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Zhao H, Wu Y, Kim SM. Enhancing doxorubicin's anticancer impact in colorectal cancer by targeting the Akt/Gsk3β/mTOR-SREBP1 signaling axis with an HDAC inhibitor. THE KOREAN JOURNAL OF PHYSIOLOGY & PHARMACOLOGY : OFFICIAL JOURNAL OF THE KOREAN PHYSIOLOGICAL SOCIETY AND THE KOREAN SOCIETY OF PHARMACOLOGY 2025; 29:321-335. [PMID: 40254556 PMCID: PMC12012316 DOI: 10.4196/kjpp.24.274] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/16/2024] [Revised: 11/05/2024] [Accepted: 11/19/2024] [Indexed: 04/22/2025]
Abstract
Colorectal cancer ranks third in global incidence and is the second leading cause of cancer-related mortality. Doxorubicin, an anthracycline chemotherapeutic drug, is integral to current cancer treatment protocols. However, toxicity and resistance to doxorubicin poses a significant challenge to effective therapy. Panobinostat has emerged as a critical agent in colorectal cancer treatment due to its potential to overcome doxorubicin resistance and enhance the efficacy of existing therapeutic protocols. This study aimed to evaluate the capability of panobinostat to surmount doxorubicin toxicity and resistance in colorectal cancer. Specifically, we assessed the efficacy of panobinostat in enhancing the therapeutic response to doxorubicin in colorectal cancer cells and explored the potential synergistic effects of their combined treatment. Our results demonstrate that the combination treatment significantly reduces cell viability and colony-forming ability in colorectal cancer cells compared to individual treatments. The combination induces significant apoptosis, as evidenced by increased levels of cleaved PARP and cleaved caspase-9, while also resulting in a greater reduction in p-Akt/p-GSK-3β/mTOR expression, along with substantial decreases in c-Myc and SREBP-1 levels, compared to monotherapies. Consistent with the in vitro experimental results, the combination treatment significantly inhibited tumor formation in colorectal cancer xenograft nude mice compared to the groups treated with either agent alone. In conclusion, our research suggests that the panobinostat effectively enhances the effect of doxorubicin and combination of two drugs significantly reduced colorectal cancer tumor growth by targeting the Akt/GSK-3β/mTOR signaling pathway, indicating a synergistic therapeutic potential of these two drugs in colorectal cancer treatment.
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Affiliation(s)
- Huaxin Zhao
- Department of Physiology, Institute for Medical Sciences, Jeonbuk National University Medical School, Jeonju 54907, Korea
| | - Yanling Wu
- Department of Physiology, Institute for Medical Sciences, Jeonbuk National University Medical School, Jeonju 54907, Korea
| | - Soo Mi Kim
- Department of Physiology, Institute for Medical Sciences, Jeonbuk National University Medical School, Jeonju 54907, Korea
- Research Institute of Clinical Medicine, Biomedical Research Institute of Jeonbuk National University Hospital, Jeonju 54907, Korea
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Xiong Z, Hu L, Peng H, Jiang X, Wang X, Tu L, Xu S. UCN expresses differently in left-sided and right-sided colon cancer contributing to distinct immune microenvironment via regulating CCL23. Hum Immunol 2025:111308. [PMID: 40274491 DOI: 10.1016/j.humimm.2025.111308] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2024] [Revised: 03/28/2025] [Accepted: 04/05/2025] [Indexed: 04/26/2025]
Abstract
PURPOSE Urocortin (UCN), is found to be overexpressed in colorectal cancer (CRC) but its role in tumor immune microenvironment (TIME) remains unclear. METHODS UCN expression was analyzed using RNA sequencing data from TCGA and detected in tumor samples from 18 patients with LC and 27 patients with RC. Tumor infiltrated T cells (TILs) were isolated from tumors and the exhaustion markers including PD-1, TIGIT, TIM-3 and LAG3 on CD8 + TILs were detected by flow cytometry. Correlations between UCN level and immunoregulatory factors were analyzed using Spearman correlation analysis. UCN was overexpressed in CRC cell lines and the CCL23 levels were detected by quantitative RT-PCR and enzyme-linked immunosorbent assay. RESULTS UCN was mainly overexpressed in Right-sided colon cancer (RC) and to be related to poor prognosis. Higher UCN level in tumors related to increased abundance of regulatory T cells and upregulated exhaustion markers in CD8 + T cells. UCN is positively correlated with CCL23 level in CRC and mainly upregulated in RC samples. Overexpression of UCN in HCT116 and HT-29 cells upregulated CCL23 expression and promoted CCL23 secretion. CD8 + T cells cultured with medium from UCN overexpressed CRC cells exhibited exhaustion phenotype with increased expression of CTLA-4, PD-1, TIGIT, TIM-3 and LAG-3, which was restored by CCL23 antibody. CONCLUSION This study successfully constructed the correlation between UCN overexpression and immunosuppressive TIME formation in CRC, providing a candidate target for new immunotherapy against CRC development.
