1
|
Wettergren Y, Rolny P, Lindegren H, Odin E, Rotter Sopasakis V, Keane S, Ejeskär K. Increased MLH1, MGMT, and p16INK4a methylation levels in colon mucosa potentially useful as early risk marker of colon cancer. Mol Cell Oncol 2025; 12:2503069. [PMID: 40357388 PMCID: PMC12068326 DOI: 10.1080/23723556.2025.2503069] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2025] [Revised: 04/30/2025] [Accepted: 05/01/2025] [Indexed: 05/15/2025]
Abstract
The genes MutL Homolog 1 (MLH1), O6-methylguanine-DNA methyltransferase (MGMT), and cyclin-dependent kinase inhibitor p16INK4a are commonly downregulated by hypermethylation in colorectal cancer. Long interspersed nucleotide element 1 (LINE-1) can be used as marker for global hypomethylation. This study compared MLH1, MGMT, p16INK4a, and LINE-1 methylation with gene expression in colon tumors, matched non-cancerous mucosa, and control mucosa to identify signs of premalignancy. Tissues were obtained from 20 colon cancer patients and 40 controls. CpG site methylation was quantified by pyrosequencing, expression by qPCR, and MSI/KRAS status by fragment analysis and droplet digital PCR. MLH1, MGMT, and p16INK4a methylation was increasingly higher in control mucosa, non-cancerous mucosa, and tumors. MLH1 expression was lower in tumors compared to non-cancerous mucosa but higher compared to control mucosa. Tumoral LINE-1 methylation correlated negatively with MLH1 (r = -0.51, p = .021) and p16INK4a (r = -0.55, p = .012) methylation, but positively (r = 0.74, p = .0002) with MLH1 expression. A p16INK4a SNP (rs3814960 C>T) was associated with methylation, expression, and MSI/KRAS status. Aberrant methylation of tumor suppressor genes in colon mucosa could be an early cancer risk marker. Control mucosa is a more reliable reference than non-cancerous mucosa when identifying premalignant changes. Extended studies will evaluate the possible association between rs3814960 and cancer susceptibility. Trial registration: NCT03072641.
Collapse
Affiliation(s)
- Yvonne Wettergren
- Department of Surgery, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
- Department of Surgery, Region Västra Götaland, Sahlgrenska University Hospital, Gothenburg, Sweden
| | - Peter Rolny
- Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
- Department of Medicine, Division of Gastroenterology and Hepatology, Region Västra Götaland, Sahlgrenska University Hospital/Östra, Gothenburg, Sweden
| | - Helena Lindegren
- Department of Medicine, Division of Gastroenterology and Hepatology, Region Västra Götaland, Sahlgrenska University Hospital/Östra, Gothenburg, Sweden
| | - Elisabeth Odin
- Department of Surgery, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Victoria Rotter Sopasakis
- Department of Clinical Chemistry, Sahlgrenska University Hospital, Gothenburg, Sweden
- Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Simon Keane
- Translational Medicine, School of Health Sciences, University of Skövde, Skövde, Sweden
| | - Katarina Ejeskär
- Translational Medicine, School of Health Sciences, University of Skövde, Skövde, Sweden
| |
Collapse
|
2
|
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.
Collapse
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.
| |
Collapse
|
3
|
Shou S, Maolan A, Zhang D, Jiang X, Liu F, Li Y, Zhang X, Geer E, Pu Z, Hua B, Guo Q, Zhang X, Pang B. Telomeres, telomerase, and cancer: mechanisms, biomarkers, and therapeutics. Exp Hematol Oncol 2025; 14:8. [PMID: 39871386 PMCID: PMC11771031 DOI: 10.1186/s40164-025-00597-9] [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: 01/08/2025] [Accepted: 01/15/2025] [Indexed: 01/29/2025] Open
Abstract
Telomeres and telomerase play crucial roles in the initiation and progression of cancer. As biomarkers, they aid in distinguishing benign from malignant tissues. Despite the promising therapeutic potential of targeting telomeres and telomerase for therapy, translating this concept from the laboratory to the clinic remains challenging. Many candidate drugs remain in the experimental stage, with only a few advancing to clinical trials. This review explores the relationship between telomeres, telomerase, and cancer, synthesizing their roles as biomarkers and reviewing the outcomes of completed trials. We propose that changes in telomere length and telomerase activity can be used to stratify cancer stages. Furthermore, we suggest that differential expression of telomere and telomerase components at the subcellular level holds promise as a biomarker. From a therapeutic standpoint, combining telomerase-targeted therapies with drugs that mitigate the adverse effects of telomerase inhibition may offer a viable strategy.
Collapse
Affiliation(s)
- Songting Shou
- Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Ayidana Maolan
- Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Di Zhang
- Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Xiaochen Jiang
- Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Fudong Liu
- Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Yi Li
- Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Xiyuan Zhang
- Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - En Geer
- Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Zhenqing Pu
- Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Baojin Hua
- Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China.
| | - Qiujun Guo
- Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China.
| | - Xing Zhang
- Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China.
| | - Bo Pang
- Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China.
| |
Collapse
|
4
|
Keshvari A, Tafti SMA, Keramati MR, Fazeli MS, Kazemeini A, Behboudi B, Asbagh RA, Mirzasadeghi A. Preoperative Carcinoembryonic Antigen as a Predictor of 5-Year Survival in Rectal Cancer: Proposing a New Prognostic Cutoff. J Gastrointest Cancer 2025; 56:46. [PMID: 39826023 DOI: 10.1007/s12029-025-01175-2] [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] [Accepted: 01/11/2025] [Indexed: 01/20/2025]
Abstract
PURPOSE Carcinoembryonic antigen (CEA) is an important prognostic factor for rectal cancer. This study aims to introduce a novel cutoff point for CEA within the normal range to improve prognosis prediction and enhance patient stratification in rectal cancer patients. METHODS A total of 316 patients with stages I to III rectal cancer who underwent surgical tumor resection were enrolled. The Cox proportional hazards regression model was used to evaluate the impact of preoperative CEA level and other co-variates on overall survival (OS). The Youden Index method was used for CEA optimal cutoff estimation. RESULTS The mean follow-up period was 46.47 months. In risk-adjusted Cox proportional analysis, higher preoperative CEA levels (HR 1.17, CI 1.131.21; P < 0.001), and T-stage were associated with poor OS. The mean preoperative CEA level was significantly higher in patients with positive lymphovascular invasion (LVI) and perineural invasion (PNI) (CI: 1.06-2.45 and 0.75-2.33, respectively, P < 0.001, t test). Pathologic complete response (pCR) occurred in 71 (22.4%) cases. Patients with pCR had lower levels of preoperative CEA than non-pCR group (P = 0.002, CEApCR-CEAnonpCR = - 1.3; t test). Using Youden Index, the estimated optimal CEA cutoff value for predicting OS was 2.8 ng/mL (sensitivity 90%; specificity 78.5%). Lower preoperative CEA levels predict higher pCR rates, aiding patient stratification and planning. CONCLUSION Preoperative CEA may play a role in the prediction of pCR in rectal cancer. Considering the CEA level of 2.8 ng/ml, as a newly defined cutoff point, patients with a worse prognosis can be identified prior to operation. PNI, along with LVI as independent predictors, may be contemplated as prognostic indicators to improve treatment strategies.
Collapse
Affiliation(s)
- Amir Keshvari
- Colorectal Research Center, Imam Khomeini Hospital complex, Tehran University of Medical Sciences, Keshavarz Blvd, Tehran, Iran
- Division of Colorectal Surgery, Department of Surgery, Tehran University of Medical Sciences, Tehran, Iran
| | - Seyed Mohsen Ahmadi Tafti
- Colorectal Research Center, Imam Khomeini Hospital complex, Tehran University of Medical Sciences, Keshavarz Blvd, Tehran, Iran
- Division of Colorectal Surgery, Department of Surgery, Tehran University of Medical Sciences, Tehran, Iran
| | - Mohammad Reza Keramati
- Colorectal Research Center, Imam Khomeini Hospital complex, Tehran University of Medical Sciences, Keshavarz Blvd, Tehran, Iran
- Division of Colorectal Surgery, Department of Surgery, Tehran University of Medical Sciences, Tehran, Iran
| | - Mohammad Sadegh Fazeli
- Colorectal Research Center, Imam Khomeini Hospital complex, Tehran University of Medical Sciences, Keshavarz Blvd, Tehran, Iran
- Division of Colorectal Surgery, Department of Surgery, Tehran University of Medical Sciences, Tehran, Iran
| | - Alireza Kazemeini
- Colorectal Research Center, Imam Khomeini Hospital complex, Tehran University of Medical Sciences, Keshavarz Blvd, Tehran, Iran
- Division of Colorectal Surgery, Department of Surgery, Tehran University of Medical Sciences, Tehran, Iran
| | - Behnam Behboudi
- Colorectal Research Center, Imam Khomeini Hospital complex, Tehran University of Medical Sciences, Keshavarz Blvd, Tehran, Iran
- Division of Colorectal Surgery, Department of Surgery, Tehran University of Medical Sciences, Tehran, Iran
| | - Reza Akbari Asbagh
- Colorectal Research Center, Imam Khomeini Hospital complex, Tehran University of Medical Sciences, Keshavarz Blvd, Tehran, Iran
- Division of Colorectal Surgery, Department of Surgery, Tehran University of Medical Sciences, Tehran, Iran
| | - Anahita Mirzasadeghi
- Colorectal Research Center, Imam Khomeini Hospital complex, Tehran University of Medical Sciences, Keshavarz Blvd, Tehran, Iran.
- Division of Colorectal Surgery, Department of Surgery, Tehran University of Medical Sciences, Tehran, Iran.
| |
Collapse
|
5
|
Muñoz RA, Ramos AA, Miranda FJ, De La Rosa JE, Muñoz AE, Ramírez AA, Chavez EP, Gallardo G, Pizarro S. Cholecystectomy Is a Risk Factor for Proximal Colon Cancer That May Also Relate to its Aggressiveness. J Surg Res 2024; 304:152-161. [PMID: 39547064 DOI: 10.1016/j.jss.2024.10.018] [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: 04/26/2024] [Revised: 09/22/2024] [Accepted: 10/15/2024] [Indexed: 11/17/2024]
Abstract
INTRODUCTION There are studies with mixed conclusions about the role cholecystectomy plays as a risk factor for proximal colorectal cancer (CRC). METHODS We performed a multicenter retrospective cohort study where the records of patients with CRC were reviewed. Data was collected regarding affected colon subsegment (cecum, ascending, transverse, descending, sigmoid, or rectum, which were also combined into proximal or distal colon), history and time since cholecystectomy, histopathology reports (TNM classification and clinical stage), and KRAS, NRAS, and BRAF mutation analysis. Univariate and multivariate analysis adjusting for age, smoking history, body mass index, sex, and family history of cancer were performed. Logistical regression for statistical analysis was used to estimate the odds ratio for the association between cholecystectomy and tumor location. RESULTS Four hundred four cases were obtained, of which 52 previously had cholecystectomy. The date of surgery was recorded in 43 patients, with a 5 y median and an interquartile range of 1.5-14 y prior to CRC diagnosis. Both crude and adjusted odds ratio (2.86 and 2.42, respectively) confirmed an associated risk for developing proximal CRC after cholecystectomy. When proximal CRC cases with previous cholecystectomy were directly compared against proximal CRC without cholecystectomy and distal CRC cases, the former had a higher distribution of prevalence for T3, T4b, N1b, M1a, and M1c. KRAS mutation also presented its highest prevalence in this group with 33%. CONCLUSIONS Cholecystectomy was related to the development of proximal CRC in all its subsegments, seemingly associated with higher stages at diagnosis. Close surveillance should be considered in patients who undergo cholecystectomy.
Collapse
Affiliation(s)
- Raymundo A Muñoz
- Department of Research and Medical Education, Hospital Angeles Chihuahua, Chihuahua, Mexico; Faculty of Medicine and Biomedical Sciences, Autonomous University of Chihuahua (UACH), Chihuahua, Mexico.
| | - Andrei A Ramos
- Department of General Surgery, Christus Muguerza Hospital del Parque, Chihuahua, Mexico
| | - Francisco J Miranda
- Department of Oncologic Surgery, Christus Muguerza Hospital del Parque, Chihuahua, Mexico
| | - José E De La Rosa
- Medical Program Coordination Office, Faculty of Medicine and Biomedical Sciences, UACH, Chihuahua, Mexico
| | - Alfonzo E Muñoz
- College Of Science, University of Texas at El Paso (UTEP), El Paso, Texas
| | - Aáron A Ramírez
- Department of General Surgery, Christus Muguerza Hospital del Parque, Chihuahua, Mexico
| | - Eva P Chavez
- Plastic Surgery, Private Practice, El Paso, Texas
| | - Guillermo Gallardo
- Department of General Surgery & Endoscopy, Hospital Angeles Chihuahua, Chihuahua, Mexico
| | - Salvador Pizarro
- Department of Rheumatology, Hospital Angeles Chihuahua, Chihuahua, Mexico
| |
Collapse
|
6
|
La Vecchia M, Sala G, Sculco M, Aspesi A, Dianzani I. Genetics, diet, microbiota, and metabolome: partners in crime for colon carcinogenesis. Clin Exp Med 2024; 24:248. [PMID: 39470880 PMCID: PMC11522171 DOI: 10.1007/s10238-024-01505-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: 08/14/2024] [Accepted: 10/15/2024] [Indexed: 11/01/2024]
Abstract
Colorectal cancer (CRC) ranks among the most prevalent malignant tumors worldwide, with a multifactorial etiology encompassing genetic, environmental, and life-style factors, as well as the intestinal microbiota and its metabolome. These risk factors often work together in specific groups of patients, influencing how CRC develops and progresses. Importantly, alterations in the gut microbiota act as a critical nexus in this interplay, significantly affecting susceptibility to CRC. This review highlights recent insights into unmodifiable and modifiable risk factors for CRC and how they might interact with the gut microbiota and its metabolome. Understanding the mechanisms of these interactions will help us develop targeted, precision-medicine strategies that can adjust the composition of the gut microbiota to meet individual health needs, preventing or treating CRC more effectively.
Collapse
Affiliation(s)
- Marta La Vecchia
- Department of Health Sciences, Università del Piemonte Orientale, 28100, Novara, Italy
| | - Gloria Sala
- Department of Health Sciences, Università del Piemonte Orientale, 28100, Novara, Italy
| | - Marika Sculco
- Department of Health Sciences, Università del Piemonte Orientale, 28100, Novara, Italy
| | - Anna Aspesi
- Department of Health Sciences, Università del Piemonte Orientale, 28100, Novara, Italy
| | - Irma Dianzani
- Department of Health Sciences, Università del Piemonte Orientale, 28100, Novara, Italy.
| |
Collapse
|
7
|
Loukopoulou C, Nikolouzakis T, Koliarakis I, Vakonaki E, Tsiaoussis J. Telomere Length and Telomerase Activity as Potential Biomarkers for Gastrointestinal Cancer. Cancers (Basel) 2024; 16:3370. [PMID: 39409990 PMCID: PMC11482595 DOI: 10.3390/cancers16193370] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2024] [Revised: 09/28/2024] [Accepted: 09/29/2024] [Indexed: 10/20/2024] Open
Abstract
Gastrointestinal (GI) cancers, such as colorectal and gastric cancers, pose significant global health challenges due to their high rates of incidence and mortality. Even with advancements in treatment and early detection, many patients still face poor outcomes, highlighting the critical need for new biomarkers and therapeutic targets. Telomere length (TL) and telomerase activity (TA) have gained attention in this context. Telomeres, protective nucleotide sequences at chromosome ends, shorten with each cell division, leading to cellular aging. Telomerase, a ribonucleoprotein enzyme, counteracts this shortening by adding telomeric repeats, a process tightly regulated in normal cells but often dysregulated in cancer. This review critically evaluates the role of TL and TA in the pathogenesis of GI cancers, examining their potential as diagnostic, prognostic, and predictive biomarkers. It explores how alterations in telomere biology contribute to the initiation and progression of GI tumors and assesses the therapeutic implications of targeting telomerase. By integrating findings from diverse studies, this review aims to elucidate the intricate relationship between telomere dynamics and gastrointestinal carcinogenesis, offering insights into how TL and TA could be leveraged to enhance the early detection, treatment, and prognosis of GI cancers.
Collapse
Affiliation(s)
- Christina Loukopoulou
- Department of Anatomy, School of Medicine, University of Crete, 71003 Heraklion, Greece; (C.L.); (T.N.); (I.K.)
| | - Taxiarchis Nikolouzakis
- Department of Anatomy, School of Medicine, University of Crete, 71003 Heraklion, Greece; (C.L.); (T.N.); (I.K.)
| | - Ioannis Koliarakis
- Department of Anatomy, School of Medicine, University of Crete, 71003 Heraklion, Greece; (C.L.); (T.N.); (I.K.)
| | - Elena Vakonaki
- Department of Forensic Sciences and Toxicology, School of Medicine, University of Crete, 71003 Heraklion, Greece;
| | - John Tsiaoussis
- Department of Anatomy, School of Medicine, University of Crete, 71003 Heraklion, Greece; (C.L.); (T.N.); (I.K.)
| |
Collapse
|
8
|
Cornish AJ, Gruber AJ, Kinnersley B, Chubb D, Frangou A, Caravagna G, Noyvert B, Lakatos E, Wood HM, Thorn S, Culliford R, Arnedo-Pac C, Househam J, Cross W, Sud A, Law P, Leathlobhair MN, Hawari A, Woolley C, Sherwood K, Feeley N, Gül G, Fernandez-Tajes J, Zapata L, Alexandrov LB, Murugaesu N, Sosinsky A, Mitchell J, Lopez-Bigas N, Quirke P, Church DN, Tomlinson IPM, Sottoriva A, Graham TA, Wedge DC, Houlston RS. The genomic landscape of 2,023 colorectal cancers. Nature 2024; 633:127-136. [PMID: 39112709 PMCID: PMC11374690 DOI: 10.1038/s41586-024-07747-9] [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: 11/14/2022] [Accepted: 06/24/2024] [Indexed: 08/17/2024]
Abstract
Colorectal carcinoma (CRC) is a common cause of mortality1, but a comprehensive description of its genomic landscape is lacking2-9. Here we perform whole-genome sequencing of 2,023 CRC samples from participants in the UK 100,000 Genomes Project, thereby providing a highly detailed somatic mutational landscape of this cancer. Integrated analyses identify more than 250 putative CRC driver genes, many not previously implicated in CRC or other cancers, including several recurrent changes outside the coding genome. We extend the molecular pathways involved in CRC development, define four new common subgroups of microsatellite-stable CRC based on genomic features and show that these groups have independent prognostic associations. We also characterize several rare molecular CRC subgroups, some with potential clinical relevance, including cancers with both microsatellite and chromosomal instability. We demonstrate a spectrum of mutational profiles across the colorectum, which reflect aetiological differences. These include the role of Escherichia colipks+ colibactin in rectal cancers10 and the importance of the SBS93 signature11-13, which suggests that diet or smoking is a risk factor. Immune-escape driver mutations14 are near-ubiquitous in hypermutant tumours and occur in about half of microsatellite-stable CRCs, often in the form of HLA copy number changes. Many driver mutations are actionable, including those associated with rare subgroups (for example, BRCA1 and IDH1), highlighting the role of whole-genome sequencing in optimizing patient care.
