leading causes of cancer-related morbidity and mortality around the world. Despite advances in surgery, chemotherapy, and targeted therapies, the prognosis for patients with metastatic or advanced CRC remains poor. Immunotherapies comprising immune checkpoint inhibitors showed disappointing responses in metastatic CRC (mCRC). However, cellular immunotherapy, specifically using classical dendritic cells (cDCs), may hold unique promise in immune recognition for CRC antigens. cDCs are substantial players in immune recognition and are instrumental in orchestrating innate and adaptive immune responses by processing and presenting tumor antigens to effector cells. Natural killer T (NKT) cells are insufficiently studied but unique effector cells because of their ability to bridge innate and adaptive immune reactions and the crosstalk with dendritic cells in cancer. This review explores the therapeutic potential of using both cDCs and NKT cells as a synergistic therapy in CRC, focusing on their biological roles, strategies for harnessing their capabilities, clinical applications, and the challenges within the tumor microenvironment. Both cDCs and NKT cells can be used as a new effective approach for cell-based therapies in cancers to provide a new hope for CRC patients that are challenging to treat.
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Affiliation(s)
- Mahmoud Singer
- Department of Radiological Sciences, School of Medicine, University of California, Irvine, CA 92617, USA
| | - Jennifer Valerin
- Department of Medicine, Chao Family Comprehensive Cancer Center, University of California, Irvine, CA 92697, USA (A.C.)
| | - Zhuoli Zhang
- Department of Radiological Sciences, School of Medicine, University of California, Irvine, CA 92617, USA
| | - Zigeng Zhang
- Department of Radiological Sciences, School of Medicine, University of California, Irvine, CA 92617, USA
| | - Farshid Dayyani
- Department of Medicine, Chao Family Comprehensive Cancer Center, University of California, Irvine, CA 92697, USA (A.C.)
| | - Vahid Yaghmai
- Department of Radiological Sciences, School of Medicine, University of California, Irvine, CA 92617, USA
| | - April Choi
- Department of Medicine, Chao Family Comprehensive Cancer Center, University of California, Irvine, CA 92697, USA (A.C.)
| | - David Imagawa
- Department of Surgery, University of California Irvine, Orange, CA 92697, USA
| | - Nadine Abi-Jaoudeh
- Department of Radiological Sciences, School of Medicine, University of California, Irvine, CA 92617, USA
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Taha SR, Karimi M, Mahdavi B, Yousefi Tehrani M, Bemani A, Kabirian S, Mohammadi J, Jabbari S, Hushmand M, Mokhtar A, Pourhanifeh MH. Crosstalk between non-coding RNAs and programmed cell death in colorectal cancer: implications for targeted therapy. Epigenetics Chromatin 2025; 18:3. [PMID: 39810224 PMCID: PMC11734566 DOI: 10.1186/s13072-024-00560-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2024] [Accepted: 11/13/2024] [Indexed: 01/16/2025] Open
Abstract
BACKGROUND Colorectal cancer (CRC) remains one of the most common causes of cancer-related mortality worldwide. Its progression is influenced by complex interactions involving genetic, epigenetic, and environmental factors. Non-coding RNAs (ncRNAs), including microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), have been identified as key regulators of gene expression, affecting diverse biological processes, notably programmed cell death (PCD). OBJECTIVE This review aims to explore the relationship between ncRNAs and PCD in CRC, focusing on how ncRNAs influence cancer cell survival, proliferation, and treatment resistance. METHODS A comprehensive literature analysis was conducted to examine recent findings on the role of ncRNAs in modulating various PCD mechanisms, including apoptosis, autophagy, necroptosis, and pyroptosis, and their impact on CRC development and therapeutic response. RESULTS ncRNAs were found to significantly regulate PCD pathways, impacting tumor growth, metastasis, and treatment sensitivity in CRC. Their influence on these pathways highlights the potential of ncRNAs as biomarkers for early CRC detection and as targets for innovative therapeutic interventions. CONCLUSION Understanding the involvement of ncRNAs in PCD regulation offers new insights into CRC biology. The targeted modulation of ncRNA-PCD interactions presents promising avenues for personalized cancer treatment, which may improve patient outcomes by enhancing therapeutic effectiveness and reducing resistance.
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Affiliation(s)
- Seyed Reza Taha
- Department of Pathology and Immunology, Washington University School of Medicine, St. LouisWashington, MO, USA
- Oncopathology Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Mehdi Karimi
- Faculty of Medicine, Bogomolets National Medical University (NMU), Kiev, Ukraine.
| | - Bahar Mahdavi
- Department of Molecular Biotechnology, Cell Science Research Center, Royan Institute for Biotechnology, ACECR, Isfahan, Iran
| | | | - Ali Bemani
- Student Research Committee, Kashan University of Medical Sciences, Kashan, Iran
| | - Shahriar Kabirian
- Student Research Committee, Kashan University of Medical Sciences, Kashan, Iran
| | - Javad Mohammadi
- Student Research Committee, Kashan University of Medical Sciences, Kashan, Iran
| | - Sina Jabbari
- Student Research Committee, Kashan University of Medical Sciences, Kashan, Iran
| | - Meysam Hushmand
- Student Research Committee, Kashan University of Medical Sciences, Kashan, Iran
| | - Alireza Mokhtar
- Student Research Committee, Kashan University of Medical Sciences, Kashan, Iran
| | - Mohammad Hossein Pourhanifeh
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran.