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Affiliation(s)
- Zhenfang Xiong
- Jiangxi Provincial Key Laboratory for Precision Pathology and Intelligent Diagnosis, The First Affiliated Hospital, Nanchang University, Nanchang, Jiangxi, China
| | - Long Hu
- Jiangxi Provincial Key Laboratory for Precision Pathology and Intelligent Diagnosis, The First Affiliated Hospital, Nanchang University, Nanchang, Jiangxi, China
| | - Haiyan Peng
- Jiangxi Provincial Key Laboratory for Precision Pathology and Intelligent Diagnosis, The First Affiliated Hospital, Nanchang University, Nanchang, Jiangxi, China
| | - Xiaoyue Jiang
- Jiangxi Provincial Key Laboratory for Precision Pathology and Intelligent Diagnosis, The First Affiliated Hospital, Nanchang University, Nanchang, Jiangxi, China
| | - Xu Wang
- Jiangxi Provincial Key Laboratory for Precision Pathology and Intelligent Diagnosis, The First Affiliated Hospital, Nanchang University, Nanchang, Jiangxi, China
| | - Luxia Tu
- Jiangxi Provincial Key Laboratory for Precision Pathology and Intelligent Diagnosis, The First Affiliated Hospital, Nanchang University, Nanchang, Jiangxi, China
| | - Shan Xu
- Jiangxi Provincial Key Laboratory for Precision Pathology and Intelligent Diagnosis, The First Affiliated Hospital, Nanchang University, Nanchang, Jiangxi, China.
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Lansom J, Liew I, Ng KS, Ly T, Naidu K, Chapuis P, Chan C. Right vs. Left colorectal cancer - Where do we draw the line? Hum Pathol 2024; 151:105634. [PMID: 39117025 DOI: 10.1016/j.humpath.2024.105634] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/13/2024] [Revised: 07/25/2024] [Accepted: 08/05/2024] [Indexed: 08/10/2024]
Abstract
PURPOSE No consensus on the definition of right and left colorectal cancer (CRC) exists, nor studies offering histological or molecular basis for such categorisation. This study investigated the regional variations in the histological and molecular characteristics of CRCs, with the objective of determining an optimal division point between right and left CRCs. MATERIALS AND METHODS An observational study of consecutive patients who underwent CRC resection (1995-2022) at Concord Hospital, Sydney was performed. Clinicopathological data were extracted from a prospective database and seven permutations of right-left divisions considered. Logistic regression tested association between the right-left divisions and pathological characteristics. Receiver operating characteristic and area under the curve (AUC) analyses determined the discriminative ability of each division to predict 18 pathology characteristics. RESULTS 3753 patients underwent a CRC resection (2120 male; mean 69.5yrs [SD12.6]). There was regional variation in tumours with respect to tumour infiltrating lymphocytes (TILs), mismatch repair deficiency (dMMR), and mutant BRAF (mBRAF). Left-sided tumours were less likely to demonstrate TILs (P < 0.001), be dMMR (P < 0.001), and express mBRAF (P < 0.001). Division at the descending-sigmoid junction yielded highest discriminative abilities: TILs - AUC 0.66, dMMR - AUC 0.76, and mBRAF - AUC 0.73. CONCLUSION This is the first study to provide a pathological basis on which right- and left-sided cancers may be defined, and found the optimal division point between the right and left colorectum to be at the descending-sigmoid junction. Further research is needed to determine whether this can facilitate individualised patient management.