Collapse
Affiliation(s)
- Alex J Cornish
- Division of Genetics and Epidemiology, Institute of Cancer Research, London, UK
| | - Andreas J Gruber
- Department of Biology, University of Konstanz, Konstanz, Germany
- Manchester Cancer Research Centre, Division of Cancer Sciences, University of Manchester, Manchester, UK
| | - Ben Kinnersley
- Division of Genetics and Epidemiology, Institute of Cancer Research, London, UK
- University College London Cancer Institute, London, UK
| | - Daniel Chubb
- Division of Genetics and Epidemiology, Institute of Cancer Research, London, UK
| | - Anna Frangou
- Big Data Institute, Nuffield Department of Medicine, University of Oxford, Oxford, UK
- Max Planck Institute for Molecular Cell Biology and Genetics, Dresden, Germany
| | - Giulio Caravagna
- Department of Mathematics and Geosciences, University of Trieste, Trieste, Italy
- Centre for Evolution and Cancer, Institute of Cancer Research, London, UK
| | - Boris Noyvert
- Cancer Research UK Centre and Centre for Computational Biology, Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK
| | - Eszter Lakatos
- Centre for Evolution and Cancer, Institute of Cancer Research, London, UK
- Department of Mathematical Sciences, Chalmers University of Technology, Gothenburg, Sweden
| | - Henry M Wood
- Pathology and Data Analytics, Leeds Institute of Medical Research at St James's, University of Leeds, Leeds, UK
| | - Steve Thorn
- Department of Oncology, University of Oxford, Oxford, UK
| | - Richard Culliford
- Division of Genetics and Epidemiology, Institute of Cancer Research, London, UK
| | - Claudia Arnedo-Pac
- Institute for Research in Biomedicine Barcelona, The Barcelona Institute of Science and Technology, Barcelona, Spain
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Barcelona, Spain
- Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain
| | - Jacob Househam
- Centre for Evolution and Cancer, Institute of Cancer Research, London, UK
| | - William Cross
- Centre for Evolution and Cancer, Institute of Cancer Research, London, UK
- Research Department of Pathology, University College London, UCL Cancer Institute, London, UK
| | - Amit Sud
- Division of Genetics and Epidemiology, Institute of Cancer Research, London, UK
| | - Philip Law
- Division of Genetics and Epidemiology, Institute of Cancer Research, London, UK
| | | | - Aliah Hawari
- Manchester Cancer Research Centre, Division of Cancer Sciences, University of Manchester, Manchester, UK
| | - Connor Woolley
- Department of Oncology, University of Oxford, Oxford, UK
| | - Kitty Sherwood
- Department of Oncology, University of Oxford, Oxford, UK
- Edinburgh Cancer Research, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK
| | - Nathalie Feeley
- Department of Oncology, University of Oxford, Oxford, UK
- Edinburgh Cancer Research, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK
| | - Güler Gül
- Edinburgh Cancer Research, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK
| | | | - Luis Zapata
- Centre for Evolution and Cancer, Institute of Cancer Research, London, UK
| | - Ludmil B Alexandrov
- Department of Cellular and Molecular Medicine, UC San Diego, La Jolla, CA, USA
- Department of Bioengineering, UC San Diego, La Jolla, CA, USA
- Moores Cancer Center, UC San Diego, La Jolla, CA, USA
| | - Nirupa Murugaesu
- Genomics England, William Harvey Research Institute, Queen Mary University of London, London, UK
| | - Alona Sosinsky
- Genomics England, William Harvey Research Institute, Queen Mary University of London, London, UK
| | - Jonathan Mitchell
- Genomics England, William Harvey Research Institute, Queen Mary University of London, London, UK
| | - Nuria Lopez-Bigas
- Institute for Research in Biomedicine Barcelona, The Barcelona Institute of Science and Technology, Barcelona, Spain
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Barcelona, Spain
- Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain
| | - Philip Quirke
- Pathology and Data Analytics, Leeds Institute of Medical Research at St James's, University of Leeds, Leeds, UK
| | - David N Church
- Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK
- Oxford NIHR Comprehensive Biomedical Research Centre, Oxford University Hospitals NHS Foundation Trust, Oxford, UK
| | | | - Andrea Sottoriva
- Centre for Evolution and Cancer, Institute of Cancer Research, London, UK
- Computational Biology Research Centre, Human Technopole, Milan, Italy
| | - Trevor A Graham
- Centre for Evolution and Cancer, Institute of Cancer Research, London, UK
| | - David C Wedge
- Manchester Cancer Research Centre, Division of Cancer Sciences, University of Manchester, Manchester, UK
| | - Richard S Houlston
- Division of Genetics and Epidemiology, Institute of Cancer Research, London, UK
| |
Collapse
|
9
|
Radić J, Nikolić I, Kolarov-Bjelobrk I, Vasiljević T, Djurić A, Vidović V, Kožik B. Prognostic and Predictive Significance of Primary Tumor Localization and HER2 Expression in the Treatment of Patients with KRAS Wild-Type Metastatic Colorectal Cancer: Single-Centre Experience from Serbia. J Pers Med 2024; 14:879. [PMID: 39202071 PMCID: PMC11355236 DOI: 10.3390/jpm14080879] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2024] [Revised: 08/02/2024] [Accepted: 08/15/2024] [Indexed: 09/03/2024] Open
Abstract
The treatment of patients with metastatic colorectal cancer (mCRC) is complex and is impacted by the location of the primary tumor (LPT). Our study aims to emphasize the importance of LPT as a prognostic and predictive marker as well as to examine the significance of HER2 overexpression in patients with mCRC, particularly in relation to the response to Epidermal Growth Factor Receptor Antibody treatment (anti-EGFR therapy). In this study, 181 patients with Kirsten RAS (KRAS) wild-type mCRC who received anti-EGFR therapy were included. Among them, 101 had left colon cancer (LCC) and 80 had right colon cancer (RCC). Results demonstrated that patients with KRAS wild-type LCC had better median overall survival (OS) (43 vs. 33 months, p = 0.005) and progression-free survival (PFS) (6 vs. 3 months, p < 0.001) compared to those with RCC. Multivariate analysis identified mucinous adenocarcinoma (p < 0.001), RCC location (p = 0.022), perineural invasion (p = 0.034), and tumors at the resection margin (p = 0.001) as independent predictors of OS, while mucinous adenocarcinoma (p = 0.001) and RCC location (p = 0.004) independently correlated with significantly shorter PFS. In addition, human epidermal growth factor receptor 2 (HER2) positive expression was significantly associated with worse PFS compared to HER2 negative results (p < 0.001). In conclusion, LPT is an important marker for predicting outcomes in the treatment of wild-type mCRC using anti-EGFR therapy, since patients with RCC have a statistically significantly shorter PFS and OS. Further investigation is needed to understand the role of HER2 overexpression in wild-type mCRC, as these patients also exhibit shorter survival.
Collapse
Affiliation(s)
- Jelena Radić
- Faculty of Medicine, University of Novi Sad, 21000 Novi Sad, Serbia; (J.R.); (I.N.); (I.K.-B.); (T.V.)
- Department of Medical Oncology, Oncology Institute of Vojvodina, 21204 Sremska Kamenica, Serbia; (A.D.); (V.V.)
| | - Ivan Nikolić
- Faculty of Medicine, University of Novi Sad, 21000 Novi Sad, Serbia; (J.R.); (I.N.); (I.K.-B.); (T.V.)
- Department of Medical Oncology, Oncology Institute of Vojvodina, 21204 Sremska Kamenica, Serbia; (A.D.); (V.V.)
| | - Ivana Kolarov-Bjelobrk
- Faculty of Medicine, University of Novi Sad, 21000 Novi Sad, Serbia; (J.R.); (I.N.); (I.K.-B.); (T.V.)
- Department of Medical Oncology, Oncology Institute of Vojvodina, 21204 Sremska Kamenica, Serbia; (A.D.); (V.V.)
| | - Tijana Vasiljević
- Faculty of Medicine, University of Novi Sad, 21000 Novi Sad, Serbia; (J.R.); (I.N.); (I.K.-B.); (T.V.)
- Department of Pathology and Laboratory Diagnostic, Oncology Institute of Vojvodina, 21204 Sremska Kamenica, Serbia
| | - Aleksandar Djurić
- Department of Medical Oncology, Oncology Institute of Vojvodina, 21204 Sremska Kamenica, Serbia; (A.D.); (V.V.)
| | - Vladimir Vidović
- Department of Medical Oncology, Oncology Institute of Vojvodina, 21204 Sremska Kamenica, Serbia; (A.D.); (V.V.)
| | - Bojana Kožik
- Laboratory for Radiobiology and Molecular Genetics, Vinča Institute of Nuclear Sciences, National Institute of Republic of Serbia, University of Belgrade, 11000 Belgrade, Serbia
| |
Collapse
|
10
|
Puspitaningtyas H, Hutajulu SH, Fachiroh J, Anggorowati N, Sanjaya GY, Lazuardi L, Sripan P. Diverging likelihood of colon and rectal cancer in Yogyakarta, Indonesia: A cross sectional study. PLoS One 2024; 19:e0301191. [PMID: 38547083 PMCID: PMC10977797 DOI: 10.1371/journal.pone.0301191] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2023] [Accepted: 03/11/2024] [Indexed: 04/02/2024] Open
Abstract
OBJECTIVES Colon and rectal cancer are associated with different risk factors and prognostic. However, this discrepancy has not been widely explored in the local population. This study aimed to investigate the site-specific likelihood of colorectal cancer (CRC) incidence in the Yogyakarta province, Indonesia. METHODS This cross-sectional study analyses 1,295 CRC cases diagnosed in 2008-2019 registered in the Yogyakarta population-based cancer registry (PBCR) database. Cases were grouped into colon and rectal cancer. Log-binomial regression was used to determine the relative risk of either colon or rectal cancer across different gender, age group, and rurality of residence. The age-specific rates were calculated by age group and temporal trend for each group were analyzed using joinpoint regression. RESULTS Females displayed higher odds of colon cancer (relative risk/RR = 1.20, 95%CI = 1.02-1.41) and lower odds of rectal cancer (RR = 0.92, 95%CI = 0.85-0.99). Elevated odds of colon cancer were observed in younger age group, especially 30-39 (RR = 1.87, 95%CI = 1.10-3.19), while decreased odds of rectal cancer was apparent in age group 30-39 and 40-49 (RR = 0.75, 95%CI = 0.60-0.93 and RR = 0.82, 95%CI = 0.69-0.98, respectively). Living in urban or rural areas did not significantly influence the odds of either having colon (RR = 0.98, 95%CI = 0.82-1.17) or rectal cancer (RR = 1.01, 95%CI = 0.93-1.10). During 2008-2019, trends of colon cancer in age <50 increased by 8.15% annually while rectal cancer displayed a 9.71% increase annually prior to 2017, followed by a 17.23% decrease until 2019. CONCLUSIONS Yogyakarta population shows higher odds of young-onset colon cancer, especially between age 30-39 years old. Overall observation of trend shows increasing incidence in young-onset colon cancer, and non-significant decrease in rectal cancer.
Collapse
Affiliation(s)
- Herindita Puspitaningtyas
- Faculty of Medicine, Public Health and Nursing, Doctorate Program of Health and Medical Science, Universitas Gadjah Mada, Yogyakarta, Indonesia
| | - Susanna Hilda Hutajulu
- Faculty of Medicine, Public Health and Nursing, Department of Internal Medicine, Division of Hematology and Medical Oncology, Universitas Gadjah Mada/Dr. Sardjito General Hospital, Yogyakarta, Indonesia
| | - Jajah Fachiroh
- Faculty of Medicine, Public Health and Nursing, Department of Histology and Cell Biology, Universitas Gadjah Mada, Yogyakarta, Indonesia
| | - Nungki Anggorowati
- Faculty of Medicine, Public Health and Nursing, of Anatomical Pathology, Universitas Gadjah Mada, Yogyakarta, Indonesia
| | - Guardian Yoki Sanjaya
- Faculty of Medicine, Public Health and Nursing, of Health Policy and Management, Universitas Gadjah Mada, Yogyakarta, Indonesia
| | - Lutfan Lazuardi
- Faculty of Medicine, Public Health and Nursing, of Health Policy and Management, Universitas Gadjah Mada, Yogyakarta, Indonesia
| | - Patumrat Sripan
- Research Institute for Health Sciences, Chiang Mai University, Chiang Mai, Thailand
| |
Collapse
|
11
|
Yadav R, Bhawale R, Srivastava V, Pardhi E, Bhalerao HA, Sonti R, Mehra NK. Innovative Nanoparticulate Strategies in Colon Cancer Treatment: A Paradigm Shift. AAPS PharmSciTech 2024; 25:52. [PMID: 38429601 DOI: 10.1208/s12249-024-02759-0] [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: 12/14/2023] [Accepted: 02/06/2024] [Indexed: 03/03/2024] Open
Abstract
As a major public health issue, colorectal cancer causes 9.4% of total cancer-related deaths and comprises 10% of new cancer diagnoses worldwide. In the year 2023, an estimated 153,020 people are expected to receive an identification of colorectal cancer (CRC), resulting in roughly 52,550 fatalities anticipated as a result of this illness. Among those impacted, approximately 19,550 cases and 3750 deaths are projected to occur in individuals under the age of 50. Irinotecan (IRN) is a compound derived from the chemical structure of camptothecin, a compound known for its action in inhibiting DNA topoisomerase I. It is employed in the treatment strategy for CRC therapies. Comprehensive in vivo and in vitro studies have robustly substantiated the anticancer efficacy of these compounds against colon cancer cell lines. Blending irinotecan in conjunction with other therapeutic cancer agents such as oxaliplatin, imiquimod, and 5 fluorouracil enhanced cytotoxicity and improved chemotherapeutic efficacy. Nevertheless, it is linked to certain serious complications and side effects. Utilizing nano-formulated prodrugs within "all-in-one" carrier-free self-assemblies presents an effective method to modify the pharmacokinetics and safety portfolio of cytotoxic chemotherapeutics. This review focuses on elucidating the mechanism of action, exploring synergistic effects, and innovating novel delivery approaches to enhance the therapeutic efficacy of irinotecan.
Collapse
Affiliation(s)
- Rati Yadav
- Pharmaceutical Nanotechnology Research Laboratory, Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research, Hyderabad, Telangana, 500 037, India
| | - Rohit Bhawale
- Pharmaceutical Nanotechnology Research Laboratory, Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research, Hyderabad, Telangana, 500 037, India
| | - Vaibhavi Srivastava
- Pharmaceutical Nanotechnology Research Laboratory, Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research, Hyderabad, Telangana, 500 037, India
| | - Ekta Pardhi
- Pharmaceutical Nanotechnology Research Laboratory, Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research, Hyderabad, Telangana, 500 037, India
| | - Harshada Anil Bhalerao
- Department of Pharmaceutical Analysis, National Institute of Pharmaceutical Education and Research, Hyderabad, Telangana, India
| | - Rajesh Sonti
- Department of Pharmaceutical Analysis, National Institute of Pharmaceutical Education and Research, Hyderabad, Telangana, India
| | - Neelesh Kumar Mehra
- Pharmaceutical Nanotechnology Research Laboratory, Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research, Hyderabad, Telangana, 500 037, India.
| |
Collapse
|
12
|
Barber LE, Bertrand KA, Sheehy S, White LF, Roy HK, Rosenberg L, Palmer JR, Petrick JL. Aspirin and nonaspirin nonsteroidal antiinflammatory drug use and occurrence of colorectal adenoma in Black American women. Int J Cancer 2023; 153:1978-1987. [PMID: 37555819 PMCID: PMC10927007 DOI: 10.1002/ijc.34674] [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: 01/23/2023] [Revised: 06/28/2023] [Accepted: 06/29/2023] [Indexed: 08/10/2023]
Abstract
Evidence suggests that aspirin use reduces the occurrence of colorectal neoplasia. Few studies have investigated the association among Black Americans, who are disproportionately burdened by the disease. We assessed aspirin use in relation to colorectal adenoma among Black women. The Black Women's Health Study is a prospective cohort of self-identified Black American women established in 1995. Participants reported regular aspirin use on baseline and follow-up questionnaires. Beginning in 1999, participants reported undergoing a colonoscopy or sigmoidoscopy, the only procedures through which colorectal adenomas can be diagnosed. Multivariable logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI) for associations between aspirin use and colorectal adenoma among 34 397 women who reported at least 1 colonoscopy or sigmoidoscopy. From 1997 through 2018, 1913 women were diagnosed with an adenoma. Compared to nonaspirin users, regular users had 14% (OR = 0.86, 95% CI: 0.78-0.95) lower odds of adenoma. The odds of adenoma decreased with increasing duration of aspirin use (≥10 years: OR = 0.80, 95% CI: 0.66-0.96). Initiating aspirin at a younger age was associated with a reduced adenoma occurrence (age < 40 years at initiation: OR = 0.69, 95% CI: 0.55-0.86). Regular aspirin use was associated with a decreased odds of colorectal adenoma in our study of Black women. These findings support evidence demonstrating a chemopreventive impact of aspirin on colorectal neoplasia and suggest that aspirin may be a useful prevention strategy among US Black women.