- PAKAN Institute, Tehran, Iran.
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Mroczkowski P, Kusian H, Jannasch O, Lippert H, Zajdel R, Zajdel K, Sadowski A, Merecz-Sadowska A. Treatment Quality of Rectal Cancer Patients in Certified Colorectal Cancer Centers Versus Non-Certified Hospitals: A Comparative Analysis. Cancers (Basel) 2025; 17:120. [PMID: 39796747 PMCID: PMC11720547 DOI: 10.3390/cancers17010120] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2024] [Revised: 12/24/2024] [Accepted: 12/30/2024] [Indexed: 01/13/2025] Open
Abstract
Background/Objectives: The certification of hospitals as colorectal cancer centers aims to improve treatment quality, but evidence supporting its effectiveness remains limited. This study evaluated the impact of certification on treatment outcomes for rectal cancer patients in Germany. Methods: We conducted a retrospective analysis of 14,905 patients with primary rectal cancer (UICC Stages I-III) treated at 271 hospitals. Treatment outcomes were compared between certified colorectal cancer centers (3624 patients in 55 hospitals) and non-certified hospitals (11,281 patients in 216 hospitals). Additionally, a subset analysis examined outcomes before and after certification within the same institutions. Results: Certified centers demonstrated higher utilization of preoperative imaging (endorectal ultrasound: 70.7% vs. 58.2%, p < 0.001; pelvic MRI: 39.1% vs. 28.5%, p < 0.001) and lower rates of intraoperative complications (4.6% vs. 6.2%, p < 0.001). Surgical quality indicators, including M.E.R.C.U.R.Y. classification (Grade 1: 86.5% both groups, p = 0.620) and anastomotic leakage rates (11.3% vs. 11.9%, p = 0.407), were comparable between certified and non-certified hospitals. Despite treating patients with more favorable tumor stages, certified centers showed no significant advantage in 5-year overall survival (82.8% vs. 82.0%, p = 0.880) or 30-day mortality (2.6% both groups, p = 0.869). Hospital stays were marginally shorter in certified centers (19.46 vs. 20.24 days, p < 0.001). Conclusions: While certification was associated with improved adherence to diagnostic protocols and reduced intraoperative complications, it did not significantly impact surgical quality or long-term survival outcomes. These findings suggest that certification alone may not guarantee superior treatment quality, as hospitals participating in quality assurance programs achieved comparable results without formal certification.
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Affiliation(s)
- Paweł Mroczkowski
- Department for General and Colorectal Surgery, Medical University of Lodz, Pl. Hallera 1, 90-647 Lodz, Poland;
- Institute for Quality Assurance in Operative Medicine Ltd., Otto-von-Guericke-University, Leipziger Str. 44, 39120 Magdeburg, Germany; (H.K.); (O.J.); (H.L.)
- Department for Surgery, University Hospital Knappschaftskrankenhaus, Ruhr-University, In der Schornau 23-25, 44892 Bochum, Germany
| | - Henry Kusian
- Institute for Quality Assurance in Operative Medicine Ltd., Otto-von-Guericke-University, Leipziger Str. 44, 39120 Magdeburg, Germany; (H.K.); (O.J.); (H.L.)
| | - Olof Jannasch
- Institute for Quality Assurance in Operative Medicine Ltd., Otto-von-Guericke-University, Leipziger Str. 44, 39120 Magdeburg, Germany; (H.K.); (O.J.); (H.L.)
| | - Hans Lippert
- Institute for Quality Assurance in Operative Medicine Ltd., Otto-von-Guericke-University, Leipziger Str. 44, 39120 Magdeburg, Germany; (H.K.); (O.J.); (H.L.)
- Department for General, Visceral and Vascular Surgery, Otto-von-Guericke-University, Leipziger Str. 44, D-39120 Magdeburg, Germany
| | - Radosław Zajdel
- Department of Economic and Medical Informatics, University of Lodz, 90-214 Lodz, Poland; (R.Z.); (A.S.)
- Department of Medical Informatics and Statistics, Medical University of Lodz, 90-645 Lodz, Poland;
| | - Karolina Zajdel
- Department of Medical Informatics and Statistics, Medical University of Lodz, 90-645 Lodz, Poland;
| | - Arkadiusz Sadowski
- Department of Economic and Medical Informatics, University of Lodz, 90-214 Lodz, Poland; (R.Z.); (A.S.)
| | - Anna Merecz-Sadowska
- Department of Economic and Medical Informatics, University of Lodz, 90-214 Lodz, Poland; (R.Z.); (A.S.)