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Affiliation(s)
- Joshua Lansom
- Colorectal Surgery Unit, Concord Hospital, Hospital Rd, Concord, NSW, 2139 Australia; Concord Institute of Academic Surgery, Concord Hospital, Hospital Rd, Concord, NSW, 2139, Australia; University of Sydney, Concord Clinical School, Clinical Sciences Building, Concord Hospital, Hospital Rd, Concord, NSW, 2139, Australia.
| | - Ian Liew
- University of Sydney, Concord Clinical School, Clinical Sciences Building, Concord Hospital, Hospital Rd, Concord, NSW, 2139, Australia; Department of Anatomical Pathology, Concord Hospital, Hospital Rd, Concord, NSW, 2139 Australia
| | - Kheng-Seong Ng
- Colorectal Surgery Unit, Concord Hospital, Hospital Rd, Concord, NSW, 2139 Australia; Concord Institute of Academic Surgery, Concord Hospital, Hospital Rd, Concord, NSW, 2139, Australia; University of Sydney, Concord Clinical School, Clinical Sciences Building, Concord Hospital, Hospital Rd, Concord, NSW, 2139, Australia
| | - Theresa Ly
- University of Sydney, Concord Clinical School, Clinical Sciences Building, Concord Hospital, Hospital Rd, Concord, NSW, 2139, Australia; Department of Anatomical Pathology, Concord Hospital, Hospital Rd, Concord, NSW, 2139 Australia
| | - Krishanth Naidu
- Colorectal Surgery Unit, Concord Hospital, Hospital Rd, Concord, NSW, 2139 Australia; Concord Institute of Academic Surgery, Concord Hospital, Hospital Rd, Concord, NSW, 2139, Australia; University of Sydney, Concord Clinical School, Clinical Sciences Building, Concord Hospital, Hospital Rd, Concord, NSW, 2139, Australia
| | - Pierre Chapuis
- Colorectal Surgery Unit, Concord Hospital, Hospital Rd, Concord, NSW, 2139 Australia; Concord Institute of Academic Surgery, Concord Hospital, Hospital Rd, Concord, NSW, 2139, Australia; University of Sydney, Concord Clinical School, Clinical Sciences Building, Concord Hospital, Hospital Rd, Concord, NSW, 2139, Australia
| | - Charles Chan
- University of Sydney, Concord Clinical School, Clinical Sciences Building, Concord Hospital, Hospital Rd, Concord, NSW, 2139, Australia; Department of Anatomical Pathology, Concord Hospital, Hospital Rd, Concord, NSW, 2139 Australia
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Wu Y, Zhang Y, Xu F, Zhang Z, Wang Y. Expression and Prognosis of Differential Gene Troponin T1 Between Right and Left Colon Cancers. Appl Immunohistochem Mol Morphol 2024; 32:336-344. [PMID: 38695548 DOI: 10.1097/pai.0000000000001200] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2023] [Accepted: 03/26/2024] [Indexed: 08/07/2024]
Abstract
Colorectal cancer (CRC) is one of the most common digestive tract tumors in humans. At present, many scholars believe that the primary site of the tumor has a direct and profound impact on its curative effect. There are significant differences in the expression of many genes, tumor microenvironment, and prognosis between the left and right colon. However, there is a lack of detailed studies on whether the differentially expressed genes in the left and right colon significantly impact the prognosis of patients with CRC. Troponin T1 ( TNNT1 ) is an important gene that affects the prognosis difference between left and right colon cancer screening from "The Cancer Genome Atlas" database. By analyzing the differential gene expression data and clinical data of the left and right hemicolons in the database, the online prognostic database was used to screen the key molecules that significantly affect the tumor immune microenvironment and patient prognosis and to predict their functions and pathways. Quantitative reverse transcription-polymerase chain reaction was used to verify the expression difference of TNNT1 in CRC cell lines SW480 and HCT116, and normal human colorectal epithelial cell line FHC. The relationship between TNNT1 expression in 88 pairs of CRC samples and clinical information and pathologic parameters of patients with CRC was analyzed to judge the impact of TNNT1 expression on patient survival. Database analysis showed that TNNT1 was significantly overexpressed in CRC, and TNNT1 was one of the main differential genes between left colon cancer (LCC) and right colon cancer (RCC). The expression of TNNT1 was significantly increased in RCC, which could lead to poor prognosis of patients. Quantitative reverse transcription-polymerase chain reaction indicated that the expression of TNNT1 was significantly up-regulated in CRC cell lines SW480 and HCT116. Eighty-eight immunohistochemistry (IHC) of CRC tissues and adjacent tissues suggested that the expression of TNNT1 in CRC was significantly higher than that in normal adjacent tissues. By analyzing the clinical information and pathologic indicators matched with these clinical samples, we found that high TNNT1 expression in the primary tumor location (right colon) and high N stage (N2, N3) were unfavorable factors affecting the prognosis of patients with CRC. Multivariate Cox regression analysis suggested that high expression of TNNT1 may be an independent risk factor for the prognosis of patients with CRC. As one of the main differential genes between LCC and RCC, TNNT1 is representative to some extent. Its high expression may be one of the reasons why the prognosis of patients with RCC is worse than that of patients with LCC.