Collapse
Affiliation(s)
- Lauren E. Barber
- Department of Epidemiology, Boston University School of Public Health, Boston, MA
- Slone Epidemiology Center at Boston University, Boston, MA
- Department of Epidemiology, Emory University Rollins School of Public Health, Atlanta, GA
| | | | | | - Laura F. White
- Department of Biostatistics, Boston University School of Public Health, Boston, MA
| | - Hemant K. Roy
- Department of Medicine, Baylor College of Medicine, Houston, TX
| | - Lynn Rosenberg
- Slone Epidemiology Center at Boston University, Boston, MA
| | | | | |
Collapse
|
13
|
Gil-Kulik P, Petniak A, Kluz N, Wallner G, Skoczylas T, Ciechański A, Kocki J. Influence of Clinical Factors on miR-3613-3p Expression in Colorectal Cancer. Int J Mol Sci 2023; 24:14023. [PMID: 37762323 PMCID: PMC10531160 DOI: 10.3390/ijms241814023] [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: 08/01/2023] [Revised: 09/07/2023] [Accepted: 09/11/2023] [Indexed: 09/29/2023] Open
Abstract
Colorectal cancer (CRC) is the second most common cause of cancer-related death globally. Because of a tendency to be an asymptomatic primary tumor and therefore resulting in late detection, most CRC patients are diagnosed in the advanced stage. Several miRNAs have the potential to become novel noninvasive biomarkers measured as diagnostic and prognostic indicators of CRC to guide surgical therapies and promote the understanding of the carcinogenesis of CRC. Since the change of miR-3613-3p was associated with several types of cancer other than colorectal cancer, there is a lack of functional evidence and the results are inconsistent. We conducted a pilot microarray study in which we noted a decreased expression of miR-3613-3p in colorectal cancer cells, then we confirmed the expression of miR-3613-3p by qPCR on a group of 83 patients, including 65 patients with colorectal cancer, 5 with a benign tumor and 13 from the control group. We noted that in both malignant and benign tumors, miR-3613-3p is downgraded relative to the surrounding tissue. As a result of the study, we also observed colorectal tumor tissue and surrounding tissue in patients with colorectal cancer who received radiotherapy before surgery, which showed a significantly higher expression of miR-3613-3p compared to patients who did not receive radiotherapy. In addition, we noted that the tissue surrounding the tumor in patients with distant metastases showed a significantly higher expression of miR-3613-3p compared to patients without distant metastases. The increased expression of miR-3613-3p in patients after radiotherapy suggests the possibility of using this miR as a therapeutic target for CRC, but this requires confirmation in further studies.
Collapse
Affiliation(s)
- Paulina Gil-Kulik
- Department of Clinical Genetics, Medical University of Lublin, 11 Radziwillowska Str., 20-080 Lublin, Poland; (N.K.); (J.K.)
| | - Alicja Petniak
- Department of Clinical Genetics, Medical University of Lublin, 11 Radziwillowska Str., 20-080 Lublin, Poland; (N.K.); (J.K.)
| | - Natalia Kluz
- Department of Clinical Genetics, Medical University of Lublin, 11 Radziwillowska Str., 20-080 Lublin, Poland; (N.K.); (J.K.)
| | - Grzegorz Wallner
- II Chair and Department of General and Gastrointestinal Surgery and Surgical Oncology of the Alimentary Tract, 16 Staszica Str., 20-081 Lublin, Poland; (G.W.); (T.S.); (A.C.)
| | - Tomasz Skoczylas
- II Chair and Department of General and Gastrointestinal Surgery and Surgical Oncology of the Alimentary Tract, 16 Staszica Str., 20-081 Lublin, Poland; (G.W.); (T.S.); (A.C.)
| | - Aleksander Ciechański
- II Chair and Department of General and Gastrointestinal Surgery and Surgical Oncology of the Alimentary Tract, 16 Staszica Str., 20-081 Lublin, Poland; (G.W.); (T.S.); (A.C.)
| | - Janusz Kocki
- Department of Clinical Genetics, Medical University of Lublin, 11 Radziwillowska Str., 20-080 Lublin, Poland; (N.K.); (J.K.)
| |
Collapse
|
14
|
Gu Q, Wu J, Xu H, Cao H, Zhang J, Jing C, Wang Z, Du M, Ma R, Feng J. CLASRP oncogene as a novel target for colorectal cancer. Funct Integr Genomics 2023; 23:290. [PMID: 37658940 PMCID: PMC10474993 DOI: 10.1007/s10142-023-01208-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2023] [Revised: 08/04/2023] [Accepted: 08/11/2023] [Indexed: 09/05/2023]
Abstract
Clk4-associated serine/arginine-rich protein (CLASRP), an alternative splicing regulator, may be involved in the development and progression of cancer by regulating the activity of the CDC-like kinase (Clk) family. This study explored the biological function of CLASRP in colorectal cancer (CRC). The expression of CLASRP, which is associated with clinicopathological features, was analysed in CRC tissues and paired noncancer tissues by RT-PCR. The roles of CLASRP were investigated in CRC cells transfected with plasmids or shRNA through proliferation, migration and invasion assays in vitro and a xenograft model in vivo. Apoptosis was analysed using CLASRP-overexpressing CRC cells by western blotting. Clk inhibitors were used to perform functional research on CLASRP in CLASRP-overexpressing CRC cells. CLASRP was significantly upregulated in CRC cell lines, while high CLASRP expression was correlated with metastasis in CRC patients. Functionally, overexpression of CLASRP significantly promoted the proliferation, migration and invasion of CRC cells in vitro and tumour growth in vivo. Mechanistically, the proliferation, migration and invasion of CLASRP-overexpressing CRC cells were inhibited by Clk inhibitors, accompanied by low expression of CLASRP at the gene and protein levels. Clk inhibitors induced apoptosis of CLASRP-overexpressing CRC cells, resulting in direct blockade of cell growth. The expression levels of cleaved caspase 3 and cleaved caspase 8 were increased in CLASRP-overexpressing CRC cells treated with Clk inhibitors. CLASRP might serve as a promotional oncogene in CRC cells and be suppressed by Clk inhibitors through activation of caspase pathways.
Collapse
Affiliation(s)
- Quan Gu
- Nanjing Medical University Affiliated Cancer Hospital and Research Center for Clinical Oncology, Jiangsu Cancer Hospital and Jiangsu Institute of Cancer Research, 42 BaiZiTing Road, Nanjing, Jiangsu, 210000, People's Republic of China
| | - Jianzhong Wu
- Nanjing Medical University Affiliated Cancer Hospital and Research Center for Clinical Oncology, Jiangsu Cancer Hospital and Jiangsu Institute of Cancer Research, 42 BaiZiTing Road, Nanjing, Jiangsu, 210000, People's Republic of China
| | - Heng Xu
- Jiangsu Provincial Institute of Materia Medica, Nanjing Tech University, Nanjing, Jiangsu, China
| | - Haixia Cao
- Nanjing Medical University Affiliated Cancer Hospital and Research Center for Clinical Oncology, Jiangsu Cancer Hospital and Jiangsu Institute of Cancer Research, 42 BaiZiTing Road, Nanjing, Jiangsu, 210000, People's Republic of China
| | - Junying Zhang
- Nanjing Medical University Affiliated Cancer Hospital and Research Center for Clinical Oncology, Jiangsu Cancer Hospital and Jiangsu Institute of Cancer Research, 42 BaiZiTing Road, Nanjing, Jiangsu, 210000, People's Republic of China
| | - Changwen Jing
- Nanjing Medical University Affiliated Cancer Hospital and Research Center for Clinical Oncology, Jiangsu Cancer Hospital and Jiangsu Institute of Cancer Research, 42 BaiZiTing Road, Nanjing, Jiangsu, 210000, People's Republic of China
| | - Zhuo Wang
- Nanjing Medical University Affiliated Cancer Hospital and Research Center for Clinical Oncology, Jiangsu Cancer Hospital and Jiangsu Institute of Cancer Research, 42 BaiZiTing Road, Nanjing, Jiangsu, 210000, People's Republic of China
| | - Mengjie Du
- Jiangsu Provincial Institute of Materia Medica, Nanjing Tech University, Nanjing, Jiangsu, China
| | - Rong Ma
- Nanjing Medical University Affiliated Cancer Hospital and Research Center for Clinical Oncology, Jiangsu Cancer Hospital and Jiangsu Institute of Cancer Research, 42 BaiZiTing Road, Nanjing, Jiangsu, 210000, People's Republic of China.
| | - Jifeng Feng
- Nanjing Medical University Affiliated Cancer Hospital and Research Center for Clinical Oncology, Jiangsu Cancer Hospital and Jiangsu Institute of Cancer Research, 42 BaiZiTing Road, Nanjing, Jiangsu, 210000, People's Republic of China.
| |
Collapse
|
15
|
Aberrant HMGA2 Expression Sustains Genome Instability That Promotes Metastasis and Therapeutic Resistance in Colorectal Cancer. Cancers (Basel) 2023; 15:cancers15061735. [PMID: 36980621 PMCID: PMC10046046 DOI: 10.3390/cancers15061735] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2023] [Revised: 03/06/2023] [Accepted: 03/11/2023] [Indexed: 03/16/2023] Open
Abstract
Colorectal cancer (CRC) is one of the most lethal cancers worldwide, accounting for nearly ~10% of all cancer diagnoses and deaths. Current therapeutic approaches have considerably increased survival for patients diagnosed at early stages; however, ~20% of CRC patients are diagnosed with late-stage, metastatic CRC, where 5-year survival rates drop to 6–13% and treatment options are limited. Genome instability is an enabling hallmark of cancer that confers increased acquisition of genetic alterations, mutations, copy number variations and chromosomal rearrangements. In that regard, research has shown a clear association between genome instability and CRC, as the accumulation of aberrations in cancer-related genes provides subpopulations of cells with several advantages, such as increased proliferation rates, metastatic potential and therapeutic resistance. Although numerous genes have been associated with CRC, few have been validated as predictive biomarkers of metastasis or therapeutic resistance. A growing body of evidence suggests a member of the High-Mobility Group A (HMGA) gene family, HMGA2, is a potential biomarker of metastatic spread and therapeutic resistance. HMGA2 is expressed in embryonic tissues and is frequently upregulated in aggressively growing cancers, including CRC. As an architectural, non-histone chromatin binding factor, it initiates chromatin decompaction to facilitate transcriptional regulation. HMGA2 maintains the capacity for stem cell renewal in embryonic and cancer tissues and is a known promoter of epithelial-to-mesenchymal transition in tumor cells. This review will focus on the known molecular mechanisms by which HMGA2 exerts genome protective functions that contribute to cancer cell survival and chemoresistance in CRC.
Collapse
|
16
|
Kazakova E, Rakina M, Sudarskikh T, Iamshchikov P, Tarasova A, Tashireva L, Afanasiev S, Dobrodeev A, Zhuikova L, Cherdyntseva N, Kzhyshkowska J, Larionova I. Angiogenesis regulators S100A4, SPARC and SPP1 correlate with macrophage infiltration and are prognostic biomarkers in colon and rectal cancers. Front Oncol 2023; 13:1058337. [PMID: 36895491 PMCID: PMC9989292 DOI: 10.3389/fonc.2023.1058337] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2022] [Accepted: 01/11/2023] [Indexed: 02/23/2023] Open
Abstract
Introduction Increasing evidence suggests that it is necessary to find effective and robust clinically validated prognostic biomarkers that can identify "high-risk" colorectal cancer (CRC) patients. Currently, available prognostic factors largely include clinical-pathological parameters and focus on the cancer stage at the time of diagnosis. Among cells of tumor microenvironment (TME) only Immunoscore classifier based on T lymphocytes showed high predictive value. Methods In the present study, we performed the complex analysis of mRNA and protein expression of crucial regulators of tumor angiogenesis and tumor progression, expressed by tumor-associated macrophages (TAMs): S100A4, SPP1 and SPARC. Colon and rectal cancer patients were investigated independently and in a combined cohort (CRC). For mRNA expression, we analyzed RNA sequencing data obtained from TCGA (N=417) and GEO (N=92) cohorts of colorectal cancer patients. For protein expression, we performed IHC digital quantification of tumor tissues obtained from 197 patients with CRC treated in the Department of abdominal oncology in Clinics of Tomsk NRMC. Results High S100A4 mRNA expression accurately predicted poor survival for patients with CRC independently of cancer type. SPARC mRNA level was independent prognostic factors for survival in colon but not in rectal cancer. SPP1 mRNA level had significant predictive value for survival in both rectal and colon cancers. Analysis of human CRC tissues revealed that S100A4, SPP1 and SPARC are expressed by stromal compartments, in particular by TAMs, and have a strong correlation with macrophage infiltration. Finally, our results indicate that chemotherapy-based treatment can change the predictive direction of S100A4 for rectal cancer patients. We found that S100A4 stromal levels were higher in patients with better response to neoadjuvant chemotherapy/chemoradiotherapy, and S100A4 mRNA levels predicted better DFS among non-responders. Discussion These findings can help improve the prognosis of patients with CRC based on S100A4, SPP1 and SPARC expression levels.
Collapse
Affiliation(s)
- Elena Kazakova
- Laboratory of Translational Cellular and Molecular Biomedicine, Tomsk State University, Tomsk, Russia
- Cancer Research Institute, Tomsk National Research Medical Center, Russian Academy of Sciences, Tomsk, Russia
| | - Militsa Rakina
- Laboratory of Translational Cellular and Molecular Biomedicine, Tomsk State University, Tomsk, Russia
- Cancer Research Institute, Tomsk National Research Medical Center, Russian Academy of Sciences, Tomsk, Russia
| | - Tatiana Sudarskikh
- Laboratory of Translational Cellular and Molecular Biomedicine, Tomsk State University, Tomsk, Russia
| | - Pavel Iamshchikov
- Laboratory of Translational Cellular and Molecular Biomedicine, Tomsk State University, Tomsk, Russia
- Cancer Research Institute, Tomsk National Research Medical Center, Russian Academy of Sciences, Tomsk, Russia
| | - Anna Tarasova
- Cancer Research Institute, Tomsk National Research Medical Center, Russian Academy of Sciences, Tomsk, Russia
| | - Liubov Tashireva
- Cancer Research Institute, Tomsk National Research Medical Center, Russian Academy of Sciences, Tomsk, Russia
| | - Sergei Afanasiev
- Cancer Research Institute, Tomsk National Research Medical Center, Russian Academy of Sciences, Tomsk, Russia
| | - Alexei Dobrodeev
- Cancer Research Institute, Tomsk National Research Medical Center, Russian Academy of Sciences, Tomsk, Russia
| | - Lilia Zhuikova
- Cancer Research Institute, Tomsk National Research Medical Center, Russian Academy of Sciences, Tomsk, Russia
| | - Nadezhda Cherdyntseva
- Laboratory of Translational Cellular and Molecular Biomedicine, Tomsk State University, Tomsk, Russia
- Cancer Research Institute, Tomsk National Research Medical Center, Russian Academy of Sciences, Tomsk, Russia
- Laboratory of Genetic Technologies, Siberian State Medical University, Tomsk, Russia
| | - Julia Kzhyshkowska
- Laboratory of Translational Cellular and Molecular Biomedicine, Tomsk State University, Tomsk, Russia
- Laboratory of Genetic Technologies, Siberian State Medical University, Tomsk, Russia
- Institute of Transfusion Medicine and Immunology, Institute for Innate Immunoscience (MI3), Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany
- German Red Cross Blood Service Baden-Württemberg – Hessen, Mannheim, Germany
| | - Irina Larionova
- Laboratory of Translational Cellular and Molecular Biomedicine, Tomsk State University, Tomsk, Russia
- Cancer Research Institute, Tomsk National Research Medical Center, Russian Academy of Sciences, Tomsk, Russia
- Laboratory of Genetic Technologies, Siberian State Medical University, Tomsk, Russia
| |
Collapse
|
17
|
Perotti V, Fabiano S, Contiero P, Michiara M, Musolino A, Boschetti L, Cascone G, Castelli M, Tagliabue G, Cancer Registries Working Group. Influence of Sex and Age on Site of Onset, Morphology, and Site of Metastasis in Colorectal Cancer: A Population-Based Study on Data from Four Italian Cancer Registries. Cancers (Basel) 2023; 15:cancers15030803. [PMID: 36765761 PMCID: PMC9913256 DOI: 10.3390/cancers15030803] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2022] [Revised: 01/10/2023] [Accepted: 01/27/2023] [Indexed: 01/31/2023] Open
Abstract
The prognosis of colorectal cancer is affected by factors such as site of origin, tumor morphology, and metastasis at diagnosis, but also age and sex seem to play a role. This study aimed to investigate within the Italian population how sex and age interact in influencing certain aspects of the disease and how they affect patient survival, particularly in the metastatic cohort. Data from four cancer registries were collected, and patients were classified by sex and age (<50, 50-69, and >69 years). Two separate analyses were conducted: one for patients having right or left colon cancer with adenocarcinoma or mucinous morphology, and one for patients having metastases at diagnosis. Women showed significant differences in right colon cases from the youngest to oldest age group (36% vs. 45% vs. 60%). Men <50 years had a significantly higher mucinous carcinoma percentage than their female counterparts (22% vs. 11%), while in the oldest age group women had the highest percentage (15% vs. 11%). The metastatic pattern differed between men and women and by age. The three-year relative survival in the <50 age group was better for women than men, but this survival advantage was reversed in the oldest group. In conclusion, sex and age are factors that influence the biological and clinical characteristics of colorectal cancer, affecting the metastatic pattern as well as patient survival.