- Department of Allergology and Respiratory Rehabilitation, Medical University of Lodz, 90-725 Lodz, Poland
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Tang YC, Ou JJ, Hsu SC, Huang CH, Lin LM, Chang HH, Wang YH, Huang ZT, Sun M, Liu KJ, Hung YM, Lai CY, Shih C, Chen CT, Chang JY, Hsieh HP, Jiaang WT, Kuo CC. Advancing precision therapy for colorectal cancer: Developing clinical indications for multi-target kinase inhibitor BPR1J481 using patient-derived xenograft models. Pharmacol Res 2025; 211:107556. [PMID: 39709137 DOI: 10.1016/j.phrs.2024.107556] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/17/2024] [Revised: 12/04/2024] [Accepted: 12/18/2024] [Indexed: 12/23/2024]
Abstract
The large and rapid increase in the incidence and mortality of colorectal cancer (CRC) demonstrates the urgent need for new drugs with higher efficacy to treat CRC. However, the lack of applicable and reliable preclinical models significantly hinders the progress of drug development. Patient-derived xenograft (PDX) models are currently considered reliable in vivo preclinical models for predicting drug efficacy in cancer patients. This study successfully uses the CRC PDX model to develop clinical indications for the new multi-target kinase inhibitor BPR1J481 and demonstrated the anti-cancer mechanism and competitive advantages of this drug candidate. The results demonstrate that BPR1J481 exhibits significant anticancer efficacy by inducing apoptosis in CRC PDX tumor tissues and corresponding PDX-derived CRC cells. Through kinase competitive binding and kinase activity assays, we discover that BPR1J481 effectively inhibits SRC kinase activity by directly binding to its active site. The reduction in SRC phosphorylation observed in CRC PDX tumor tissues and derived cells upon treatment with BPR1J481 further validates its inhibitory potential. Furthermore, the decrease in viable cells after SRC knockout and the poorer prognosis observed in patients with higher SRC expression, emphasizes the critical significance and clinical relevance of SRC in CRC. Additionally, BPR1J481 exhibits robust anti-angiogenic effects by suppressing VEGF- and PDGF-induced endothelial cell proliferation, migration, and capillary-like tube formation through inhibition of VEGFR2 and PDGFRβ phosphorylation. Remarkably, BPR1J481 appears to demonstrate greater efficacy against CRC compared to regorafenib. These findings highlight the therapeutic potential of BPR1J481 for patients with CRC.
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Affiliation(s)
- Ya-Chu Tang
- Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli County 350401, Taiwan
| | - Jing-Jim Ou
- Department of Surgery, Chang Bing Show Chwan Memorial Hospital, Changhua County 505029, Taiwan
| | - Shu-Ching Hsu
- Institute of Infectious Diseases and Vaccinology, National Health Research Institutes, Miaoli County 350401, Taiwan
| | - Chih-Hsiang Huang
- Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli County 350401, Taiwan
| | - Li-Mei Lin
- Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli County 350401, Taiwan
| | - Hsin-Huei Chang
- Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli County 350401, Taiwan
| | - Yi-Hsin Wang
- Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli County 350401, Taiwan
| | - Zih-Ting Huang
- Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli County 350401, Taiwan
| | - Manwu Sun
- Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli County 350401, Taiwan
| | - Ko-Jiunn Liu
- National Institute of Cancer Research, National Health Research Institutes, Tainan City 704016, Taiwan
| | - Yi-Mei Hung
- National Institute of Cancer Research, National Health Research Institutes, Tainan City 704016, Taiwan
| | - Chi-Yun Lai
- Pathology Core Laboratory, National Health Research Institutes, Miaoli County 350401, Taiwan
| | - Chuan Shih
- Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli County 350401, Taiwan
| | - Chiung-Tong Chen
- Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli County 350401, Taiwan
| | - Jang-Yang Chang
- Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli County 350401, Taiwan; Taipei Medical University Hospital, College of Medicine, Taipei Medical University, Taipei City 110301, Taiwan; Taipei Cancer Center, Taiwan; TMU Research Center of Cancer Translational Medicine, 110301, Taiwan
| | - Hsing-Pang Hsieh
- Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli County 350401, Taiwan
| | - Weir-Torn Jiaang
- Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli County 350401, Taiwan.
| | - Ching-Chuan Kuo
- Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli County 350401, Taiwan.