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Affiliation(s)
- Yue Wu
- Department of General Surgery
| | | | | | - Ziyan Zhang
- Department of Medical Insurance Office, Jiaozuo Second People's Hospital, The First Affiliated Hospital of Henan Polytechnic University, Jiaozuo, Henan, China
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Cai Z, Xu Z, Chen Y, Zhang R, Guo B, Chen H, Ouyang F, Chen X, Chen X, Liu D, Luo C, Li X, Liu W, Zhou C, Guan X, Liu Z, Zhao H, Hu Q. Multiparametric MRI subregion radiomics for preoperative assessment of high-risk subregions in microsatellite instability of rectal cancer patients: a multicenter study. Int J Surg 2024; 110:4310-4319. [PMID: 38498392 PMCID: PMC11254239 DOI: 10.1097/js9.0000000000001335] [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: 01/09/2024] [Accepted: 03/04/2024] [Indexed: 03/20/2024]
Abstract
BACKGROUND Microsatellite instability (MSI) is associated with treatment response and prognosis in patients with rectal cancer (RC). However, intratumoral heterogeneity limits MSI testing in patients with RC. The authors developed a subregion radiomics model based on multiparametric MRI to preoperatively assess high-risk subregions with MSI and predict the MSI status of patients with RC. METHODS This retrospective study included 475 patients (training cohort, 382; external test cohort, 93) with RC from two participating hospitals between April 2017 and June 2023. In the training cohort, subregion radiomic features were extracted from multiparametric MRI, which included T2-weighted, T1-weighted, diffusion-weighted, and contrast-enhanced T1-weighted imaging. MSI-related subregion radiomic features, classical radiomic features, and clinicoradiological variables were gathered to build five predictive models using logistic regression. Kaplan-Meier survival analysis was conducted to explore the prognostic information. RESULTS Among the 475 patients [median age, 64 years (interquartile range, IQR: 55-70 years); 304 men and 171 women], the prevalence of MSI was 11.16% (53/475). The subregion radiomics model outperformed the classical radiomics and clinicoradiological models in both training [area under the curve (AUC)=0.86, 0.72, and 0.59, respectively] and external test cohorts (AUC=0.83, 0.73, and 0.62, respectively). The subregion-clinicoradiological model combining clinicoradiological variables and subregion radiomic features performed the optimal, with AUCs of 0.87 and 0.85 in the training and external test cohorts, respectively. The 3-year disease-free survival rate of MSI groups predicted based on the model was higher than that of the predicted microsatellite stability groups in both patient cohorts (training, P =0.032; external test, P =0.046). CONCLUSIONS The authors developed and validated a model based on subregion radiomic features of multiparametric MRI to evaluate high-risk subregions with MSI and predict the MSI status of RC preoperatively, which may assist in individualized treatment decisions and positioning for biopsy.