Collapse
Affiliation(s)
- Viviana Perotti
- Cancer Registry Unit, Fondazione IRCCS, Istituto Nazionale dei Tumori, 20133 Milan, Italy
| | - Sabrina Fabiano
- Cancer Registry Unit, Fondazione IRCCS, Istituto Nazionale dei Tumori, 20133 Milan, Italy
| | - Paolo Contiero
- Environmental Epidemiology Unit, Fondazione IRCCS, Istituto Nazionale dei Tumori, 20133 Milan, Italy
| | - Maria Michiara
- Department of Medicine and Surgery, University of Parma, Medical Oncology, Cancer Registry, University Hospital of Parma, 43100 Parma, Italy
| | - Antonio Musolino
- Department of Medicine and Surgery, University of Parma, Medical Oncology, Cancer Registry, University Hospital of Parma, 43100 Parma, Italy
| | - Lorenza Boschetti
- Epidemiology Unit, Health Protection Agency of Pavia (ATS Pavia), 27100 Pavia, Italy
| | - Giuseppe Cascone
- Ragusa Cancer Registry, Department of Prevention, Ragusa Health Authority, 97100 Ragusa, Italy
| | - Maurizio Castelli
- Cancer Registry, Aosta Valley Health Authorities Department of Public Health, 11100 Aosta, Italy
| | - Giovanna Tagliabue
- Cancer Registry Unit, Fondazione IRCCS, Istituto Nazionale dei Tumori, 20133 Milan, Italy
- Correspondence:
| | | |
Collapse
|
18
|
Chang WY, Chiu HM. Beyond colonoscopy: Physical activity as a viable adjunct to prevent colorectal cancer. Dig Endosc 2023; 35:33-46. [PMID: 35694899 DOI: 10.1111/den.14377] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/20/2022] [Accepted: 06/09/2022] [Indexed: 01/17/2023]
Abstract
Colorectal cancer (CRC) is a common cancer with an increasing incidence worldwide. The implementation of a mass screening program has been proven effective in reducing the global burden of CRC, but its effectiveness is not ideal and some metabolic derangements and lifestyle factors were reported to be attributable for such a deficit. Implementing positive lifestyle intervention as primary prevention therefore becomes critical because colorectal carcinogenesis can be promoted by several lifestyle factors, such as a lack of physical activity. Herein, we review the current evidence on the association and possible mechanisms between physical activity and CRC carcinogenesis. In addition, since CRC prevention heavily relies on resection of precancerous polyps and subsequent surveillance by colonoscopy, this review will also explore the impact of physical activity on populations with different colorectal polyp risks and its potential adjunct role in altering surveillance outcomes.
Collapse
Affiliation(s)
- Wei-Yuan Chang
- Department of Internal Medicine, National Taiwan University Hospital Hsinchu Branch, Hsinchu, Taiwan
| | - Han-Mo Chiu
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
| |
Collapse
|
19
|
Jomehei MG, General Surgery Department, Ghaem Hospital, Mashhad University of Medical Sciences, Mashhad, Iran, Ravan RR, Emadzadeh M, Ansari M, Abdollahi A, Endoscopic and Minimally Invasive Surgery Research Center, Ghaem Hospital, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran, Clinical Research Development Unit, Ghaem Hospital, Mashhad University of Medical Sciences, Mashhad, Iran, Endoscopic and Minimally Invasive Surgery Research Center, Ghaem Hospital, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran, Endoscopic and Minimally Invasive Surgery Research Center, Ghaem Hospital, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran. Quality of life assessment for rectal cancer patients: A comparison between sphincter preservation and permanent colostomy. ROMANIAN JOURNAL OF MILITARY MEDICINE 2022. [DOI: 10.55453/rjmm.2022.125.4.17] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
"This study aims to compare the quality of life in patients with rectal cancer between sphincter preservation and permanent colostomy. The present study is a cross-sectional study that was performed on 120 patients (60 cases in the sphincter maintenance group and 60 cases in the permanent colostomy group) who underwent surgery from February 2017 to November 2016. Quality of life assessment was provided with QLQ-C30 and QLQ-CR29 questionnaires. Finally, the collected data were analyzed using SPSS23 software. According to the results of the QLQ-C30 questionnaire, there was no statistically significant difference in patients' quality of life in terms of performance in the study groups (P˃0.05). Symptoms such as nausea, pain, shortness of breath, sleep disturbance, loss of appetite, constipation and economic problems in the study groups were not statistically significant (P˃0.05). But the mean symptoms of fatigue (P=0.038) and diarrhea (P=0.037) were significantly higher in the sphincter maintenance group than the permanent colostomy group. The mean score of patients' quality of life was 53.43 ± 8.40 in the sphincter retention group and 52.23 ± 11.45 in the permanent colostomy group (P = 0.556). According to the results, the quality of life in the two surgical methods of sphincter preservation and permanent colostomy was not statistically significant. Therefore, treatment decisions should be made by informing patients, both based on their preferences and the physician's clinical judgment."
Collapse
|
20
|
Li C, Lu Y, Zhang MM, Wu H, Li H, Ye YJ, Jiang K. Clinicopathological features and prognosis of colonic and rectal gastrointestinal stromal tumors: A propensity score matching analysis. Front Surg 2022; 9:968585. [PMID: 36338632 PMCID: PMC9634480 DOI: 10.3389/fsurg.2022.968585] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2022] [Accepted: 10/03/2022] [Indexed: 11/07/2022] Open
Abstract
Background Colonic gastrointestinal stromal tumor (cGIST) and rectal gastrointestinal stromal tumor (rGIST) are two rare subtypes of gastrointestinal stromal tumor (GIST). The view that colonic and rectal carcinoma are different is generally accepted; however, whether there is a difference between cGIST and rGIST is still unknown. Here, we aimed to provide evidence for future clinical management and research by comparing the differences between the two types of GIST in the above-mentioned aspects. Methods Patients were enrolled from three medical centers in China and published literature was collected following the inclusion and exclusion criteria. Propensity score matching was used to eliminate differences between cohorts. Results Between cGIST and rGIST patients, significant differences were observed in age, tumor size, mitotic index, NIH risk category, growth pattern, and symptoms. Adjuvant therapy is used in a high proportion of cGIST patients, and neoadjuvant therapy is used in a high proportion of rGIST patients. Although local resection is the main surgical method in both cohorts, the proportion is higher in cGIST patients. The overall survival of rGIST patients was better than that of the cGIST patients before propensity score matching (PSM). Interestingly, no significant differences in prognosis were observed after PSM. Conclusions Although there were significant differences between cGIST and rGIST patients in baseline characteristics, clinicopathological features, treatment choice, and overall survival rate before PSM, no significant differences in long-term survival were observed between the two groups after PSM. In our study, there may be no differences in the tumor entity between cGIST and rGIST.
Collapse
Affiliation(s)
- Chen Li
- Department of Gastroenterological Surgery, Laboratory of Surgical Oncology, Beijing Key Laboratory of Colorectal Cancer Diagnosis and Treatment Research, Peking University People's Hospital, Beijing, China
| | - Yunwei Lu
- Department of Gastroenterological Surgery, Laboratory of Surgical Oncology, Beijing Key Laboratory of Colorectal Cancer Diagnosis and Treatment Research, Peking University People's Hospital, Beijing, China
| | - Meng-meng Zhang
- Department of Gastroenterological Surgery, Laboratory of Surgical Oncology, Beijing Key Laboratory of Colorectal Cancer Diagnosis and Treatment Research, Peking University People's Hospital, Beijing, China
| | - Hao Wu
- Department of Gastroenterological Surgery, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Han Li
- Department of General Surgery, The First Affiliated Hospital of Shandong First Medical University, Jinan, China
| | - Ying-Jiang Ye
- Department of Gastroenterological Surgery, Laboratory of Surgical Oncology, Beijing Key Laboratory of Colorectal Cancer Diagnosis and Treatment Research, Peking University People's Hospital, Beijing, China
| | - Kewei Jiang
- Department of Gastroenterological Surgery, Laboratory of Surgical Oncology, Beijing Key Laboratory of Colorectal Cancer Diagnosis and Treatment Research, Peking University People's Hospital, Beijing, China
- Correspondence: Kewei Jiang
| |
Collapse
|
21
|
Wang L, Du M, Wang K, Khandpur N, Rossato SL, Drouin-Chartier JP, Steele EM, Giovannucci E, Song M, Zhang FF. Association of ultra-processed food consumption with colorectal cancer risk among men and women: results from three prospective US cohort studies. BMJ 2022; 378:e068921. [PMID: 38752573 PMCID: PMC9430376 DOI: 10.1136/bmj-2021-068921] [Citation(s) in RCA: 52] [Impact Index Per Article: 17.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 06/07/2022] [Indexed: 12/12/2022]
Abstract
OBJECTIVE To examine the association between consumption of ultra-processed foods and risk of colorectal cancer among men and women from three large prospective cohorts. DESIGN Prospective cohort study with dietary intake assessed every four years using food frequency questionnaires. SETTING Three large US cohorts. PARTICIPANTS Men (n= 46 341) from the Health Professionals Follow-up Study (1986-2014) and women (n=159 907) from the Nurses' Health Study (1986-2014; n=67 425) and the Nurses' Health Study II (1991-2015; n=92 482) with valid dietary intake measurement and no cancer diagnosis at baseline. MAIN OUTCOME MEASURE Association between ultra-processed food consumption and risk of colorectal cancer, estimated using time varying Cox proportional hazards regression models adjusted for potential confounding factors. RESULTS 3216 cases of colorectal cancer (men, n=1294; women, n=1922) were documented during the 24-28 years of follow-up. Compared with those in the lowest fifth of ultra-processed food consumption, men in the highest fifth of consumption had a 29% higher risk of developing colorectal cancer (hazard ratio for highest versus lowest fifth 1.29, 95% confidence interval 1.08 to 1.53; P for trend=0.01), and the positive association was limited to distal colon cancer (72% increased risk; hazard ratio 1.72, 1.24 to 2.37; P for trend<0.001). These associations remained significant after further adjustment for body mass index or indicators of nutritional quality of the diet (that is, western dietary pattern or dietary quality score). No association was observed between overall ultra-processed food consumption and risk of colorectal cancer among women. Among subgroups of ultra-processed foods, higher consumption of meat/poultry/seafood based ready-to-eat products (hazard ratio for highest versus lowest fifth 1.44, 1.20 to 1.73; P for trend<0.001) and sugar sweetened beverages (1.21, 1.01 to 1.44; P for trend=0.013) among men and ready-to-eat/heat mixed dishes among women (1.17, 1.01 to 1.36; P for trend=0.02) was associated with increased risk of colorectal cancer; yogurt and dairy based desserts were negatively associated with the risk of colorectal cancer among women (hazard ratio 0.83, 0.71 to 0.97; P for trend=0.002). CONCLUSIONS In the three large prospective cohorts, high consumption of total ultra-processed foods in men and certain subgroups of ultra-processed foods in men and women was associated with an increased risk of colorectal cancer. Further studies are needed to better understand the potential attributes of ultra-processed foods that contribute to colorectal carcinogenesis.
Collapse
Affiliation(s)
- Lu Wang
- Friedman School of Nutrition Science and Policy, Tufts University, Boston, MA, USA
| | - Mengxi Du
- Friedman School of Nutrition Science and Policy, Tufts University, Boston, MA, USA
| | - Kai Wang
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA
| | - Neha Khandpur
- Department of Nutrition, School of Public Health, University of São Paulo, São Paulo, Brazil
- Center for Epidemiological Studies in Health and Nutrition (NUPENS), Faculty of Public Health, University of São Paulo, Brazil
- Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA
| | - Sinara Laurini Rossato
- Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA
- Institute of Geography, Universidade Federal de Uberlândia, Minas Gerais, Brazil
| | - Jean-Philippe Drouin-Chartier
- Centre Nutrition, Santé et Société (NUTRISS), Institut sur la Nutrition et les Aliments Fonctionnels (INAF), Faculté de Pharmacie, Université Laval, Québec, QC, Canada
| | - Euridice Martínez Steele
- Department of Nutrition, School of Public Health, University of São Paulo, São Paulo, Brazil
- Center for Epidemiological Studies in Health and Nutrition (NUPENS), Faculty of Public Health, University of São Paulo, Brazil
| | - Edward Giovannucci
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA
- Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA
- Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA
| | - Mingyang Song
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA
- Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA
- Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
- Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Fang Fang Zhang
- Friedman School of Nutrition Science and Policy, Tufts University, Boston, MA, USA
| |
Collapse
|
22
|
Hajipour M, Mokhtari K, Mahdevar M, Esmaeili M, Peymani M, Nasr-Esfahani MH, Mirzaei S, Hasehmi M, Hushmandi K, Ghaedi K. Identification of a novel interplaying loop of PPARγ and respective lncRNAs are involved in colorectal cancer progress. Int J Biol Macromol 2022; 219:779-787. [PMID: 35940433 DOI: 10.1016/j.ijbiomac.2022.07.247] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2022] [Revised: 07/24/2022] [Accepted: 07/26/2022] [Indexed: 12/14/2022]
Abstract
Long noncoding RNAs (lncRNAs) as regulatory molecules play important roles in early treatment and diagnosis of cancers. Considering the role of PPARγ in colorectal cancer (CRC) as a tumor suppressor, the GEO database was used to identify candidate genes that affect the activation of PPARγ protein in CRC cell lines. Then were selected 5 genes containing PPARγ response element (PPRE) in up to 4000 bp upstream and were affected by PPARγ protein activation in HT-29 colon cancer cell line using UCSC database. Expression meta-analysis was applied to map the expression network between candidate genes and all known lncRNAs through expression correlation and lncRNAs that correlated with a greater number of candidate genes (R > 0.5, P.value < 0.001). Moreover, were selected 3 lncRNAs as lncRNAs affected by PPARγ protein activation. Next, the expression levels of candidate genes and lncRNAs were evaluated using RT-qPCR in HT-29 cell line. Results showed a significant increase (FDR <0.05) in the expression level of 5 candidate genes and lncRNAs LINC01133, MBNL1-AS, LOC100288911 after treatment with pioglitazone as PPARγ ligand compared to the untreated group in HT-29 cells. Although additional tests are needed to confirm bioinformatics predictions, it can be concluded that increased expression of PPARγ may increase genes and lncRNAs expression. In summary, this study could be suggested identifying lncRNAs affected by PPARγ activation could be a new strategy in understanding the function and activity of PPARγ in colon cancer.
Collapse
Affiliation(s)
- Maral Hajipour
- Department of Modern Biology, ACECR Institute of Higher Education (Isfahan Branch), Isfahan, Iran; Department of Animal Biotechnology, Cell Science Research Center, Royan Institute for Biotechnology, ACECR, Isfahan, Iran
| | - Khatereh Mokhtari
- Department of Modern Biology, ACECR Institute of Higher Education (Isfahan Branch), Isfahan, Iran; Department of Animal Biotechnology, Cell Science Research Center, Royan Institute for Biotechnology, ACECR, Isfahan, Iran
| | - Mohammad Mahdevar
- Department of Animal Biotechnology, Cell Science Research Center, Royan Institute for Biotechnology, ACECR, Isfahan, Iran
| | - Maryam Esmaeili
- Department of Animal Biotechnology, Cell Science Research Center, Royan Institute for Biotechnology, ACECR, Isfahan, Iran
| | - Maryam Peymani
- Department of Biology, Faculty of Basic Sciences, Shahrekord Branch, Islamic Azad University, Shahrekord, Iran.
| | - Mohammad Hossein Nasr-Esfahani
- Department of Animal Biotechnology, Cell Science Research Center, Royan Institute for Biotechnology, ACECR, Isfahan, Iran
| | - Sepideh Mirzaei
- Department of Biology, Faculty of Science, Islamic Azad University, Science and Research Branch, Tehran, Iran
| | - Mehrdad Hasehmi
- Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran; Farhikhtegan Medical Convergence sciences Research Center, Farhikhtegan Hospital, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Kiavash Hushmandi
- Department of Food Hygiene and Quality Control, Division of Epidemiology & Zoonoses, Faculty of Veterinary Medicine, University of Tehran, Tehran, Iran.
| | - Kamran Ghaedi
- Department of Cell and Molecular Biology and Microbiology, Faculty of Biological Science and Technology, University of Isfahan, Isfahan, Iran.
| |
Collapse
|
23
|
Bennedsen ALB, Furbo S, Bjarnsholt T, Raskov H, Gögenur I, Kvich L. The gut microbiota can orchestrate the signaling pathways in colorectal cancer. APMIS 2022; 130:121-139. [PMID: 35007370 DOI: 10.1111/apm.13206] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2021] [Accepted: 01/04/2022] [Indexed: 12/14/2022]
Abstract
Current evidence suggests that bacteria contribute to the development of certain cancers, such as colorectal cancer (CRC), partly by stimulating chronic inflammation. However, little is known about the bacterial impact on molecular pathways in CRC. Recent studies have demonstrated how specific bacteria can influence the major CRC-related pathways, i.e., Wnt, PI3K-Akt, MAPK, TGF-β, EGFR, mTOR, and p53. In order to advance the current understanding and facilitate the choice of pathways to investigate, we have systematically collected and summarized the current knowledge within bacterial altered major pathways in CRC. Several pro-tumorigenic and anti-tumorigenic bacterial species and their respective metabolites interfere with the major signaling pathways addressed in this review. Not surprisingly, some of these studies investigated known CRC drivers, such as Escherichia coli, Fusobacterium nucleatum, and Bacteroides fragilis. Interestingly, some metabolites produced by bacterial species typically considered pathogenic, e.g., Vibrio cholera, displayed anti-tumorigenic activities, emphasizing the caution needed when classifying healthy and unhealthy microorganisms. The results collectively emphasize the complexity of the relationship between the microbiota and the tumorigenesis of CRC, and future studies should verify these findings in more realistic models, such as organoids, which constitute a promising platform. Moreover, future trials should investigate the clinical potential of preventive modulation of the gut microbiota regarding CRC development.