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Xiong L, Yang X, Liu H, Wu X, Cai T, Yuan M, Huang L, Zhou C, Zheng X, Li W, Zeng Z, Li S, Lan P, Kang L, Liang Z. Glutamic-pyruvic transaminase 1 deficiency-mediated metabolic reprogramming facilitates colorectal adenoma-carcinoma progression. Sci Transl Med 2025; 17:eadp9805. [PMID: 39742507 DOI: 10.1126/scitranslmed.adp9805] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2024] [Revised: 09/10/2024] [Accepted: 12/04/2024] [Indexed: 01/03/2025]
Abstract
The tumorigenesis of colorectal cancer (CRC) often follows the normal-adenoma-carcinoma (N-A-C) sequence. However, the molecular mechanisms underlying colorectal adenoma carcinogenesis remain largely unknown. Here, we analyzed transcriptomic profile changes in normal, advanced adenoma, and carcinoma tissues from patients with CRC, revealing that glutamic-pyruvic transaminase 1 (GPT1) in colorectal tissues was down-regulated during the N-A-C process and correlated with poor CRC prognosis. Mechanistically, GPT1 was transcriptionally activated by Krüppel-like factor 4 (KLF4). GPT1 reprogrammed metabolism and suppressed CRC tumorigenesis in cells and mouse models not only through enzyme-dependent α-ketoglutarate (α-KG) production and WNT signaling inhibition but also through enzyme-independent disruption of the folate cycle through binding with methylenetetrahydrofolate dehydrogenase 1-like (MTHFD1L). Furthermore, we identified poliumoside as a GPT1 activator that restrained CRC progression in cells, patient-derived CRC organoids, and patient-derived xenograft (PDX) models of CRC. Our study uncovers a role for GPT1 in CRC tumorigenesis and shows that poliumoside is a potential drug for the prevention and treatment of CRC.
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Affiliation(s)
- Li Xiong
- Department of Colorectal Surgery (General Surgery), Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China
- Biomedical Innovation Center, Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China
| | - Xin Yang
- Department of Colorectal Surgery (General Surgery), Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China
- Biomedical Innovation Center, Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China
| | - Huashan Liu
- Department of Colorectal Surgery (General Surgery), Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China
- Biomedical Innovation Center, Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China
| | - Xianrui Wu
- Department of Gastrointestinal Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510120, China
| | - Tanxing Cai
- Department of Colorectal Surgery (General Surgery), Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China
- Biomedical Innovation Center, Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China
| | - Ming Yuan
- Department of Colorectal Surgery (General Surgery), Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China
- Biomedical Innovation Center, Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China
| | - Liang Huang
- Department of Colorectal Surgery (General Surgery), Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China
- Biomedical Innovation Center, Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China
| | - Chi Zhou
- State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong 510050, China
| | - Xiaobin Zheng
- Department of Colorectal Surgery (General Surgery), Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China
- Biomedical Innovation Center, Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China
| | - Wenxin Li
- Department of Colorectal Surgery (General Surgery), Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China
- Biomedical Innovation Center, Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China
| | - Ziwei Zeng
- Department of Colorectal Surgery (General Surgery), Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China
- Biomedical Innovation Center, Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China
| | - Shujuan Li
- Department of Pharmacy, Third Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China
| | - Ping Lan
- Department of Colorectal Surgery (General Surgery), Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China
- Biomedical Innovation Center, Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China
| | - Liang Kang
- Department of Colorectal Surgery (General Surgery), Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China
- Biomedical Innovation Center, Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China
| | - Zhenxing Liang
- Department of Colorectal Surgery (General Surgery), Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China
- Biomedical Innovation Center, Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China
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Mandal S, Baker AM, Graham TA, Bräutigam K. The tumour histopathology "glossary" for AI developers. PLoS Comput Biol 2025; 21:e1012708. [PMID: 39847582 PMCID: PMC11756763 DOI: 10.1371/journal.pcbi.1012708] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2025] Open
Abstract
The applications of artificial intelligence (AI) and deep learning (DL) are leading to significant advances in cancer research, particularly in analysing histopathology images for prognostic and treatment-predictive insights. However, effective translation of these computational methods requires computational researchers to have at least a basic understanding of histopathology. In this work, we aim to bridge that gap by introducing essential histopathology concepts to support AI developers in their research. We cover the defining features of key cell types, including epithelial, stromal, and immune cells. The concepts of malignancy, precursor lesions, and the tumour microenvironment (TME) are discussed and illustrated. To enhance understanding, we also introduce foundational histopathology techniques, such as conventional staining with hematoxylin and eosin (HE), antibody staining by immunohistochemistry, and including the new multiplexed antibody staining methods. By providing this essential knowledge to the computational community, we aim to accelerate the development of AI algorithms for cancer research.