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Affiliation(s)
- Zhiping Cai
- Department of Radiology, Shunde Hospital, Southern Medical University (The First People’s Hospital of Shunde)
| | - Zhenyu Xu
- Department of Radiology, The First People’s Hospital of Foshan, Foshan
| | - Yifan Chen
- Department of Radiology, Shunde Hospital, Southern Medical University (The First People’s Hospital of Shunde)
| | - Rong Zhang
- Department of Radiology, Shunde Hospital, Southern Medical University (The First People’s Hospital of Shunde)
| | - Baoliang Guo
- Department of Radiology, Shunde Hospital, Southern Medical University (The First People’s Hospital of Shunde)
| | - Haixiong Chen
- Department of Radiology, Shunde Hospital, Southern Medical University (The First People’s Hospital of Shunde)
| | - Fusheng Ouyang
- Department of Radiology, Shunde Hospital, Southern Medical University (The First People’s Hospital of Shunde)
| | - Xinjie Chen
- Department of Radiology, Shunde Hospital, Southern Medical University (The First People’s Hospital of Shunde)
| | - Xiaobo Chen
- Department of Radiology, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University
- Guangdong Provincial Key Laboratory of Artificial Intelligence in Medical Image Analysis and Application, Guangzhou, People’s Republic of China
| | - Dechao Liu
- Department of Radiology, Shunde Hospital, Southern Medical University (The First People’s Hospital of Shunde)
| | - Chun Luo
- Department of Radiology, The First People’s Hospital of Foshan, Foshan
| | - Xiaohong Li
- Department of Radiology, Shunde Hospital, Southern Medical University (The First People’s Hospital of Shunde)
| | - Wei Liu
- Department of Radiology, Shunde Hospital, Southern Medical University (The First People’s Hospital of Shunde)
| | - Cuiru Zhou
- Department of Radiology, Shunde Hospital, Southern Medical University (The First People’s Hospital of Shunde)
| | - Xinqun Guan
- Department of Radiology, Shunde Hospital, Southern Medical University (The First People’s Hospital of Shunde)
| | - Ziwei Liu
- Department of Radiology, Shunde Hospital, Southern Medical University (The First People’s Hospital of Shunde)
| | - Hai Zhao
- Department of Radiology, The First People’s Hospital of Foshan, Foshan
| | - Qiugen Hu
- Department of Radiology, Shunde Hospital, Southern Medical University (The First People’s Hospital of Shunde)
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Devalle S, Aran V, Bastos Júnior CDS, Pannain VL, Brackmann P, Gregório ML, Ferreira Manso JE, Moura Neto V. A panorama of colon cancer in the era of liquid biopsy. THE JOURNAL OF LIQUID BIOPSY 2024; 4:100148. [PMID: 40027146 PMCID: PMC11863817 DOI: 10.1016/j.jlb.2024.100148] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/19/2024] [Revised: 03/13/2024] [Accepted: 03/13/2024] [Indexed: 03/05/2025]
Abstract
Colon cancer (CC) is one of the most frequent cancers worldwide being responsible for over 500 thousand deaths in 2022. Its financial and human burden is expected to increase in the next decades accompanying the growing and aging of the global population. Much of this burden could be alleviated considering that the lethality of CC is mostly due to its late diagnosis and failure in the individualized management of patients. Coordinated government actions and implementation of better diagnostic tools capable of detecting CC earlier and of tracking tumoral evolution are mandatory to achieve a reduction in CC's social impact. CtDNA-based liquid biopsy (LB) has great potential to contribute to patients' screening adhesion, CC earlier detection, and to longitudinal tumor follow-up. In this review, we will discuss the latest epidemiological data on CC disease, diagnostic, subtypes, genetics, and treatment management focusing on the advantages and limitations of ctDNA-based LB, including important bottlenecks and solutions necessary for its clinical translation. The latest ctDNA-directed CC clinical trials will also be examined.