Collapse
Affiliation(s)
- Astrid L B Bennedsen
- Department of Surgery, Center for Surgical Science, Zealand University Hospital, Koege, Denmark
| | - Sara Furbo
- Department of Surgery, Center for Surgical Science, Zealand University Hospital, Koege, Denmark
| | - Thomas Bjarnsholt
- Department of Immunology and Microbiology, Costerton Biofilm Center, University of Copenhagen, Copenhagen, Denmark.,Department of Clinical Microbiology, Rigshospitalet, Copenhagen, Denmark
| | - Hans Raskov
- Department of Surgery, Center for Surgical Science, Zealand University Hospital, Koege, Denmark
| | - Ismail Gögenur
- Department of Surgery, Center for Surgical Science, Zealand University Hospital, Koege, Denmark.,Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
| | - Lasse Kvich
- Department of Surgery, Center for Surgical Science, Zealand University Hospital, Koege, Denmark.,Department of Immunology and Microbiology, Costerton Biofilm Center, University of Copenhagen, Copenhagen, Denmark
| |
Collapse
|
24
|
Dong H, Liu Q, Chen C, Lu T, Xu K. LncRNA OGFRP1 promotes angiogenesis and epithelial-mesenchymal transition in colorectal cancer cells through miR-423-5p/CTCF axis. Immunobiology 2022; 227:152176. [DOI: 10.1016/j.imbio.2022.152176] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2021] [Revised: 12/09/2021] [Accepted: 01/02/2022] [Indexed: 01/29/2023]
|
25
|
Farinha P, Pinho JO, Matias M, Gaspar MM. Nanomedicines in the treatment of colon cancer: a focus on metallodrugs. Drug Deliv Transl Res 2022; 12:49-66. [PMID: 33616870 DOI: 10.1007/s13346-021-00916-7] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/18/2021] [Indexed: 02/06/2023]
Abstract
Worldwide, colon cancer (CC) represents the fourth most common type of cancer and the fifth major cause of cancer-associated deaths. Surgical resection is considered the standard therapeutic choice for CC in early stages. However, in latter stages of the disease, adjuvant chemotherapy is essential for an appropriate management of this pathology. Metal-based complexes displaying cytotoxic properties towards tumor cells emerge as potential chemotherapeutic options. One metallodrug, oxaliplatin, was already approved for clinical use, playing an important role in the treatment of CC patients. Unfortunately, most of the newly designed metal-based complexes exhibit lack of selectivity against cancer cells, low solubility and permeability, high dose-limiting toxicity, and emergence of resistances. Nanodelivery systems enable the incorporation of metallodrugs at adequate payloads, solving the above-referred drawbacks. Moreover, drug delivery systems, depending on their physicochemical properties, are able to release the incorporated material preferentially at affected tissues/organs, enhancing the therapeutic activity in vivo, with concomitant fewer side effects. In this review, the general features and therapeutic management of CC will be addressed, with a special focus on preclinical or clinical studies using metal-based compounds. Furthermore, the use of different nanodelivery systems will also be described as tools to potentiate the therapeutic index of metallodrugs for the management of CC.
Collapse
Affiliation(s)
- Pedro Farinha
- Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003, Lisboa, Portugal
| | - Jacinta O Pinho
- Faculty of Pharmacy, Research Institute for Medicines, iMed.ULisboa, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003, Lisboa, Portugal
| | - Mariana Matias
- Faculty of Pharmacy, Research Institute for Medicines, iMed.ULisboa, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003, Lisboa, Portugal.
| | - M Manuela Gaspar
- Faculty of Pharmacy, Research Institute for Medicines, iMed.ULisboa, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003, Lisboa, Portugal.
| |
Collapse
|
26
|
Cabral LKD, Mapua CA, Natividad FF, Sukowati CHC, Cortez ER, Enriquez MLD. MutL homolog 1 methylation and microsatellite instability in sporadic colorectal tumors among Filipinos. World J Gastrointest Oncol 2021; 13:2101-2113. [PMID: 35070045 PMCID: PMC8713326 DOI: 10.4251/wjgo.v13.i12.2101] [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: 05/11/2021] [Revised: 06/24/2021] [Accepted: 09/14/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Colorectal cancer (CRC) ranks third in terms of incidence and second in mortality worldwide. In CRC, the silencing of mismatch repair genes, including the mutL homolog 1 (hMLH1) has been linked to microsatellite instability (MSI), the lengthening or shortening of microsatellite repeats. Very limited data have been presented so far on the link of hMLH1 methylation and MSI in Southeast Asia populations with sporadic CRC, and on its clinical significance. AIM To investigate the significance of the MSI status and hMLH1 methylation in CRC Filipino patients. METHODS Fifty-four sporadic CRC patients with complete clinical data were included in this study. Genomic DNA from CRC tumor biopsies and their normal tissue counterparts were profiled for MSI by high resolution melting (HRM) analysis using the Bethesda Panel of Markers (BAT25, BAT26, D2S123, D5S346, and D17S250). hMLH1 methylation screening was performed using bisulfite conversion and methylation specific polymerase chain reaction. Statistical analysis was conducted to calculate their associations to clinicopathological characteristics and survival relevance (Kaplan-Meier curves and the log-rank test). RESULTS hMLH1 methylation was observed in 9% and 35% of CRC and normal samples, respectively. Higher incidence of consistently methylated hMLH1 found in both normal and CRC was noticed for relation to location of tumor (P < 0.05). As for MSI status, D2S123 the most common unstable microsatellite and MSI-high (MSI-H) was the most common MSI profile, counted for 46% and 50% of normal and CRC tissues, respectively. The presence of MSI-low (MSI-L) and microsatellite stable (MSS) was 43% and 11% for normal, and 31% and 19% for CRC samples. The mean month of patients' survival was shorter in patients whose normal and tumor tissues had methylated compared to those with unmethylated hMLH1 and with MSI-H compared to those with MSI-L/MSS (P < 0.05). This was supported by significant difference in Kaplan-Meier with log-rank analysis. This data indicated that hMLH1 methylation and high MSI status have prognostic value. CONCLUSION This study showed the clinical significance of hMLH1 methylation and MSI status in sporadic CRC Filipino patients, especially in the normal part of the tumor.
Collapse
Affiliation(s)
- Loraine Kay D Cabral
- Research and Biotechnology Group, St. Luke's Medical Center, Quezon City 1112, Philippines
- Centro Studi Fegato, Fondazione Italiana Fegato ONLUS, Trieste 34149, Italy
| | - Cynthia A Mapua
- Research and Biotechnology Group, St. Luke's Medical Center, Quezon City 1112, Philippines
| | - Filipinas F Natividad
- Research and Biotechnology Group, St. Luke's Medical Center, Quezon City 1112, Philippines
| | | | - Edgardo R Cortez
- Department of Surgery, St. Luke's Medical Center, Quezon City 1112, Philippines
| | - Ma Luisa D Enriquez
- Research and Biotechnology Group, St. Luke's Medical Center, Quezon City 1112, Philippines
- Center for Natural Science and Environmental Research, De La Salle University, Manila 1004, Philippines
| |
Collapse
|
27
|
Barber LE, Bertrand KA, Petrick JL, Gerlovin H, White LF, Adams-Campbell LL, Rosenberg L, Roy HK, Palmer JR. Predicted Vitamin D Status and Colorectal Cancer Incidence in the Black Women's Health Study. Cancer Epidemiol Biomarkers Prev 2021; 30:2334-2341. [PMID: 34620630 PMCID: PMC8643345 DOI: 10.1158/1055-9965.epi-21-0675] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2021] [Revised: 07/20/2021] [Accepted: 09/30/2021] [Indexed: 11/16/2022] Open
Abstract
BACKGROUND Observational studies, mostly among White populations, suggest that low vitamin D levels increase colorectal cancer risk. African Americans, who are disproportionately burdened by colorectal cancer, often have lower vitamin D levels compared with other populations. METHODS We assessed predicted vitamin D score in relation to colorectal cancer among 49,534 participants in the Black Women's Health Study, a cohort of African American women followed from 1995 to 2017 through biennial questionnaires. We derived predicted vitamin D scores at each questionnaire cycle for all participants using a previously validated prediction model based on actual 25-hydroxyvitamin D values from a subset of participants. We calculated cumulative average predicted vitamin D score at every cycle by averaging scores from cycles up to and including that cycle. Using Cox proportional hazards regression, we estimated hazard ratios (HR) and 95% confidence intervals (CI) for colorectal cancer incidence according to predicted score quartiles. RESULTS Over follow-up, 488 incident colorectal cancers occurred. Compared with women in the highest quartile of predicted vitamin D score, those in the lowest had an estimated 41% (HR = 1.41; 95% CI, 1.05-1.90) higher colorectal cancer risk. Comparable HRs were 1.44 (95% CI, 1.02-2.01) for colon and 1.34 (95% CI, 0.70-2.56) for rectal cancer. CONCLUSIONS Low vitamin D status may lead to elevated colorectal cancer risk in African American women. IMPACT Our findings, taken together with established evidence that vitamin D levels are generally lower in African Americans than other U.S. groups, suggest that low vitamin D status may contribute to the disproportionately high colorectal cancer incidence among African Americans.
Collapse
Affiliation(s)
- Lauren E Barber
- Department of Epidemiology, Boston University School of Public Health, Boston, Massachusetts
| | | | - Jessica L Petrick
- Slone Epidemiology Center at Boston University, Boston, Massachusetts
| | - Hanna Gerlovin
- U.S. Department of Veterans Affairs, Boston, Massachusetts
| | - Laura F White
- Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts
| | | | - Lynn Rosenberg
- Slone Epidemiology Center at Boston University, Boston, Massachusetts
| | - Hemant K Roy
- Department of Medicine, Baylor College of Medicine, Houston, Texas
| | - Julie R Palmer
- Slone Epidemiology Center at Boston University, Boston, Massachusetts.
| |
Collapse
|
28
|
Xi Y, Xu P. Global colorectal cancer burden in 2020 and projections to 2040. Transl Oncol 2021; 14:101174. [PMID: 34243011 PMCID: PMC8273208 DOI: 10.1016/j.tranon.2021.101174] [Citation(s) in RCA: 1288] [Impact Index Per Article: 322.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2021] [Revised: 07/01/2021] [Accepted: 07/02/2021] [Indexed: 02/07/2023] Open
Abstract
As the third most common malignancy and the second most deadly cancer, colorectal cancer (CRC) induces estimated 1.9 million incidence cases and 0.9 million deaths worldwide in 2020. The incidence of CRC is higher in highly developed countries, and it is increasing in middle- and low-income countries due to westernization. Moreover, a rising incidence of early-onset CRC is also emerging. The large number of CRC cases poses a growing global public health challenge. Raising awareness of CRC is important to promote healthy lifestyle choices, novel strategies for CRC management, and implementation of global screening programs, which are critical to reducing CRC morbidity and mortality in the future. CRC is a heterogeneous disease, and its subtype affiliation influences prognosis and therapeutic response. An accurate CRC subtype classification system is of great significance for basic research and clinical outcome. Here, we present the global epidemiology of CRC in 2020 and projections for 2040, review the major CRC subtypes to better understand CRC molecular basis, and summarize current risk factors, prevention, and screening strategies for CRC.
Collapse
Affiliation(s)
- Yue Xi
- Center for Pharmacogenetics and Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA 15261, USA
| | - Pengfei Xu
- Center for Pharmacogenetics and Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA 15261, USA.
| |
Collapse
|
29
|
Cervena K, Novosadova V, Pardini B, Naccarati A, Opattova A, Horak J, Vodenkova S, Buchler T, Skrobanek P, Levy M, Vodicka P, Vymetalkova V. Analysis of MicroRNA Expression Changes During the Course of Therapy In Rectal Cancer Patients. Front Oncol 2021; 11:702258. [PMID: 34540669 PMCID: PMC8444897 DOI: 10.3389/fonc.2021.702258] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2021] [Accepted: 08/16/2021] [Indexed: 12/28/2022] Open
Abstract
MicroRNAs (miRNAs) regulate gene expression in a tissue-specific manner. However, little is known about the miRNA expression changes induced by the therapy in rectal cancer (RC) patients. We evaluated miRNA expression levels before and after therapy and identified specific miRNA signatures reflecting disease course and treatment responses of RC patients. First, miRNA expression levels were assessed by next-generation sequencing in two plasma samplings (at the time of diagnosis and a year after) from 20 RC patients. MiR-122-5p and miR-142-5p were classified for subsequent validation in plasma and plasma extracellular vesicles (EVs) on an independent group of RC patients (n=107). Due to the intrinsic high differences in miRNA expression levels between samplings, cancer-free individuals (n=51) were included in the validation phase to determine the baseline expression levels of the selected miRNAs. Expression levels of these miRNAs were significantly different between RC patients and controls (for all p <0.001). A year after diagnosis, miRNA expression profiles were significantly modified in patients responding to treatment and were no longer different from those measured in cancer-free individuals. On the other hand, patients not responding to therapy maintained low expression levels in their second sampling (miR-122-5p: plasma: p=0.05, EVs: p=0.007; miR-142-5p: plasma: p=0.008). Besides, overexpression of miR-122-5p and miR-142-5p in RC cell lines inhibited cell growth and survival. This study provides novel evidence that circulating miR-122-5p and miR-142-5p have a high potential for RC screening and early detection as well as for the assessment of patients' outcomes and the effectiveness of treatment schedule.
Collapse
Affiliation(s)
- Klara Cervena
- Department of Molecular Biology of Cancer, Institute of Experimental Medicine of the Czech Academy of Sciences, Prague, Czechia.,Institute of Biology and Medical Genetics, 1stMedical Faculty, Charles University, Prague, Czechia
| | - Vendula Novosadova
- Czech Centre for Phenogenomics, Institute of Molecular Genetics of the Czech Academy of Sciences, Vestec, Prague, Czechia
| | - Barbara Pardini
- Molecular Genetics Epidemiology Unit, Italian Institute for Genomic Medicine, c/o IRCCS Candiolo,, Turin, Italy.,Candiolo Cancer Institute, FPO-IRCCS, Candiolo, Italy
| | - Alessio Naccarati
- Molecular Genetics Epidemiology Unit, Italian Institute for Genomic Medicine, c/o IRCCS Candiolo,, Turin, Italy.,Candiolo Cancer Institute, FPO-IRCCS, Candiolo, Italy
| | - Alena Opattova
- Department of Molecular Biology of Cancer, Institute of Experimental Medicine of the Czech Academy of Sciences, Prague, Czechia.,Institute of Biology and Medical Genetics, 1stMedical Faculty, Charles University, Prague, Czechia.,Biomedical Centre, Faculty of Medicine in Pilsen, Charles University, Pilsen, Czechia
| | - Josef Horak
- Department of Molecular Biology of Cancer, Institute of Experimental Medicine of the Czech Academy of Sciences, Prague, Czechia.,Third Faculty of Medicine, Charles University, Prague, Czechia
| | - Sona Vodenkova
- Department of Molecular Biology of Cancer, Institute of Experimental Medicine of the Czech Academy of Sciences, Prague, Czechia.,Biomedical Centre, Faculty of Medicine in Pilsen, Charles University, Pilsen, Czechia
| | - Tomas Buchler
- Department of Oncology, First Faculty of Medicine, Charles University and Thomayer Hospital, Prague, Czechia
| | - Pavel Skrobanek
- Department of Oncology, First Faculty of Medicine, Charles University and Thomayer Hospital, Prague, Czechia
| | - Miroslav Levy
- Department of Surgery, First Faculty of Medicine, Charles University and Thomayer Hospital, Prague, Czechia
| | - Pavel Vodicka
- Department of Molecular Biology of Cancer, Institute of Experimental Medicine of the Czech Academy of Sciences, Prague, Czechia.,Institute of Biology and Medical Genetics, 1stMedical Faculty, Charles University, Prague, Czechia.,Biomedical Centre, Faculty of Medicine in Pilsen, Charles University, Pilsen, Czechia
| | - Veronika Vymetalkova
- Department of Molecular Biology of Cancer, Institute of Experimental Medicine of the Czech Academy of Sciences, Prague, Czechia.,Institute of Biology and Medical Genetics, 1stMedical Faculty, Charles University, Prague, Czechia.,Biomedical Centre, Faculty of Medicine in Pilsen, Charles University, Pilsen, Czechia
| |
Collapse
|
30
|
Hu H, Wu D, Liu X, Yu H, Xu J, Cai W, Huang Y, Bai R, Zhang J, Gu Y, Zheng S, Ge W. SPARCL1 exhibits different expressions in left- and right-sided colon cancer and is downregulated via DNA methylation. Epigenomics 2021; 13:1269-1282. [PMID: 34435512 DOI: 10.2217/epi-2021-0231] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Aim: The authors previously found that SPARCL1 functions to suppress colorectal cancer metastasis. Here, the epigenetic mechanism of SPARCL1 regulation and its relationship with clinicopathological features in colon cancer were investigated. Materials & methods: SPARCL1 expression was evaluated by immunohistochemistry staining in a tissue array containing 271 left-sided colon cancer samples and 257 right-sided colon cancer samples. In vivo and in vitro DNA methylation states were measured by biochemical sulfide potential assay. The transcription and DNA methylation states in cells were altered by siRNA or decitabine treatment, respectively. Cellular motility properties were compared through transwell assay. Results & conclusion: SPARCL1, mediated by its DNA methylation, may arrest colorectal carcinoma motility. Furthermore, SPARCL1 expression is higher and may have a specific prognostic value in left-sided colon cancer.