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Affiliation(s)
- Soham Mandal
- Centre for Evolution and Cancer, Institute of Cancer Research, London, United Kingdom
- Data Science Team, Institute of Cancer Research, London, United Kingdom
| | - Ann-Marie Baker
- Centre for Evolution and Cancer, Institute of Cancer Research, London, United Kingdom
| | - Trevor A. Graham
- Centre for Evolution and Cancer, Institute of Cancer Research, London, United Kingdom
| | - Konstantin Bräutigam
- Centre for Evolution and Cancer, Institute of Cancer Research, London, United Kingdom
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46
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Tian TT, Chen G, Sun K, Wang XY, Liu Y, Wang FQ, Yang B, Liu J, Han JY, Tang DX. ChanLingGao alleviates intestinal mucosal barrier damage and suppresses the onset and progression of Colorectal cancer in AOM/DSS murine model. Int Immunopharmacol 2024; 143:113193. [PMID: 39368132 DOI: 10.1016/j.intimp.2024.113193] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2024] [Revised: 07/26/2024] [Accepted: 09/14/2024] [Indexed: 10/07/2024]
Abstract
BACKGROUND The occurrence of Colorectal Cancer (CRC) is influenced by various factors, including host susceptibility, immune imbalance, and environmental triggers. Numerous studies have underscored the critical role of chronic intestinal inflammation and dysbiosis in the development of CRC. Traditional Chinese Medicine (TCM) holds unique advantages in regulating the intricate process of and comprehensive treatment for systemic disease. Previous investigations by our team have confirmed the anti-cancer properties of the TCM compound ChanLingGao (CLG), including inhibiting cancer cell migration, and alleviating bone cancer pain. However, the mechanisms underlying its efficacy in alleviating chronic intestinal inflammation, modulating the gut microbiota, and protecting the intestinal mucosal barrier remain largely unknown. PURPOSE This study aims to explore the inhibitory effects of CLG on CRC tumors in mice and its potential mechanisms. METHODS A chronic inflammation-related CRC mouse model was established using AOM/DSS. The study examined the mechanisms of intestinal inflammation and tumor cell proliferation through intestinal histological morphology. High-throughput sequencing was employed to analyze changes in gut microbiota diversity and intestinal mucosal barrier integrity in CRC mice. Based on network pharmacology target prediction and Wnt/β-catenin signaling pathway analysis, the study analyzed and discussed the potential mechanisms of CLG on CRC. RESULTS CLG significantly ameliorated weight loss and increased survival rates in CRC mice, while suppressing tumor growth in the intestinal tract. Post-CLG treatment improved intestinal inflammation in CRC mice, with a significant reduction in inflammatory factors IL-6, IL-23 and LCN2, and inhibition of tumor cell proliferation markers Proliferating Cell Nuclear Antigen (PCNA), Recombinant Ki-67 Protein (Ki-67), and CCND1. 16sV3-V4 region microbiota sequencing results indicated that CLG improved dysbiosis, and significantly increased the abundance of Akkermansia bacteria, further promoting the expression of MUC-2 protein and mucin secretion. Additionally, CLG prevented the disruption of intestinal epithelial cell junction proteins Occludin, Claudin-1, ZO-1, and E-cadherin, restored the number of goblet cells, and preserved the integrity of the intestinal mucosal barrier. Further experiments suggested that CLG inhibited abnormal activation of the Wnt/β-catenin pathway, and its potential mechanism in maintaining mucosal barrier integrity might be related to blocking Wnt/β-catenin pathway. CONCLUSIONS This study demonstrates that CLG can inhibit CRC tumor growth by regulating the gut microbiota structure, reducing intestinal inflammation, improving intestinal mucosal barrier function, and inhibiting the complex process of cancer cell proliferation. This provides new clinical insights into the "membrane-oriented" treatment of CRC with CLG.
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Affiliation(s)
- Ting-Ting Tian
- Scientific Research Department, First Affiliated Hospital of Guizhou University of Traditional Chinese Medicine, Guiyang, Guizhou Province, China
| | - Guo Chen
- Scientific Research Department, First Affiliated Hospital of Guizhou University of Traditional Chinese Medicine, Guiyang, Guizhou Province, China
| | - Kai Sun
- Department of Integration of Chinese and Western Medicine, School of Basic Medical Sciences, Peking University, Beijing, China
| | - Xiao-Yi Wang
- Department of Integration of Chinese and Western Medicine, School of Basic Medical Sciences, Peking University, Beijing, China
| | - Yang Liu
- Scientific Research Department, First Affiliated Hospital of Guizhou University of Traditional Chinese Medicine, Guiyang, Guizhou Province, China
| | - Fei-Qing Wang
- Scientific Research Department, First Affiliated Hospital of Guizhou University of Traditional Chinese Medicine, Guiyang, Guizhou Province, China
| | - Bing Yang
- Scientific Research Department, First Affiliated Hospital of Guizhou University of Traditional Chinese Medicine, Guiyang, Guizhou Province, China
| | - Jian Liu
- Department of Integration of Chinese and Western Medicine, School of Basic Medical Sciences, Peking University, Beijing, China
| | - Jing-Yan Han
- Department of Integration of Chinese and Western Medicine, School of Basic Medical Sciences, Peking University, Beijing, China.
| | - Dong-Xin Tang
- Scientific Research Department, First Affiliated Hospital of Guizhou University of Traditional Chinese Medicine, Guiyang, Guizhou Province, China.