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Affiliation(s)
- Sylvie Devalle
- Instituto Estadual do Cérebro Paulo Niemeyer, Secretaria de Estado de Saúde, Rio de Janeiro, Brazil
| | - Veronica Aran
- Instituto Estadual do Cérebro Paulo Niemeyer, Secretaria de Estado de Saúde, Rio de Janeiro, Brazil
| | | | - Vera Lucia Pannain
- Departamento de Patologia, Faculdade de Medicina, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Paulo Brackmann
- Clínica de Coloproctologia do Hospital Naval Marcílio Dias - IPB/HNMD, Rio de Janeiro, Brazil
| | - Marcelo Leal Gregório
- Instituto de Pesquisas Biomédicas do Hospital Naval Marcílio Dias - IPB/HNMD, Rio de Janeiro, Brazil
| | - José Eduardo Ferreira Manso
- Departamento de Cirurgia, Faculdade de Medicina, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Vivaldo Moura Neto
- Instituto Estadual do Cérebro Paulo Niemeyer, Secretaria de Estado de Saúde, Rio de Janeiro, Brazil
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Asghari-Jafarabadi M, Wilkins S, Plazzer JP, Yap R, McMurrick PJ. Prognostic factors and survival disparities in right-sided versus left-sided colon cancer. Sci Rep 2024; 14:12306. [PMID: 38811769 PMCID: PMC11136990 DOI: 10.1038/s41598-024-63143-3] [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: 12/17/2023] [Accepted: 05/24/2024] [Indexed: 05/31/2024] Open
Abstract
Right-sided colon cancer (RCC) and left-sided colon cancer (LCC) differ in features and outcomes because of variations in embryology, epidemiology, pathology, and prognosis. This study sought to identify significant factors impacting patient survival through Bayesian modelling. Data was retrospectively analysed from a colorectal neoplasia database. Data on demographics, perioperative risks, treatment, mortality, and survival was analysed from patients who underwent colon cancer surgery from January 2010 to December 2021. This study involved 2475 patients, with 58.7% having RCC and 41.3% having LCC. RCC patients had a notably higher mortality rate, and their overall survival (OS) rates were slightly lower than those with LCC (P < 0.05). RCC stages I-IV consistently exhibited worse OS and relapse-free survival (RFS) than LCC (P < 0.05). Factors like age, BMI, ASA score, cancer stage, and comorbidities had significant associations with OS and RFS. Poor and moderate differentiation, lower lymph node yield, and organ resection were linked to lower survival while receiving chemotherapy; higher BMI levels and elective surgery were associated with better survival (all P < 0.05). Our study reveals key differences between RCC and LCC, emphasising the impact of age, BMI, ASA score, cancer stage, and comorbidities on patient survival. These findings could inform personalised treatment strategies for colon cancer patients.
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Affiliation(s)
- Mohammad Asghari-Jafarabadi
- Cabrini Research, Cabrini Hospital, Malvern, VIC, 3144, Australia
- School of Public Health and Preventive Medicine, Monash University, Melbourne, VIC, 3004, Australia
- Department of Psychiatry, School of Clinical Sciences, Monash University, Clayton, VIC, 3168, Australia
| | - Simon Wilkins
- Cabrini Monash University Department of Surgery, Cabrini Hospital, 183 Wattletree Road, Malvern, VIC, 3144, Australia.
- Department of Biochemistry and Molecular Biology, Monash University, Melbourne, VIC, 3800, Australia.
| | - John Paul Plazzer
- Cabrini Monash University Department of Surgery, Cabrini Hospital, 183 Wattletree Road, Malvern, VIC, 3144, Australia
| | - Raymond Yap
- Cabrini Monash University Department of Surgery, Cabrini Hospital, 183 Wattletree Road, Malvern, VIC, 3144, Australia
| | - Paul John McMurrick
- Cabrini Monash University Department of Surgery, Cabrini Hospital, 183 Wattletree Road, Malvern, VIC, 3144, Australia
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Ra H, Jeong S, Lee H, Chung JW, Kim KO, Lee WS, Kim J, Kwon KA, Kim JH. Clinicopathological Differences between Right and Left Colorectal Cancer by Sex. J Clin Med 2024; 13:2810. [PMID: 38792352 PMCID: PMC11122515 DOI: 10.3390/jcm13102810] [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: 03/27/2024] [Revised: 04/26/2024] [Accepted: 04/30/2024] [Indexed: 05/26/2024] Open
Abstract
Background: Until now, studies on colorectal cancer (CRC) have focused on clinicopathological characteristics based on location without considering sex differences. However, as men and women have fundamentally different physiological characteristics, research results in the clinical field are limited. We aimed to elucidate the differences in the clinicopathological characteristics between right-sided CRC (RCC) and left-sided CRC (LCC) according to sex. Methods: We classified 1492 South Korean patients with no history of colon surgery between July 2005 and June 2015 based on tumor location and sex. For these patients, differences in the clinical characteristics according to sex were compared using univariate and multivariate analyses. Results: Of the 1269 patients, 951 (74.9%) had LCC, and 318 (25.1%) had RCC, making LCC approximately three times more common than RCC. When sex was not taken into account, patients with RCC had significantly higher rates of anemia and undifferentiated cancers than the rates in those with LCC. Even considering sex, anemia and undifferentiated cancer were more prevalent in RCC than in LCC in both men and women. In contrast, age over 65 years and abnormal white blood cell count differed between RCC and LCC only in women. Conclusions: The clinicopathologic characteristics of CRC vary according to the location and sex. Therefore, sex must be considered as a fundamental characteristic of personalized treatment.