Collapse
Affiliation(s)
- Hanguang Hu
- Cancer Institute, Key Laboratory of Cancer Prevention & Intervention, China National Ministry of Education; Key Laboratory of Molecular Biology in Medical Sciences; the Second Affiliated Hospital, Zhejiang University School of Medicine, No. 88 Jiefang Road, Hangzhou 310009, Zhejiang Province, China.,Department of Oncology, the Second Affiliated Hospital of Zhejiang University School of Medicine, No. 88 Jiefang Road, Hangzhou, 310009, Zhejiang Province, China
| | - Dehao Wu
- Cancer Institute, Key Laboratory of Cancer Prevention & Intervention, China National Ministry of Education; Key Laboratory of Molecular Biology in Medical Sciences; the Second Affiliated Hospital, Zhejiang University School of Medicine, No. 88 Jiefang Road, Hangzhou 310009, Zhejiang Province, China
| | - Xibo Liu
- Department of Pathology, Shaoxing People's Hospital, No. 568, Zhongxing North Road, Shaoxing, 312000, Zhejiang Province, China
| | - Haifeng Yu
- Department of Oncology, the Second Affiliated Hospital of Zhejiang University School of Medicine, No. 88 Jiefang Road, Hangzhou, 310009, Zhejiang Province, China.,Department of Lymphatic Medical Oncology, Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Hangzhou, 310005, Zhejiang Province, China.,Institute of Cancer & Basic Medicine (IBMC), Chinese Academy of Sciences, Hangzhou, Zhejiang Province, China
| | - Junxi Xu
- Department of Gastroenterology, the Second Affiliated Hospital of Zhejiang University School of Medicine, No. 88 Jiefang Road, Hangzhou, 310009, Zhejiang Province, China
| | - Wen Cai
- Cancer Institute, Key Laboratory of Cancer Prevention & Intervention, China National Ministry of Education; Key Laboratory of Molecular Biology in Medical Sciences; the Second Affiliated Hospital, Zhejiang University School of Medicine, No. 88 Jiefang Road, Hangzhou 310009, Zhejiang Province, China.,Department of Gastroenterology, the Second Affiliated Hospital of Zhejiang University School of Medicine, No. 88 Jiefang Road, Hangzhou, 310009, Zhejiang Province, China
| | - Yanqin Huang
- Cancer Institute, Key Laboratory of Cancer Prevention & Intervention, China National Ministry of Education; Key Laboratory of Molecular Biology in Medical Sciences; the Second Affiliated Hospital, Zhejiang University School of Medicine, No. 88 Jiefang Road, Hangzhou 310009, Zhejiang Province, China
| | - Rui Bai
- Cancer Institute, Key Laboratory of Cancer Prevention & Intervention, China National Ministry of Education; Key Laboratory of Molecular Biology in Medical Sciences; the Second Affiliated Hospital, Zhejiang University School of Medicine, No. 88 Jiefang Road, Hangzhou 310009, Zhejiang Province, China
| | - Jiawei Zhang
- Cancer Institute, Key Laboratory of Cancer Prevention & Intervention, China National Ministry of Education; Key Laboratory of Molecular Biology in Medical Sciences; the Second Affiliated Hospital, Zhejiang University School of Medicine, No. 88 Jiefang Road, Hangzhou 310009, Zhejiang Province, China
| | - Ying Gu
- Institute of genetics, Zhejiang University, Zijingang Campus of Zhejiang University, Yuhangtang Road No.388, Hangzhou, 310058, Zhejiang Province, China
| | - Shu Zheng
- Cancer Institute, Key Laboratory of Cancer Prevention & Intervention, China National Ministry of Education; Key Laboratory of Molecular Biology in Medical Sciences; the Second Affiliated Hospital, Zhejiang University School of Medicine, No. 88 Jiefang Road, Hangzhou 310009, Zhejiang Province, China
| | - Weiting Ge
- Cancer Institute, Key Laboratory of Cancer Prevention & Intervention, China National Ministry of Education; Key Laboratory of Molecular Biology in Medical Sciences; the Second Affiliated Hospital, Zhejiang University School of Medicine, No. 88 Jiefang Road, Hangzhou 310009, Zhejiang Province, China.,Cancer Center, Zhejiang University, Hangzhou, 310000, Zhejiang Province, China
| |
Collapse
|
31
|
Sugimoto A, Fukuoka T, Nagahara H, Shiutani M, Iseki Y, Wang E, Okazaki Y, Tachimori A, Maeda K, Ohira M. The Surgical Apgar Score Predicts Postoperative Complications in Elderly Patients After Surgery for Colorectal Cancer. Am Surg 2021:31348211038576. [PMID: 34396795 DOI: 10.1177/00031348211038576] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
OBJECTIVE The surgical Apgar score (SAS) has been validated as a risk assessment tool for postoperative complications. However, the utility of the SAS in elderly patients with colorectal cancer remains unclear. In this study, we evaluated the utility of the SAS for predicting the severe complications in elderly patients with colorectal cancer. METHODS We retrospectively analyzed 295 patients underwent radical surgery for colorectal cancer in elderly patients ≥75 years old. The SAS was calculated based on 3 intraoperative parameters: estimated blood loss (EBL), lowest mean arterial pressure, and lowest heart rate. Severe complications were defined as Clavien-Dindo classification grade ≥ IIIa. We divided all patients into 2 groups according to with or without severe complications. The optimal cut-off value of SAS for severe complications has been determined by receiver operator characteristic curve. Predictors for severe complications were analyzed by logistic regression modeling. RESULTS Severe complications were observed in 57 patients (19.3%). Male, rectal cancer, operation time (>240 minutes), EBL (≥120 mL), and a low SAS (≤6) were significantly associated with severe complications in univariate analysis. A multivariate analysis revealed that male, rectal cancer, and a low SAS (≤6) were independent predictors for severe complications. CONCLUSIONS A low SAS (≤6) was associated with severe complications after colorectal cancer surgery in elderly patients. The SAS is a valuable predictor for severe complications in elderly patients with colorectal cancer.
Collapse
Affiliation(s)
- Atsushi Sugimoto
- Department of Gastroenterological Surgery, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Tatsunari Fukuoka
- Department of Gastroenterological Surgery, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Hisashi Nagahara
- Department of Gastroenterological Surgery, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Masatsune Shiutani
- Department of Gastroenterological Surgery, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Yasuhito Iseki
- Department of Gastroenterological Surgery, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - En Wang
- Department of Gastroenterological Surgery, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Yuki Okazaki
- Department of Gastroenterological Surgery, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Akiko Tachimori
- Department of Gastroenterological Surgery, 13877Osaka City General Hospital, Osaka, Japan
| | - Kiyoshi Maeda
- Department of Gastroenterological Surgery, 13877Osaka City General Hospital, Osaka, Japan
| | - Masaichi Ohira
- Department of Gastroenterological Surgery, Osaka City University Graduate School of Medicine, Osaka, Japan
| |
Collapse
|
32
|
Bordry N, Germann M, Foukas PG, Sempoux C, Yan P, Dormond O, Speiser DE, Demartines N, Sauvain MO. Immune cell infiltration in colonic cancer: correlation between biopsy and surgical specimens. Br J Surg 2021; 108:346-350. [PMID: 33792645 DOI: 10.1093/bjs/znaa142] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2020] [Accepted: 11/22/2020] [Indexed: 11/14/2022]
Abstract
Infiltration of CD3+ and CD8+ T cells in tumour biopsies of patients with colonic cancer correlated positively with CD3+ and CD8+ T cell infiltration in matched tumour surgical specimens. This opens new perspectives in the potential of tumour biopsies for prognosis and treatment decisions.
Collapse
Affiliation(s)
- N Bordry
- Department of Oncology, University Hospital of Geneva, Geneva, Switzerland
| | - M Germann
- Ecole Polytechnique Fédérale de Lausanne, School of Life Sciences, Swiss Institute for Experimental Cancer Research, Lausanne, Switzerland
| | - P G Foukas
- Second Department of Pathology, Attikon University Hospital, National and Kapodistrian University of Athens, Athens, Greece
| | - C Sempoux
- Institute of Pathology, Lausanne University Hospital Centre and University of Lausanne, Lausanne, Switzerland
| | - P Yan
- Institute of Pathology, Lausanne University Hospital Centre and University of Lausanne, Lausanne, Switzerland
| | - O Dormond
- Department of Visceral Surgery, Lausanne University Hospital Centre and University of Lausanne, Lausanne, Switzerland
| | - D E Speiser
- Department of Oncology, University of Lausanne, Lausanne, Switzerland
| | - N Demartines
- Department of Visceral Surgery, Lausanne University Hospital Centre and University of Lausanne, Lausanne, Switzerland
| | - M-O Sauvain
- Department of Visceral Surgery, Lausanne University Hospital Centre and University of Lausanne, Lausanne, Switzerland.,Service de Chirurgie, Réseau Hospitalier Neuchâtelois, Neuchâtel, Switzerland
| |
Collapse
|
33
|
Martínez-Casillas KCE, Saucedo-Sariñana AM, Barros-Núñez P, Gallegos-Arreola MP, Pineda-Razo TD, Marín-Contreras ME, Flores-Martínez SE, Rosales-Reynoso MA. MKK4 variants rs3826392 and rs3809728 are associated with susceptibility and clinicopathological features in colorectal cancer patients. IRANIAN JOURNAL OF BASIC MEDICAL SCIENCES 2021; 24:1033-1040. [PMID: 34804420 PMCID: PMC8591758 DOI: 10.22038/ijbms.2021.56874.12690] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/07/2021] [Accepted: 07/05/2021] [Indexed: 11/06/2022]
Abstract
OBJECTIVES The mitogen-activated protein kinase kinase 4 (MKK4) plays a key role in several processes like inflammation, apoptosis, and tumorigenesis. Several authors have proposed that genetic variations in these genes may alter their expression with subsequent cancer risk. This study aimed to examine the possible association of MKK4 rs3826392 and rs3809728 variants in Mexican patients with colorectal cancer (CRC). These variants were also compared with clinical features as sex, age, TNM stage, and tumor location. MATERIALS AND METHODS The study included genomic DNA from 218 control subjects and 250 patients. Genotyping of the MKK4 variants was performed using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) procedure. RESULTS Individuals with A/T and T/T genotypes for the rs3809728 (-1044 A>T) variant showed a significantly increased risk for CRC (P=0.012 and 0.007, respectively); while individuals with the G/G genotype for the rs3826392 (-1304 T>G) variant showed a decreased risk for CRC (P=0.012). Genotypes of the MKK4 rs3809728 variant were also significantly related to colon localization and advanced TNM stage in CRC patients. T-T haplotype (rs3826392 and rs3809728) of the MKK4 gene was associated with risk in patients with CRC. CONCLUSION The rs3826392 variant in the MKK4 gene could be a cancer protective factor, while the rs3809728 variant could be a risk factor. These variants play a significant role in CRC risk.
Collapse
Affiliation(s)
| | - Anilú Margarita Saucedo-Sariñana
- División de Medicina Molecular, Centro de Investigación Biomédica de Occidente, Instituto Mexicano del Seguro Social (IMSS), Guadalajara, Jalisco, México
| | - Patricio Barros-Núñez
- Unidad de Investigación Seguimiento Enfermedades Metabólicas, Unidad Médica de Alta Especialidad Pediatría, Instituto Mexicano del Seguro Social (IMSS), Guadalajara, Jalisco. México
| | - Martha Patricia Gallegos-Arreola
- División de Genética, Centro de Investigación Biomédica de Occidente, Instituto Mexicano del Seguro Social (IMSS), Guadalajara, Jalisco, México
| | - Tomás Daniel Pineda-Razo
- Servicio de Oncología Médica, Hospital de Especialidades, Instituto Mexicano del Seguro Social (IMSS), Guadalajara, Jalisco, México
| | - María Eugenia Marín-Contreras
- Servicio de Gastroenterología, Hospital de Especialidades, Instituto Mexicano del Seguro Social (IMSS), Guadalajara, Jalisco, México
| | - Silvia Esperanza Flores-Martínez
- División de Medicina Molecular, Centro de Investigación Biomédica de Occidente, Instituto Mexicano del Seguro Social (IMSS), Guadalajara, Jalisco, México
| | - Mónica Alejandra Rosales-Reynoso
- División de Medicina Molecular, Centro de Investigación Biomédica de Occidente, Instituto Mexicano del Seguro Social (IMSS), Guadalajara, Jalisco, México,Corresponding author: Mónica Alejandra Rosales-Reynoso. División de Medicina Molecular, Centro de Investigación Biomédica de Occidente, Instituto Mexicano del Seguro Social (IMSS), Guadalajara, Jalisco, México. Tel/ Fax: +52-3336683000;
| |
Collapse
|
34
|
Chadha S, Kumar A, Srivastava SA, Behl T, Ranjan R. Inulin as a Delivery Vehicle for Targeting Colon-Specific Cancer. Curr Drug Deliv 2021; 17:651-674. [PMID: 32459607 DOI: 10.2174/1567201817666200527133719] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2020] [Revised: 03/11/2020] [Accepted: 04/01/2020] [Indexed: 12/12/2022]
Abstract
Natural polysaccharides, as well as biopolymers, are now days widely developed for targeting colon cancer using various drug delivery systems. Currently, healing conformations are being explored that can efficiently play a multipurpose role. Owing to the capability of extravagance colonic diseases with the least adverse effects, biopolymers for site specific colon delivery have developed an increased curiosity over the past decades. Inulin (INU) was explored for its probable application as an entrapment material concerning its degradation by enzymes in the colonic microflora and its drug release behavior in a sustained and controlled manner. INU is a polysaccharide and it consists of 2 to 1 linkage having an extensive array of beneficial uses such as a carrier for delivery of therapeutic agents as an indicative/investigative utensil or as a dietary fiber with added well-being aids. In the main, limited research, as well as information, is available on the delivery of therapeutic agents using inulin specifically for colon cancer because of its capability to subsist in the stomach's acidic medium. This exceptional steadiness and robustness properties are exploited in numerous patterns to target drugs securely for the management of colonic cancer, where they effectively act and kills colonic tumor cells easily. In this review article, recent efforts and inulin-based nano-technological approaches for colon cancer targeting are presented and discussed.
Collapse
Affiliation(s)
- Swati Chadha
- Department of Pharmaceutics, Chitkara College of Pharmacy, Chitkara University, Punjab, India
| | - Arun Kumar
- Department of Pharmaceutics, Chitkara College of Pharmacy, Chitkara University, Punjab, India
| | | | - Tapan Behl
- Department of Pharmaceutics, Chitkara College of Pharmacy, Chitkara University, Punjab, India
| | - Rishu Ranjan
- Department of Pharmaceutics, Chitkara College of Pharmacy, Chitkara University, Punjab, India
| |
Collapse
|
35
|
Physical activity and mortality in patients with colorectal cancer: a meta-analysis of prospective cohort studies. Eur J Cancer Prev 2021; 29:15-26. [PMID: 30964753 DOI: 10.1097/cej.0000000000000511] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
The association between physical activity (PA) and colorectal cancer (CRC) patients' survival is inconsistent. We conducted a systematic review and meta-analysis to summarize published articles on this issue. We performed a comprehensive search of the PubMed, Embase, and Web of Science databases for relevant articles through 28 February 2018. The summary hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using a random-effects model. Eighteen prospective cohort studies were included in the meta-analysis, with a total of 9257 cases of total mortality (TM) and 4015 cases of colorectal cancer-specific mortality (CRCSM) among 31 873 CRC survivors and 557 150 general populations. Among CRC survivors, the highest versus the lowest levels of prediagnosis PA showed decreased risks of TM (summary HR = 0.81, 95% CI: 0.76-0.87, I = 1.8%) and CRCSM (summary HR = 0.85, 95% CI: 0.77-0.98, I = 0), respectively. Significant risk reductions for TM and CRCSM were also demonstrated for postdiagnosis PA (HR = 0.63, 95% CI: 0.54-0.74; and HR = 0.64, 95% CI: 0.47-0.88, respectively). The inverse association between prediagnosis PA and cancer mortality was more pronounced for colon cancer than that for rectal cancer (P = 0.08). The summary HRs (95% CIs) of TM were 0.89 (0.83-0.97) and 0.79 (0.69-0.90) per 10 metabolic equivalent task-h/week increase in prediagnosis and postdiagnosis PA, respectively. Our meta-analysis provides comprehensive evidence that PA performed before or after cancer diagnosis is related to reduced mortality risk among CRC survivors.
Collapse
|
36
|
Abdalla TSA, Meiners J, Riethdorf S, König A, Melling N, Gorges T, Karstens KF, Izbicki JR, Pantel K, Reeh M. Prognostic value of preoperative circulating tumor cells counts in patients with UICC stage I-IV colorectal cancer. PLoS One 2021; 16:e0252897. [PMID: 34111181 PMCID: PMC8191913 DOI: 10.1371/journal.pone.0252897] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2021] [Accepted: 05/25/2021] [Indexed: 02/06/2023] Open
Abstract
Colorectal cancer (CRC) is one of the leading causes of cancer death worldwide. There is an urgent need to identify prognostic markers for patients undergoing curative resection of CRC. The detection of circulating tumor cells in peripheral blood is a promising approach to identify high-risk patients with disseminated disease in colorectal cancer. This study aims to evaluate the prognostic relevance of preoperative CTCs using the Cellsearch® system (CS) in patients, who underwent resection with curative intent of different stages (UICC I-IV) of colorectal cancer. Out of 91 Patients who underwent colorectal resection, 68 patients were included in this study. CTC analysis was performed in patients with CRC UICC stages I-IV immediately before surgery. Data were correlated with clinicopathological parameters and patient outcomes. One or more CTCs/7.5 mL were detected in 45.6% (31/68) of patients. CTCs were detected in all stages of the Union of International Cancer Control (UICC), in stage I (1/4, 25%), in stage II (4/12, 33.3%), in stage III (5/19, 26.3%) and in stage IV (21/33, 63.6%). The detection of ≥ 1 CTCs/ 7.5ml correlated to the presence of distant overt metastases (p = 0.014) as well as with shorter progression-free (p = 0.008) and overall survival (p = 0.008). Multivariate analyses showed that the detection of ≥ 1 CTCs/ 7.5ml is an independent prognostic indicator for overall survival (HR, 3.14; 95% CI, 1.18-8.32; p = 0.021). The detection of CTCs is an independent and strong prognostic factor in CRC, which might improve the identification of high-risk patients in future clinical trials.
Collapse
Affiliation(s)
- Thaer S. A. Abdalla
- Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- * E-mail:
| | - Jan Meiners
- Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Sabine Riethdorf
- Department of Tumor Biology, University Cancer Center Hamburg, Center for Experimental Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Alexandra König
- Department of General Surgery, Hospital Wilhelmshaven, Wilhelmshaven, Germany
| | - Nathaniel Melling
- Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Tobias Gorges
- Department of Tumor Biology, University Cancer Center Hamburg, Center for Experimental Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Karl-F. Karstens
- Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Jakob R. Izbicki
- Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Klaus Pantel
- Department of Tumor Biology, University Cancer Center Hamburg, Center for Experimental Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Matthias Reeh
- Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| |
Collapse
|
37
|
Corlin L, Ruan M, Tsilidis KK, Bouras E, Yu YH, Stolzenberg-Solomon R, Klein AP, Risch HA, Amos CI, Sakoda LC, Vodička P, Rish PK, Beck J, Platz EA, Michaud DS. Two-Sample Mendelian Randomization Analysis of Associations Between Periodontal Disease and Risk of Cancer. JNCI Cancer Spectr 2021; 5:pkab037. [PMID: 34222791 PMCID: PMC8242136 DOI: 10.1093/jncics/pkab037] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2021] [Revised: 03/10/2021] [Accepted: 03/30/2021] [Indexed: 12/12/2022] Open
Abstract
Background Observational studies indicate that periodontal disease may increase the risk of colorectal, lung, and pancreatic cancers. Using a 2-sample Mendelian randomization (MR) analysis, we assessed whether a genetic predisposition index for periodontal disease was associated with colorectal, lung, or pancreatic cancer risks. Methods Our primary instrument included single nucleotide polymorphisms with strong genome-wide association study evidence for associations with chronic, aggressive, and/or severe periodontal disease (rs729876, rs1537415, rs2738058, rs12461706, rs16870060, rs2521634, rs3826782, and rs7762544). We used summary-level genetic data for colorectal cancer (n = 58 131 cases; Genetics and Epidemiology of Colorectal Cancer Consortium, Colon Cancer Family Registry, and Colorectal Transdisciplinary Study), lung cancer (n = 18 082 cases; International Lung Cancer Consortium), and pancreatic cancer (n = 9254 cases; Pancreatic Cancer Consortia). Four MR approaches were employed for this analysis: random-effects inverse-variance weighted (primary analyses), Mendelian Randomization-Pleiotropy RESidual Sum and Outlier, simple median, and weighted median. We conducted secondary analyses to determine if associations varied by cancer subtype (colorectal cancer location, lung cancer histology), sex (colorectal and pancreatic cancers), or smoking history (lung and pancreatic cancer). All statistical tests were 2-sided. Results The genetic predisposition index for chronic or aggressive periodontitis was statistically significantly associated with a 3% increased risk of colorectal cancer (per unit increase in genetic index of periodontal disease; P = .03), 3% increased risk of colon cancer (P = .02), 4% increased risk of proximal colon cancer (P = .01), and 3% increased risk of colorectal cancer among females (P = .04); however, it was not statistically significantly associated with the risk of lung cancer or pancreatic cancer, overall or within most subgroups. Conclusions Genetic predisposition to periodontitis may be associated with colorectal cancer risk. Further research should determine whether increased periodontitis prevention and increased cancer surveillance of patients with periodontitis is warranted.