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Opperman RCM, Bosch S, Nazmi K, Bikker FJ, Brand HS, Jimenez CR, de Meij TGJ, Dekker E, de Boer NKH, Kaman WE. Detecting Colorectal Neoplasia Using Specific Fecal Fluorogenic Protease-Sensitive Substrates: A Pilot Study. Anal Chem 2024; 96:20239-20246. [PMID: 39665576 DOI: 10.1021/acs.analchem.4c04586] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2024]
Abstract
BACKGROUND identification and removal of advanced adenomas (AA) reduce colorectal cancer (CRC) incidence and potentially mortality. CRC screening often uses fecal immunochemical testing to select high-risk individuals for colonoscopy, despite its low sensitivity for AA and relatively high false-positivity rate. Previous studies have linked proteases to CRC development through their ability to facilitate angiogenesis and immunoregulation. This study aims to identify colorectal neoplasia-associated proteases and their substrates as a potential noninvasive screening test, introducing an innovative application of fecal protease profiling, which has previously been limited to tissue samples. METHODS eighteen fluorogenic substrates were designed based on literature. Proteolytic degradation of these substrates was measured in fecal samples of patients with CRC (n = 12), AA (n = 9), nonadvanced adenomas (n = 10), and controls (n = 14). Substrate degradation was correlated to a matched human proteome data set, and underlying proteases were identified based on their recognition patterns. Experiments with protease inhibitors and ZnCl2 were performed to further characterize the involved proteases. RESULTS in total, 7 of the 18 substrates tested showed a significantly decreased proteolytic degradation in feces from patients with any colorectal neoplasia compared to the control group. The l-aspartic acid-l-glutamic acid substrate (ED) showed significantly decreased degradation in AA and CRC patients. ED degradation significantly decreased with the addition of ZnCl2 and the cysteine protease inhibitor NEM. CONCLUSION we successfully developed colorectal neoplasia-specific fluorogenic substrates, highlighting the ED substrate as a potential substrate for the detection of AA and CRC. Although the responsible proteases require further identification, our results suggest an association with calcium-dependent cysteine proteases.
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Affiliation(s)
- Roza C M Opperman
- Department of Gastroenterology and Hepatology, Amsterdam UMC, Vrije Universiteit Amsterdam, 1081 HV Amsterdam, The Netherlands
- Amsterdam Gastroenterology Endocrinology Metabolism (AGEM) Research Institute, 1081 HV Amsterdam, The Netherlands
- Research Program, Cancer Center Amsterdam, 1081 HV Amsterdam, The Netherlands
| | - Sofie Bosch
- Department of Gastroenterology and Hepatology, Amsterdam UMC, Vrije Universiteit Amsterdam, 1081 HV Amsterdam, The Netherlands
- Amsterdam Gastroenterology Endocrinology Metabolism (AGEM) Research Institute, 1081 HV Amsterdam, The Netherlands
| | - Kamran Nazmi
- Department of Oral Biochemistry, Academic Centre for Dentistry Amsterdam, University of Amsterdam and VU University Amsterdam, Gustav Mahlerlaan 3004, 1081 LA Amsterdam, The Netherlands
| | - Floris J Bikker
- Department of Oral Biochemistry, Academic Centre for Dentistry Amsterdam, University of Amsterdam and VU University Amsterdam, Gustav Mahlerlaan 3004, 1081 LA Amsterdam, The Netherlands
| | - Henk S Brand
- Department of Oral Biochemistry, Academic Centre for Dentistry Amsterdam, University of Amsterdam and VU University Amsterdam, Gustav Mahlerlaan 3004, 1081 LA Amsterdam, The Netherlands
| | - Connie R Jimenez
- Research Program, Cancer Center Amsterdam, 1081 HV Amsterdam, The Netherlands
- Department of Medical Oncology, Amsterdam UMC, VU University Medical Center, 1081 HV Amsterdam, The Netherlands
| | - Tim G J de Meij
- Amsterdam Gastroenterology Endocrinology Metabolism (AGEM) Research Institute, 1081 HV Amsterdam, The Netherlands
- Department of Pediatric Gastroenterology, Emma Children's Hospital, Amsterdam UMC, Vrije Universiteit Amsterdam, 1081 HV Amsterdam, The Netherlands
- Department of Pediatric Gastroenterology, Emma Children's Hospital, Amsterdam UMC, Academic Medical Centre, 1105 AZ Amsterdam, The Netherlands
| | - Evelien Dekker
- Amsterdam Gastroenterology Endocrinology Metabolism (AGEM) Research Institute, 1081 HV Amsterdam, The Netherlands
- Research Program, Cancer Center Amsterdam, 1081 HV Amsterdam, The Netherlands
- Department of Gastroenterology and Hepatology, Amsterdam UMC, University of Amsterdam, 1081 HV Amsterdam, The Netherlands
| | - Nanne K H de Boer
- Department of Gastroenterology and Hepatology, Amsterdam UMC, Vrije Universiteit Amsterdam, 1081 HV Amsterdam, The Netherlands
- Amsterdam Gastroenterology Endocrinology Metabolism (AGEM) Research Institute, 1081 HV Amsterdam, The Netherlands
| | - Wendy E Kaman
- Department of Oral Biochemistry, Academic Centre for Dentistry Amsterdam, University of Amsterdam and VU University Amsterdam, Gustav Mahlerlaan 3004, 1081 LA Amsterdam, The Netherlands
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Thomas CE, Takashima Y, Wesselink E, Ugai T, Steinfelder RS, Buchanan DD, Qu C, Hsu L, Dias Costa A, Gallinger S, Grant RC, Huyghe JR, Thomas SS, Ogino S, Phipps AI, Nowak JA, Peters U. Association between somatic microsatellite instability, hypermutation status, and specific T cell subsets in colorectal cancer tumors. Front Immunol 2024; 15:1505896. [PMID: 39763680 PMCID: PMC11701007 DOI: 10.3389/fimmu.2024.1505896] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2024] [Accepted: 12/03/2024] [Indexed: 01/11/2025] Open
Abstract