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Affiliation(s)
- Hannah Ra
- Department of Internal Medicine, Gachon University Gil Medical Center, Gachon University College of Medicine, Incheon 21565, Republic of Korea; (H.R.); (H.L.); (J.-W.C.); (K.O.K.); (K.A.K.)
| | - Soyeon Jeong
- Gachon Biomedical Convergence Institute, Gachon University Gil Medical Center, College of Medicine, Incheon 21565, Republic of Korea;
- Gachon Medical Research Institute, Gachon University Gil Medical Center, Gachon University College of Medicine, Incheon 21565, Republic of Korea
| | - Hannah Lee
- Department of Internal Medicine, Gachon University Gil Medical Center, Gachon University College of Medicine, Incheon 21565, Republic of Korea; (H.R.); (H.L.); (J.-W.C.); (K.O.K.); (K.A.K.)
| | - Jun-Won Chung
- Department of Internal Medicine, Gachon University Gil Medical Center, Gachon University College of Medicine, Incheon 21565, Republic of Korea; (H.R.); (H.L.); (J.-W.C.); (K.O.K.); (K.A.K.)
| | - Kyoung Oh Kim
- Department of Internal Medicine, Gachon University Gil Medical Center, Gachon University College of Medicine, Incheon 21565, Republic of Korea; (H.R.); (H.L.); (J.-W.C.); (K.O.K.); (K.A.K.)
| | - Won-Suk Lee
- Department of Surgery, Gachon University Gil Medical Center, Gachon University College of Medicine, Incheon 21565, Republic of Korea;
| | - Jisup Kim
- Department of Pathology, Gachon University Gil Medical Center, Gachon University College of Medicine, Incheon 21565, Republic of Korea;
| | - Kwang An Kwon
- Department of Internal Medicine, Gachon University Gil Medical Center, Gachon University College of Medicine, Incheon 21565, Republic of Korea; (H.R.); (H.L.); (J.-W.C.); (K.O.K.); (K.A.K.)
| | - Jung Ho Kim
- Department of Internal Medicine, Gachon University Gil Medical Center, Gachon University College of Medicine, Incheon 21565, Republic of Korea; (H.R.); (H.L.); (J.-W.C.); (K.O.K.); (K.A.K.)
- Gachon Biomedical Convergence Institute, Gachon University Gil Medical Center, College of Medicine, Incheon 21565, Republic of Korea;
- Gachon Medical Research Institute, Gachon University Gil Medical Center, Gachon University College of Medicine, Incheon 21565, Republic of Korea
- Department of Translational-Clinical Medicine, Gachon Advanced Institute for Health Sciences and Technology (GAIHST), Gachon University, Incheon 21999, Republic of Korea
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9
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Luo S, Cai S, Zhao R, Xu L, Zhang X, Gong X, Zhang Z, Liu Q. Comparison of left- and right-sided colorectal cancer to explore prognostic signatures related to pyroptosis. Heliyon 2024; 10:e28091. [PMID: 38571659 PMCID: PMC10987941 DOI: 10.1016/j.heliyon.2024.e28091] [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: 07/06/2023] [Revised: 03/08/2024] [Accepted: 03/12/2024] [Indexed: 04/05/2024] Open
Abstract
Background Colorectal cancer (CRC) is one of the most common malignancies, and pyroptosis exerts an immunoregulatory role in CRC. Although the location of the primary tumor is a prognostic factor for patients with CRC, the mechanisms of pyroptosis in left- and right-sided CRC remain unclear. Methods Expression and clinical data were collected from The Cancer Genome Atlas and Gene Expression Omnibus databases. Differences in clinical characteristics, immune cell infiltration, and somatic mutations between left- and right-sided CRC were then compared. After screening for differentially expressed genes, Pearson correlation analysis was performed to select pyroptosis-related genes, followed by a gene set enrichment analysis. Univariate and multivariate Cox regression analyses were used to construct and validate the prognostic model and nomogram for predicting prognosis. Collected left- and right-sided CRC samples were subjected to reverse transcription-quantitative polymerase chain reaction (RT-qPCR) to validate the expression of key pyroptosis-related genes. Results Left- and right-sided CRC exhibited significant differences in clinical features and immune cell infiltration. Five prognostic signatures were identified from among 134 pyroptosis-related differentially expressed genes to construct a risk score-based prognostic model, and adverse outcomes for high-risk patients were further verified using an external cohort. A nomogram was also generated based on three independent prognostic factors to predict survival probabilities, while calibration curves confirmed the consistency between the predicted and actual survival. Experiment data confirmed the significant differential expression of five genes between left- and right-sided CRC. Conclusion The five identified pyroptosis-related gene signatures may be potential biomarkers for predicting prognosis in left- and right-sided CRC and may help improve the clinical outcomes of patients with CRC.