Collapse
Affiliation(s)
- Laura Corlin
- Department of Public Health and Community Medicine, Tufts University School of Medicine, Boston, MA, USA
- Department of Civil and Environmental Engineering, Tufts University School of Engineering, Medford, MA, USA
| | - Mengyuan Ruan
- Department of Public Health and Community Medicine, Tufts University School of Medicine, Boston, MA, USA
| | - Konstantinos K Tsilidis
- Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK
- Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina, Greece
| | - Emmanouil Bouras
- Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina, Greece
| | - Yau-Hua Yu
- Department of Periodontology, Tufts University School of Dental Medicine, Boston, MA, USA
| | | | - Alison P Klein
- Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, USA
| | - Harvey A Risch
- Department of Chronic Disease Epidemiology, Yale School of Public Health, New Haven, CT, USA
| | | | - Lori C Sakoda
- Division of Research, Kaiser Permanente Northern California, Oakland, CA, USA
| | - Pavel Vodička
- Department of the Molecular Biology of Cancer, Institute of Experimental Medicine, Academy of Sciences of the Czech Republic, Prague, Czech Republic
| | - Pai K Rish
- Laboratory Medicine and Pathology, The Colon Cancer Family Registry at Mayo Clinic, Rochester, MN, USA
| | - James Beck
- Department of Dental Ecology, University of North Carolina, Chapel Hill, NC, USA
| | - Elizabeth A Platz
- The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, USA
- Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA for CCFR, CORECT, GECCO, ILCCO, PanScan, and PanC4
| | - Dominique S Michaud
- Department of Public Health and Community Medicine, Tufts University School of Medicine, Boston, MA, USA
| |
Collapse
|
38
|
Trabulsi NH, Halawani HM, Alshahrani EA, Alamoudi RM, Jambi SK, Akeel NY, Farsi AH, Nassif MO, Samkari AA, Saleem AM, Malibary NH, Abbas MM, Gianotti L, Lamazza A, Yoon JY, Farsi NJ. Short-term outcomes of stents in obstructive rectal cancer: A systematic review and meta-analysis. Saudi J Gastroenterol 2021; 27:127-135. [PMID: 33976008 PMCID: PMC8265400 DOI: 10.4103/sjg.sjg_506_20] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/13/2020] [Accepted: 01/01/2021] [Indexed: 11/17/2022] Open
Abstract
BACKGROUND With acute obstruction due to rectal or recto-sigmoid cancer, the safety and success of deploying self-expandable metal stents has been controversial. The aim of this systematic review was to synthesize the existing evidence on the outcomes and complication rates of stent placement in these patients. METHODS We performed a literature search of PubMed by using appropriate keywords, and manual reference screening of included articles was done. The article screening, data extraction, and quality assessment was done by four independent reviewers. A meta analyses was performed for the main outcome measures: technical and clinical success and complication rates. RESULTS We identified 962 articles in the search. After applying inclusion and exclusion criteria, we included 32 articles in the meta-analysis. The pooled technical success rate across 26 studies that reported it was 97% [95% confidence interval (CI): 95%-99%] without evidence of significant heterogeneity (I2 = 0.0%, P = 0.84), and the clinical success rate across 26 studies that reported it was 69% (95% CI: 58%-79%) with evidence of significant heterogeneity (I2 = 81.7%, P < 0.001). The pooled overall complication rate across the 32 studies was 28% (95% CI: 20%-37%) with evidence of significant heterogeneity (I2 = 79.3%, P < 0.001). CONCLUSION The use of rectal stents in obstructing rectal or recto-sigmoid tumors seems to be technically feasible. A high rate of technical success, however, does not always translate into clinical success. A considerable complication rate is associated with this approach. Randomized controlled trials are needed to compare the outcomes of rectal stent placement with those of surgery.
Collapse
Affiliation(s)
- Nora H. Trabulsi
- Department of Surgery, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Hajar M. Halawani
- Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia
| | | | - Rawan M. Alamoudi
- Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Sama K. Jambi
- Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Nouf Y. Akeel
- Department of Surgery, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Ali H. Farsi
- Department of Surgery, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Mohammed O. Nassif
- Department of Surgery, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Ali A. Samkari
- Department of Surgery, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Abdulaziz M. Saleem
- Department of Surgery, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Nadim H. Malibary
- Department of Surgery, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Mohammad M. Abbas
- Department of Surgery, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Luca Gianotti
- Department of Surgery, School of Medicine and Surgery, University of Milano-Bicocca, and San Gerardo Hospital, Monza, Italy
| | - Antonietta Lamazza
- Department Pietro Valdoni-Policlinico Umberto I, University of Rome La Sapienza, Rome, Italy
| | - Jin Young Yoon
- Department of Internal Medicine and Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea
| | - Nada J. Farsi
- Department of Dental Public Health, Faculty of Dentistry, King Abdulaziz University, Jeddah, Saudi Arabia
| |
Collapse
|
39
|
Darooghegi Mofrad M, Mozaffari H, Askari MR, Amini MR, Jafari A, Surkan PJ, Azadbakht L. Potato Consumption and Risk of Site-Specific Cancers in Adults: A Systematic Review and Dose-Response Meta-Analysis of Observational Studies. Adv Nutr 2021; 12:1705-1722. [PMID: 33861304 PMCID: PMC8483953 DOI: 10.1093/advances/nmab024] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2020] [Revised: 05/29/2020] [Accepted: 02/04/2021] [Indexed: 12/29/2022] Open
Abstract
The etiology of cancer type may vary significantly due to anatomy, embryology, and physiology of the cancer site. Although the association between potato consumption and colorectal cancer (CRC) was summarized in a 2018 meta-analysis of 5 cohort studies, to the best of our knowledge, no meta-analysis has evaluated potato consumption in relation to multiple cancer sites in adults. Medline/PubMed, ISI Web of Knowledge, Scopus, and the Cochrane Database of Systematic Reviews were searched for relevant publications through August 2020. We selected cohort or case-control studies conducted in adults that reported risk estimates (relative risk [RRs], HRs, and ORs) of potato intake for any cancer type. Random effects meta-analyses compared high and low intake categories. Twenty prospective cohort studies (total n = 785,348) including 19,882 incident cases, and 36 case-control studies (21,822 cases; 66,502 controls) were included. Among cohort studies, we did not find an association between high versus low intake of total potato (white and yellow) consumption and overall cancers: 1.04 (95% CI: 0.96, 1.11; tau2 = 0.005, n = 18). We found no relation between total potato consumption (high compared with low intake) and risk of CRC, pancreatic cancer, colon, gastric, breast, prostate, kidney, lung, or bladder cancer in cohort or case-control studies. We did not find an association between high versus low consumption of potato preparations (boiled/fried/mashed/roasted/baked) and risk of gastrointestinal-, sex-hormone-, or urinary-related cancers in cohort or case-control studies. Certainty of the evidence was low for total cancer, CRC, colon, rectal, renal, pancreatic, breast, prostate, and lung cancer and very low for gastric and bladder cancer. In conclusion, potato intake or potato preparations were not associated with multiple cancer sites when comparing high and low intake categories. This finding was consistent with the findings from the 2018 meta-analysis regarding potato intake and risk of CRC.
Collapse
Affiliation(s)
- Manije Darooghegi Mofrad
- Department of Community Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences, Tehran, Iran
| | - Hadis Mozaffari
- Faculty of Land and Food Systems, University of British Columbia, Vancouver, Canada
| | - Mohammad Reza Askari
- Department of Community Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences, Tehran, Iran
| | - Mohammad Reza Amini
- Department of Clinical Nutrition, Faculty of Nutrition Sciences and Food Technology, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Alireza Jafari
- Department of Community Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences, Tehran, Iran
| | - Pamela J Surkan
- Department of International Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA
| | | |
Collapse
|
40
|
Ahmad R, Singh JK, Wunnava A, Al-Obeed O, Abdulla M, Srivastava SK. Emerging trends in colorectal cancer: Dysregulated signaling pathways (Review). Int J Mol Med 2021; 47:14. [PMID: 33655327 PMCID: PMC7834960 DOI: 10.3892/ijmm.2021.4847] [Citation(s) in RCA: 103] [Impact Index Per Article: 25.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2020] [Accepted: 12/14/2020] [Indexed: 02/06/2023] Open
Abstract
Colorectal cancer (CRC) is the third most frequently detected type of cancer, and the second most common cause of cancer‑related mortality globally. The American Cancer Society predicted that approximately 147,950 individuals would be diagnosed with CRC, out of which 53,200 individuals would succumb to the disease in the USA alone in 2020. CRC‑related mortality ranks third among both males and females in the USA. CRC arises from 3 major pathways: i) The adenoma‑carcinoma sequence; ii) serrated pathway; and iii) the inflammatory pathway. The majority of cases of CRC are sporadic and result from risk factors, such as a sedentary lifestyle, obesity, processed diets, alcohol consumption and smoking. CRC is also a common preventable cancer. With widespread CRC screening, the incidence and mortality from CRC have decreased in developed countries. However, over the past few decades, CRC cases and mortality have been on the rise in young adults (age, <50 years). In addition, CRC cases are increasing in developing countries with a low gross domestic product (GDP) due to lifestyle changes. CRC is an etiologically heterogeneous disease classified by tumor location and alterations in global gene expression. Accumulating genetic and epigenetic perturbations and aberrations over time in tumor suppressor genes, oncogenes and DNA mismatch repair genes could be a precursor to the onset of colorectal cancer. CRC can be divided as sporadic, familial, and inherited depending on the origin of the mutation. Germline mutations in APC and MLH1 have been proven to play an etiological role, resulting in the predisposition of individuals to CRC. Genetic alterations cause the dysregulation of signaling pathways leading to drug resistance, the inhibition of apoptosis and the induction of proliferation, invasion and migration, resulting in CRC development and metastasis. Timely detection and effective precision therapies based on the present knowledge of CRC is essential for successful treatment and patient survival. The present review presents the CRC incidence, risk factors, dysregulated signaling pathways and targeted therapies.
Collapse
Affiliation(s)
- Rehan Ahmad
- Colorectal Research Chair, Department of Surgery, King Saud University College of Medicine, Riyadh 11472, Saudi Arabia
| | - Jaikee Kumar Singh
- Department of Biosciences, Manipal University Jaipur, Jaipur, Rajasthan 303007, India
| | - Amoolya Wunnava
- Department of Biosciences, Manipal University Jaipur, Jaipur, Rajasthan 303007, India
| | - Omar Al-Obeed
- Colorectal Research Chair, Department of Surgery, King Saud University College of Medicine, Riyadh 11472, Saudi Arabia
| | - Maha Abdulla
- Colorectal Research Chair, Department of Surgery, King Saud University College of Medicine, Riyadh 11472, Saudi Arabia
| | | |
Collapse
|
41
|
Grahn O, Lundin M, Lydrup ML, Angenete E, Rutegård M. Postoperative non-steroidal anti-inflammatory drug use and oncological outcomes of rectal cancer. BJS Open 2021; 5:6137422. [PMID: 33609397 PMCID: PMC7893477 DOI: 10.1093/bjsopen/zraa050] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2020] [Accepted: 11/06/2020] [Indexed: 12/30/2022] Open
Abstract
BACKGROUND Non-steroidal anti-inflammatory drugs (NSAIDs) are known to suppress the inflammatory response after surgery and are often used for pain control. This study aimed to investigate NSAID use after radical surgical resection for rectal cancer and long-term oncological outcomes. METHODS A cohort of patients who underwent anterior resection for rectal cancer between 2007 and 2013 in 15 hospitals in Sweden was investigated retrospectively. Data were obtained from the Swedish Colorectal Cancer Registry and medical records; follow-up was undertaken until July 2019. Patients who received NSAID treatment for at least 2 days after surgery were compared with controls who did not, and the primary outcome was recurrence-free survival. Cox regression modelling with confounder adjustment, propensity score matching, and an instrumental variables approach were used; missing data were handled by multiple imputation. RESULTS The cohort included 1341 patients, 362 (27.0 per cent) of whom received NSAIDs after operation. In analyses using conventional regression and propensity score matching, there was no significant association between postoperative NSAID use and recurrence-free survival (adjusted hazard ratio (HR) 1.02, 0.79 to 1.33). The instrumental variables approach, including individual hospital as the instrumental variable and clinicopathological variables as co-variables, suggested a potential improvement in the NSAID group (HR 0.61, 0.38 to 0.99). CONCLUSION conventional modelling did not demonstrate an association between postoperative NSAID use and recurrence-free survival in patients with rectal cancer, although an instrumental variables approach suggested a potential benefit.
Collapse
Affiliation(s)
- O Grahn
- Department of Surgical and Perioperative Sciences, Surgery, Umeå University, Umeå, Sweden
| | - M Lundin
- Department of Surgical and Perioperative Sciences, Surgery, Umeå University, Umeå, Sweden.,Department of Statistics, Umeå School of Business, Economics and Statistics, Umeå University, Umeå, Sweden
| | - M-L Lydrup
- Department of Surgery, Skåne University Hospital, Malmö, Lund University, Lund, Sweden
| | - E Angenete
- Department of Surgery, Institute of Clinical Sciences, Scandinavian Surgical Outcomes Research Group, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden.,Region Västra Götaland, Department of Surgery, Sahlgrenska University Hospital, Gothenburg, Sweden
| | - M Rutegård
- Department of Surgical and Perioperative Sciences, Surgery, Umeå University, Umeå, Sweden.,Wallenberg Centre for Molecular Medicine, Umeå University, Umeå, Sweden
| |
Collapse
|
42
|
Yu H, Hemminki K. Genetic epidemiology of colorectal cancer and associated cancers. Mutagenesis 2021; 35:207-219. [PMID: 31424514 DOI: 10.1093/mutage/gez022] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2019] [Accepted: 07/31/2019] [Indexed: 02/06/2023] Open
Abstract
We review here data on familial risk in colorectal cancer (CRC) generated from the Swedish Family-Cancer Database, the largest resource of its kind in the world. Although the concordant familial risk for CRC (i.e. CRC risk in families of CRC patients) has been reasonably well established, the studies on discordant familial risks (i.e. CRC risk in families with any other cancers) are rare. Because different cancers could be caused by shared genetic susceptibility or shared environment, data of associations of discordant cancers may provide useful information for identifying common risk factors. In analyses between any of 33 discordant cancers relative risks (RRs) for discordant cancers were estimated in families with increasing numbers of probands with CRC; in the reverse analyses, RRs for CRC were estimated in families with increasing numbers of probands with discordant cancers. In separate analyses, hereditary non-polyposis colorectal cancer (HNPCC) families were excluded from the study, based on HNPCC related double primary cancers, to assess the residual familial RRs. We further reviewed familial risks of colon and rectal cancers separately in search for distinct discordant associations. The reviewed data suggested that colon cancer was associated with a higher familial risk for CRC compared to rectal cancer. The previous data had reported associations of CRC with melanoma, thyroid and eye cancers. Nervous system cancer was only associated with colon cancer, and lung cancer only associated with rectal cancer. The reviewed data on discordant association may provide guidance to gene identification and may help genetic counseling.