Background Microsatellite instability-high (MSI-high) tumors comprise ~15% of sporadic colorectal cancers (CRC) and are associated with elevated T cell infiltration. However, the universality of this response across T cell subtypes with distinct functions is unknown. Methods Including 1,236 CRC tumors from three observational studies, we conducted in-situ T cell profiling using a customized 9-plex (CD3, CD4, CD8, CD45RA, CD45RO, FOXP3, KRT, MKI67, and DAPI) multispectral immunofluorescence assay. MSI status was assessed through polymerase chain reaction or immunohistochemical assays. We used multivariable ordinal logistic regression to estimate odds ratios (OR per increasing quantile) and 95% confidence intervals (CIs) for the association of MSI status with quantiles of T cell densities in either tumor epithelial or stromal tissue areas. Results Compared to microsatellite instability low or microsatellite stable (MSI-low/MSS) tumors, MSI-high status was associated with higher density for the majority of immune subsets (twelve out of eighteen) in both epithelial and stromal tissue areas. The strongest associations were for CD3+CD8+ T cells in epithelial areas [OR (95% CI) for naive, memory, and regulatory subsets = 3.49 (2.57, 4.75); 2.82 (2.10, 3.78); 3.04 (2.24, 4.13), respectively]. Conversely, stromal area CD3+CD4+ memory T cells were inversely associated [OR (95% CI) = 0.68 (0.51, 0.91)]. Discussion MSI-high status was strongly associated with higher densities of most T cell subsets in both epithelial and stromal tissue areas. Our investigation supports efforts to identify patients who may be more likely to respond to current immunotherapy treatments. Significance This study helps us better understand how a clinically relevant tumor phenotype, microsatellite instability status, is related to different functioning T cell densities in colorectal tumors, which may impact future immunotherapy strategies.
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Affiliation(s)
- Claire E. Thomas
- Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, WA, United States
| | - Yasutoshi Takashima
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, United States
| | - Evertine Wesselink
- Division of Human Nutrition and Health, Wageningen University & Research, Wageningen, Netherlands
| | - Tomotaka Ugai
- Program in Molecular Pathological Epidemiology (MPE), Department of Pathology, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, United States
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, United States
- Cancer Epidemiology Program, Dana-Farber/Harvard Cancer Center, Boston, MA, United States
| | - Robert S. Steinfelder
- Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, WA, United States
| | - Daniel D. Buchanan
- Colorectal Oncogenomics Group, Department of Clinical Pathology, Melbourne Medical School, The University of Melbourne, Parkville, VIC, Australia
- University of Melbourne Centre for Cancer Research, The University of Melbourne, Parkville, VIC, Australia
- Genomic Medicine and Family Cancer Clinic, The Royal Melbourne Hospital, Parkville, VIC, Australia
| | - Conghui Qu
- Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, WA, United States
| | - Li Hsu
- Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, WA, United States
- Department of Biostatistics, University of Washington, Seattle, WA, United States
| | - Andressa Dias Costa
- Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, United States
| | - Steven Gallinger
- Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, ON, Canada
| | - Robert C. Grant
- Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada
| | - Jeroen R. Huyghe
- Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, WA, United States
| | - Sushma S. Thomas
- Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, WA, United States
| | - Shuji Ogino
- Program in Molecular Pathological Epidemiology (MPE), Department of Pathology, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, United States
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, United States
- Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA, United States
- Institute of Science Tokyo, Tokyo, Japan
| | - Amanda I. Phipps
- Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, WA, United States
- Department of Epidemiology, University of Washington, Seattle, WA, United States
| | - Jonathan A. Nowak
- Program in Molecular Pathological Epidemiology (MPE), Department of Pathology, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, United States
- Department of Pathology, Dana-Farber Cancer Institute, Boston, MA, United States
| | - Ulrike Peters
- Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, WA, United States
- Department of Epidemiology, University of Washington, Seattle, WA, United States
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Wang S, Peng F, Dang M, Jiao H, Zhang H, Zhou K, Guo W, Gong Z, Guo L, Lu R, Li D, Liu B, Guo X, Xing J, Liu Y. Early detection of colorectal cancer using aberrant circulating cell-free mitochondrial DNA fragmentomics. Gut 2024:gutjnl-2024-333533. [PMID: 39694683 DOI: 10.1136/gutjnl-2024-333533] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/05/2024] [Accepted: 11/26/2024] [Indexed: 12/20/2024]
Abstract
BACKGROUND Early detection of colorectal cancer (CRC) is crucial for improving the survival rates of patients. OBJECTIVE We aimed to develop a novel strategy for early CRC detection using the fragmentomic features of circulating cell-free mitochondrial DNA (ccf-mtDNA). DESIGN Here, a total of 1147 participants, including 478 healthy controls (HCs), 112 patients with advanced adenomas (AAs) and 557 patients with CRC, were enrolled from five hospitals and plasma samples were collected for capture-based ccf-mtDNA sequencing. RESULTS Our data analysis revealed significantly aberrant ccf-mtDNA fragmentomic features in patients with CRC and AA when compared with HCs. Then, a CRC detection (CD) model was constructed based on the fragmentomic features of ccf-mtDNA from 246 patients with CRC and 168 HC in the training cohort, showing area under the curve of 0.9863, sensitivity of 92.68% and specificity of 93.45%. Both internal and two external validation cohorts demonstrated the excellent capacity of CD model in distinguishing patients with early-stage CRC from HCs, greatly surpassing the performance of serum biomarkers. Furthermore, our CD model can also detect patients with AA with a sensitivity of 79.35% in AA cohort 1 and 85.00% in AA cohort 2. CONCLUSION In conclusion, based on aberrant ccf-mtDNA fragmentomic features, a novel and non-invasive approach was established for the detection of patients with early-stage CRC or AA, with high performance.
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Affiliation(s)
- Siyuan Wang
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and Department of Physiology and Pathophysiology, Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Fan Peng
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and Department of Physiology and Pathophysiology, Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Miao Dang
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and Department of Physiology and Pathophysiology, Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Huanmin Jiao
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and Department of Physiology and Pathophysiology, Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Huanqin Zhang
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and Department of Physiology and Pathophysiology, Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Kaixiang Zhou
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and Department of Physiology and Pathophysiology, Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Wenjie Guo
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and Department of Physiology and Pathophysiology, Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Zhiyun Gong
- Department of Clinical Laboratory, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Lin Guo
- Department of Clinical Laboratory, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Renquan Lu
- Department of Clinical Laboratory, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Deliang Li
- Department of Gatroenterology and Hepatology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Bingrong Liu
- Department of Gatroenterology and Hepatology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Xu Guo
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and Department of Physiology and Pathophysiology, Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Jinliang Xing
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and Department of Physiology and Pathophysiology, Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Yang Liu
- Department of Clinical Diagnosis, Tangdu Hospital, Fourth Military Medical University, Xi'an, China
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50
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Obeidat IM, Yahia Y, Chandra P, Altaiam A, Mohamed E, Saffo H, Abualsuod R, Mousa AAD, Shalatouni D, Alsa'ed K, Arabyat MY. Evaluating the necessity of colonoscopy in patients under 40 with rectal bleeding: insights from a large-scale retrospective analysis. Int J Colorectal Dis 2024; 39:202. [PMID: 39680187 PMCID: PMC11649774 DOI: 10.1007/s00384-024-04784-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 12/08/2024] [Indexed: 12/17/2024]
Abstract
PURPOSE Bleeding per rectum (BPR) is a common clinical presentation, and colonoscopy is the gold standard for evaluating patients aged ≥ 45 years. However, its role in younger patients remains unclear. This study evaluated the appropriateness of colonoscopy in patients < 40 years of age who presented with BPR. METHODS This retrospective observational study was conducted over 10 years, including 3422 patients aged 18-40 years who underwent colonoscopy for BPR. The cohort was divided into two age groups: younger (aged 18-30 years) and older (31-40 years). The patients' baseline characteristics, colonoscopy findings, and histopathological results were analyzed. RESULTS Hemorrhoids were the most common finding (48%), with a higher prevalence in younger age groups (50.7%). Polyps were detected in 12.5% of patients, with 1.75% having advanced adenoma polyps (AAP) and 1.3% diagnosed with colorectal cancer (CRC). A family history of CRC/AAP was significantly associated with increased CRC risk (adjusted OR 6.35, 95% CI 2.24-18.02, p = 0.001) in explorative logistic regression analysis. CONCLUSION AAP and CRC were detected in a small but significant proportion of patients, particularly among those aged 18-30 years. The detection of significant lesions in this age group highlights the need for targeted colonoscopy based on specific risk factors such as family history and clinical presentation. Future research should prioritize the creation of targeted assessment models to improve clinical decision making in this context.
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Affiliation(s)
- Ibrahim M Obeidat
- Gastroenterology and Hepatology Department, Hamad Medical Corporation, Doha, Qatar.
| | - Yousef Yahia
- Gastroenterology and Hepatology Department, Hamad Medical Corporation, Doha, Qatar.
| | - Prem Chandra
- Medical Research Centre, Hamad Medical Corporation, Doha, Qatar
| | - Amani Altaiam
- Family Medicine Department, Primary Health Care Corporation, Doha, Qatar
| | - Ethar Mohamed
- Gastroenterology and Hepatology Department, Hamad Medical Corporation, Doha, Qatar
| | - Husam Saffo
- Gastroenterology and Hepatology Department, Hamad Medical Corporation, Doha, Qatar
| | - Raya Abualsuod
- Internal Medicine Department, Hamad Medical Corporation, Doha, Qatar
| | | | - Duha Shalatouni
- Internal Medicine Department, Hamad Medical Corporation, Doha, Qatar
| | - Khaled Alsa'ed
- Internal Medicine Department, Hamad Medical Corporation, Doha, Qatar
| | - Mahmoud Y Arabyat
- Internal Medicine Department, Hamad Medical Corporation, Doha, Qatar
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