Collapse
Affiliation(s)
- Hongyao Yu
- Division of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld, Heidelberg, Germany.,Guangzhou Key Laboratory of Environmental Pollution and Health Risk Assessment, Department of Preventive Medicine, School of Public Health, Sun Yat-sen University, Guangzhou, China
| | - Kari Hemminki
- Division of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld, Heidelberg, Germany
| |
Collapse
|
43
|
Gotfrit J, Thangarasa T, Dudani S, Goodwin R, Tang PA, Monzon J, Dennis K, Cheung WY, Marginean H, Vickers M. The impact of driving time, distance, and socioeconomic factors on outcomes of patients with locally advanced rectal cancer. PUBLIC HEALTH IN PRACTICE 2020; 1:100012. [PMID: 36101686 PMCID: PMC9461354 DOI: 10.1016/j.puhip.2020.100012] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2020] [Revised: 05/06/2020] [Accepted: 05/12/2020] [Indexed: 11/25/2022] Open
|
44
|
Hutchings C, Phillips JA, Djamgoz MBA. Nerve input to tumours: Pathophysiological consequences of a dynamic relationship. Biochim Biophys Acta Rev Cancer 2020; 1874:188411. [PMID: 32828885 DOI: 10.1016/j.bbcan.2020.188411] [Citation(s) in RCA: 52] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2020] [Revised: 08/13/2020] [Accepted: 08/13/2020] [Indexed: 12/13/2022]
Abstract
It is well known that tumours arising in different organs are innervated and that 'perineural invasion' (cancer cells escaping from the tumour by following the nerve trunk) is a negative prognostic factor. More surprisingly, increasing evidence suggests that the nerves can provide active inputs to tumours and there is two-way communication between nerves and cancer cells within the tumour microenvironment. Cells of the immune system also interact with the nerves and cancer cells. Thus, the nerve connections can exert significant control over cancer progression and modulating these (physically or chemically) can affect significantly the cancer process. Nerve inputs to tumours are derived mainly from the sympathetic (adrenergic) and the parasympathetic (cholinergic) systems, which are interactive. An important component of the latter is the vagus nerve, the largest of the cranial nerves. Here, we present a two-part review of the nerve inputs to tumours and their effects on tumorigenesis. First, we review briefly some relevant general issues including ultrastructural aspects, stemness, interactions between neurones and primary tumours, and communication between neurones and metastasizing tumour cells. Ultrastructural characteristics include synaptic vesicles, tumour microtubes and gap junctions enabling formation of cellular networks. Second, we evaluate the pathophysiology of the nerve input to five major carcinomas: cancers of prostate, stomach, colon, lung and pancreas. For each cancer, we present (i) the nerve inputs normally present in the cancer organ and (ii) how these interact and influence the cancer process. The best clinical evidence for the role of nerves in promoting tumorigenesis comes from prostate cancer patients where metastatic progression has been shown to be suppressed significantly in cases of spinal cord injury. The balance of the sympathetic and parasympathetic contributions to early versus late tumorigenesis varies amongst the different cancers. Different branches of the vagus provide functional inputs to several of the carcinomas and, in two-way interaction with the sympathetic nervous system, affect different stages of the cancer process. Overall, the impact of the vagus nerve can be 'direct' or 'indirect'. Directly, the effect of the vagus is primarily to promote tumorigenesis and this is mediated through cholinergic receptor mechanisms. Indirectly, pro- and anti-tumour effects can occur by stimulation or inhibition of the sympathetic nervous system, respectively. Less well understood are the 'indirect' anti-tumour effect of the vagus nerve via immunomodulation/inflammation, and the role of sensory innervation. A frequent occurrence in the nerve-tumour interactions is the presence of positive feedback driven by agents like nerve growth factor. We conclude that the nerve inputs to tumours can actively and dynamically impact upon cancer progression and are open to clinical exploitation.
Collapse
Affiliation(s)
- Charlotte Hutchings
- Imperial College London, Department of Life Sciences, Neuroscience Solutions to Cancer Research Group, Sir Alexander Fleming Building, South Kensington Campus, London SW7 2AZ, UK
| | - Jade A Phillips
- Imperial College London, Department of Life Sciences, Neuroscience Solutions to Cancer Research Group, Sir Alexander Fleming Building, South Kensington Campus, London SW7 2AZ, UK
| | - Mustafa B A Djamgoz
- Imperial College London, Department of Life Sciences, Neuroscience Solutions to Cancer Research Group, Sir Alexander Fleming Building, South Kensington Campus, London SW7 2AZ, UK; Biotechnology Research Centre, Cyprus International University, Haspolat, Nicosia, TRNC, Mersin 10, Turkey.
| |
Collapse
|
45
|
Ramirez R, Chiu YC, Hererra A, Mostavi M, Ramirez J, Chen Y, Huang Y, Jin YF. Classification of Cancer Types Using Graph Convolutional Neural Networks. FRONTIERS IN PHYSICS 2020; 8:203. [PMID: 33437754 PMCID: PMC7799442 DOI: 10.3389/fphy.2020.00203] [Citation(s) in RCA: 49] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/04/2023]
Abstract
BACKGROUND Cancer has been a leading cause of death in the United States with significant health care costs. Accurate prediction of cancers at an early stage and understanding the genomic mechanisms that drive cancer development are vital to the improvement of treatment outcomes and survival rates, thus resulting in significant social and economic impacts. Attempts have been made to classify cancer types with machine learning techniques during the past two decades and deep learning approaches more recently. RESULTS In this paper, we established four models with graph convolutional neural network (GCNN) that use unstructured gene expressions as inputs to classify different tumor and non-tumor samples into their designated 33 cancer types or as normal. Four GCNN models based on a co-expression graph, co-expression+singleton graph, protein-protein interaction (PPI) graph, and PPI+singleton graph have been designed and implemented. They were trained and tested on combined 10,340 cancer samples and 731 normal tissue samples from The Cancer Genome Atlas (TCGA) dataset. The established GCNN models achieved excellent prediction accuracies (89.9-94.7%) among 34 classes (33 cancer types and a normal group). In silico gene-perturbation experiments were performed on four models based on co-expression graph, co-expression+singleton, PPI graph, and PPI+singleton graphs. The co-expression GCNN model was further interpreted to identify a total of 428 markers genes that drive the classification of 33 cancer types and normal. The concordance of differential expressions of these markers between the represented cancer type and others are confirmed. Successful classification of cancer types and a normal group regardless of normal tissues' origin suggested that the identified markers are cancer-specific rather than tissue-specific. CONCLUSION Novel GCNN models have been established to predict cancer types or normal tissue based on gene expression profiles. We demonstrated the results from the TCGA dataset that these models can produce accurate classification (above 94%), using cancer-specific markers genes. The models and the source codes are publicly available and can be readily adapted to the diagnosis of cancer and other diseases by the data-driven modeling research community.
Collapse
Affiliation(s)
- Ricardo Ramirez
- Department of Electrical and Computer Engineering, the University of Texas at San Antonio, San Antonio, Texas 78249, USA
| | - Yu-Chiao Chiu
- Greehey Children’s Cancer Research Institute, The University of Texas Health San Antonio, San Antonio, TX, 78229, USA
| | - Allen Hererra
- Department of Electrical and Computer Engineering, the University of Texas at San Antonio, San Antonio, Texas 78249, USA
| | - Milad Mostavi
- Department of Electrical and Computer Engineering, the University of Texas at San Antonio, San Antonio, Texas 78249, USA
| | - Joshua Ramirez
- Department of Electrical and Computer Engineering, the University of Texas at San Antonio, San Antonio, Texas 78249, USA
| | - Yidong Chen
- Greehey Children’s Cancer Research Institute, The University of Texas Health San Antonio, San Antonio, TX, 78229, USA
- Department of Population Health Sciences, The University of Texas Health San Antonio, San Antonio, Texas 78229, USA
| | - Yufei Huang
- Department of Electrical and Computer Engineering, the University of Texas at San Antonio, San Antonio, Texas 78249, USA
- Department of Population Health Sciences, The University of Texas Health San Antonio, San Antonio, Texas 78229, USA
| | - Yu-Fang Jin
- Department of Electrical and Computer Engineering, the University of Texas at San Antonio, San Antonio, Texas 78249, USA
| |
Collapse
|
46
|
Del Rio P, Rossini M, Giuffrida M, Cozzani F, Guarnieri E, Dell'abate P. Rightward shift in colorectal cancer: experience in 1101 patients. MINERVA CHIR 2020; 75:225-233. [PMID: 32456392 DOI: 10.23736/s0026-4733.20.08263-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
BACKGROUND In the past decades the right colon cancer showed a higher incidence rate than left colon cancer. This trend is known as "proximal shift" or "rightwards shift." We evaluated rightward shift phenomenon in our region. METHODS We collected data from 1101 colorectal cancer patients who underwent curative surgery at Parma University Hospital from 01 January 2004 through 01 January 2018. We divided patients into seven subgroups according to the time of surgery to evaluate epidemiological changes through the years of colon cancer. RESULTS We found a non-linear rightward shift trend of CRC. The incidence of RCC was the 40% between 2004-2005 and 51% in the biennium 2016-2017 (60% in 2012-2013 and 57% in 2014-2015). The patients with RCC were significantly older than patients with LCC. RCCs have poor differentiated tumors. Metastatic disease showed a similar distribution both in left and right CRCs. Peritoneum was the most common metastasis location from right-sided colon cancer. CONCLUSIONS Data suggest the existence of two different tumor entities in CRC between right-sided colon cancer and left-sided colon cancer. The proximal shift may be a reflection of improved screening programs, diagnostic accuracy and population aging. Ethnicity, gender, diet, environment, and socioeconomic status contribute to CRC incidence and prevalence in different regions.
Collapse
Affiliation(s)
- Paolo Del Rio
- Unit of General Surgery, Parma University Hospital, Parma, Italy
| | - Matteo Rossini
- Unit of General Surgery, Parma University Hospital, Parma, Italy -
| | - Mario Giuffrida
- Unit of General Surgery, Parma University Hospital, Parma, Italy
| | - Federico Cozzani
- Unit of General Surgery, Parma University Hospital, Parma, Italy
| | - Elena Guarnieri
- Unit of General Surgery, Parma University Hospital, Parma, Italy
| | - Paolo Dell'abate
- Unit of General Surgery, Parma University Hospital, Parma, Italy
| |
Collapse
|
47
|
Holm M, Joenväärä S, Saraswat M, Tohmola T, Ristimäki A, Renkonen R, Haglund C. Plasma protein expression differs between colorectal cancer patients depending on primary tumor location. Cancer Med 2020; 9:5221-5234. [PMID: 32452655 PMCID: PMC7367633 DOI: 10.1002/cam4.3178] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2020] [Revised: 05/07/2020] [Accepted: 05/09/2020] [Indexed: 12/25/2022] Open
Abstract
Colorectal cancer (CRC) includes tumors in the right colon, left colon, and rectum, although they differ significantly from each other in aspects such as prognosis and treatment. Few previous mass spectrometry-based studies have analyzed differences in protein expression depending on the tumor location. In this study, we have used mass spectrometry-based proteomics to analyze plasma samples from 83 CRC patients to study if differences in plasma protein expression can be seen depending on primary tumor location (right colon, left colon, or rectum). Differences were studied between the groups both regardless of and according to tumor stage (II or III). Large differences in plasma protein expression were seen, and we found that plasma samples from patients with rectal cancer separated from samples from patients with colon cancer when analyzed by principal component analysis and hierarchical clustering. Samples from patients with cancer in the right and left colon also tended to separate from each other. Pathway analysis discovered canonical pathways involved in lipid metabolism and inflammation to be enriched. This study will help to further define CRC as distinct entities depending on tumor location, as shown by the widespread differences in plasma protein profile and dysregulated pathways.
Collapse
Affiliation(s)
- Matilda Holm
- Department of Surgery, Faculty of Medicine, University of Helsinki and Helsinki University Hospital, University of Helsinki, Helsinki, Finland.,Department of Pathology, Faculty of Medicine, University of Helsinki and Helsinki University Hospital, University of Helsinki, Helsinki, Finland.,Translational Cancer Medicine Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland.,Applied Tumor Genomics Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | - Sakari Joenväärä
- Transplantation Laboratory, Haartman Institute, University of Helsinki, Helsinki, Finland.,HUSLAB, Helsinki University Hospital, Helsinki, Finland
| | - Mayank Saraswat
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA
| | - Tiialotta Tohmola
- Transplantation Laboratory, Haartman Institute, University of Helsinki, Helsinki, Finland.,HUSLAB, Helsinki University Hospital, Helsinki, Finland.,Department of Biosciences, Faculty of Biological and Environmental Sciences, University of Helsinki, Helsinki, Finland
| | - Ari Ristimäki
- Department of Pathology, Faculty of Medicine, University of Helsinki and Helsinki University Hospital, University of Helsinki, Helsinki, Finland.,Applied Tumor Genomics Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland.,HUSLAB, Helsinki University Hospital, Helsinki, Finland
| | - Risto Renkonen
- Transplantation Laboratory, Haartman Institute, University of Helsinki, Helsinki, Finland.,HUSLAB, Helsinki University Hospital, Helsinki, Finland
| | - Caj Haglund
- Department of Surgery, Faculty of Medicine, University of Helsinki and Helsinki University Hospital, University of Helsinki, Helsinki, Finland.,Translational Cancer Medicine Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland.,HUSLAB, Helsinki University Hospital, Helsinki, Finland
| |
Collapse
|
48
|
Abundance of the Organic Anion-transporting Polypeptide OATP4A1 in Early-Stage Colorectal Cancer Patients: Association With Disease Relapse. Appl Immunohistochem Mol Morphol 2020; 27:185-194. [PMID: 29734253 DOI: 10.1097/pai.0000000000000557] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
The abundance of OATP4A1 in colorectal cancer (CRC) might be related to tumor progression. This was studied by immunohistochemistry on paraffin-embedded samples obtained from 178 patients (43 patients with a relapse within 5 y) with early-stage CRC. Positivity for OATP4A1 in tumor cells and noncancerous mucosal cells was proved by double-immunofluorescence staining with antibodies against OATP4A1 and keratin 8, whereas antibodies against appropriate CD markers were used to identify immune cells. Automated microscopic image analysis was used to measure the percentage of OATP4A1-positive cells and OATP4A1 staining intensity in tumor, immune, and adjacent normal-looking mucosal cells separately, as well as in the mucosal and immune cells of 14 nonmalignant tissue samples. In CRC the percentage of OATP4A1-positive cells, but not staining intensity, was significantly higher in tumor and mucosal cells adjacent to the tumor compared to the mucosa of nonmalignant samples (P<0.001 each). No difference was registered between immune cells in malignant and nonmalignant samples. Importantly, high levels of OATP4A1 in immune (odds ratio, 0.73; confidence interval, 0.63-0.85; P<0.001), and tumor cells (odds ratio, 0.79; confidence interval, 0.69-0.91; P<0.001) are significantly associated with a low risk of recurrence and also significantly enhance the discriminative power of other clinical parameters [such as International Union Against Cancer (UICC), adjuvant therapy, localization of the primary tumor] of the risk of relapse (receiver operating characteristics analysis; P=0.002). Using an advanced digital microscopic quantification procedure, we showed that OATP4A1 abundance is negatively associated with tumor recurrence in early-stage CRC. This digital scoring procedure may serve as a novel tool for the assessment of potential prognostic markers in early-stage CRC.
Collapse
|
49
|
Oliveira RC, Abrantes AM, Tralhão JG, Botelho MF. The role of mouse models in colorectal cancer research-The need and the importance of the orthotopic models. Animal Model Exp Med 2020; 3:1-8. [PMID: 32318654 PMCID: PMC7167241 DOI: 10.1002/ame2.12102] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2019] [Revised: 01/06/2020] [Accepted: 02/21/2020] [Indexed: 12/11/2022] Open
Abstract
Colorectal cancer is a worldwide health burden, with high incidence and mortality, especially in the advanced stages of the disease. Preclinical models are very important and valuable to discover and validate early and specific biomarkers as well as new therapeutic targets. In order to accomplish that, the animal models must replicate the clinical evolution of the disease in all of its phases. In this article, we review the existent mouse models, with their strengths and weaknesses in the replication of human cancer disease progression, with major focus on orthotopic models.
Collapse
Affiliation(s)
- Rui C. Oliveira
- Biophysics UnitFaculty of MedicineUniversity of CoimbraCoimbraPortugal
- Pathology DepartmentUniversity Hospital (CHUC)CoimbraPortugal
| | - Ana Margarida Abrantes
- Biophysics UnitFaculty of MedicineUniversity of CoimbraCoimbraPortugal
- Centre of Investigation on Environment, Genetics and Oncobiology (CIMAGO)CoimbraPortugal
| | - José Guilherme Tralhão
- Biophysics UnitFaculty of MedicineUniversity of CoimbraCoimbraPortugal
- Centre of Investigation on Environment, Genetics and Oncobiology (CIMAGO)CoimbraPortugal
- Surgery A DepartmentFaculty of MedicineUniversity Hospital (CHUC)CoimbraPortugal
| | - Maria Filomena Botelho
- Biophysics UnitFaculty of MedicineUniversity of CoimbraCoimbraPortugal
- Centre of Investigation on Environment, Genetics and Oncobiology (CIMAGO)CoimbraPortugal
| |
Collapse
|
50
|
Daniel SK, Seo YD, Pillarisetty VG. The CXCL12-CXCR4/CXCR7 axis as a mechanism of immune resistance in gastrointestinal malignancies. Semin Cancer Biol 2019; 65:176-188. [PMID: 31874281 DOI: 10.1016/j.semcancer.2019.12.007] [Citation(s) in RCA: 141] [Impact Index Per Article: 23.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2019] [Revised: 12/03/2019] [Accepted: 12/11/2019] [Indexed: 02/07/2023]
Abstract
Single agent checkpoint inhibitor therapy has not been effective for most gastrointestinal solid tumors, but combination therapy with drugs targeting additional immunosuppressive pathways is being attempted. One such pathway, the CXCL12-CXCR4/CXCR7 chemokine axis, has attracted attention due to its effects on tumor cell survival and metastasis as well as immune cell migration. CXCL12 is a small protein that functions in normal hematopoietic stem cell homing in addition to repair of damaged tissue. Binding of CXCL12 to CXCR4 leads to activation of G protein signaling kinases such as P13K/mTOR and MEK/ERK while binding to CXCR7 leads to β-arrestin mediated signaling. While some gastric and colorectal carcinoma cells have been shown to make CXCL12, the primary source in pancreatic cancer and peritoneal metastases is cancer-associated fibroblasts. Binding of CXCL12 to CXCR4 and CXCR7 on tumor cells leads to anti-apoptotic signaling through Bcl-2 and survivin upregulation, as well as promotion of the epithelial-to-mesechymal transition through the Rho-ROCK pathway and alterations in cell adhesion molecules. High levels of CXCL12 seen in the bone marrow, liver, and spleen could partially explain why these are popular sites of metastases for many tumors. CXCL12 is a chemoattractant for lymphocytes at lower levels, but becomes chemorepellant at higher levels; it is unclear exactly what gradient exists in the tumor microenvironment and how this influences tumor-infiltrating lymphocytes. AMD3100 (Plerixafor or Mozobil) is a small molecule CXCR4 antagonist and is the most frequently used drug targeting the CXCL12-CXCR4/CXCR7 axis in clinical trials for gastrointestinal solid tumors currently. Other small molecules and monoclonal antibodies against CXCR4 are being trialed. Further understanding of the CXCL12- CXCR4/CXCR7 chemokine axis in the tumor microenvironment will allow more effective targeting of this pathway in combination immunotherapy.
Collapse
Affiliation(s)
- Sara K Daniel
- University of Washington, Dept. of Surgery, Seattle, WA, USA
| | - Y David Seo
- University of Washington, Dept. of Surgery, Seattle, WA, USA
| | | |
Collapse
|