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Affiliation(s)
- Shibi Luo
- Department of General Surgery, Ganmei Affiliated Hospital of Kunming Medical University (First People's Hospital of Kunming), Kunming, Yunnan, 650034, China
| | - Shenggang Cai
- Department of General Surgery, Ganmei Affiliated Hospital of Kunming Medical University (First People's Hospital of Kunming), Kunming, Yunnan, 650034, China
| | - Rong Zhao
- Department of General Surgery, Ganmei Affiliated Hospital of Kunming Medical University (First People's Hospital of Kunming), Kunming, Yunnan, 650034, China
| | - Lin Xu
- Department of General Surgery, Ganmei Affiliated Hospital of Kunming Medical University (First People's Hospital of Kunming), Kunming, Yunnan, 650034, China
| | - Xiaolong Zhang
- Department of General Surgery, Ganmei Affiliated Hospital of Kunming Medical University (First People's Hospital of Kunming), Kunming, Yunnan, 650034, China
| | - Xiaolei Gong
- Department of General Surgery, Ganmei Affiliated Hospital of Kunming Medical University (First People's Hospital of Kunming), Kunming, Yunnan, 650034, China
| | - Zhiping Zhang
- Department of General Surgery, Affiliated Hospital of Yunnan University, Kunming, Yunnan, 650031, China
| | - Qiyu Liu
- Department of General Surgery, Ganmei Affiliated Hospital of Kunming Medical University (First People's Hospital of Kunming), Kunming, Yunnan, 650034, China
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10
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Ji L, Fu G, Huang M, Kao X, Zhu J, Dai Z, Chen Y, Li H, Zhou J, Chu X, Lei Z. scRNA-seq of colorectal cancer shows regional immune atlas with the function of CD20 + B cells. Cancer Lett 2024; 584:216664. [PMID: 38253219 DOI: 10.1016/j.canlet.2024.216664] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2023] [Revised: 12/25/2023] [Accepted: 01/18/2024] [Indexed: 01/24/2024]
Abstract
Colorectal cancer (CRC) from different regions exhibits different histological, genetic characteristics, and molecular subtypes, even in response to conventional chemotherapies and immunotherapies. To characterize the immune landscape in different regions of CRC and search for potential therapeutic targets, we analyzed 39,484 single-cell transcription data from 19 samples of CRC and paired normal tissues from four regions to identify the immune characteristics of CRC among anatomic locations, especially in B cells. We discovered that immune cell infiltration in tumors significantly varied among different regions of CRC. B cells from right- and left-sided CRC had different development trajectories, but both had extensive interactions with myeloid cells and T cells. Survival analysis suggested that CD20+ B cells correlated with good prognosis in CRC patients, especially on the right side. Furthermore, the depletion of CD20+ B cells demonstrated that anti-CD20 promoted tumor growth progression and reversed the tumor-killing activity of anti-PD-1 treatment in vivo and in vitro. Our results highlight the characterization of the immune landscape of CRC in different regions. CD20+ B-cell infiltration has been associated with CRC patient prognosis and may promote the tumor-killing role of PD-1 antibodies.
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Affiliation(s)
- Linlin Ji
- Department of Medical Oncology, Nanjing Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, 210000, China
| | - Gongbo Fu
- Department of Medical Oncology, Nanjing Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, 210000, China; Department of Medical Oncology, Jinling Hospital, The First School of Clinical Medicine, Southern Medical University, Nanjing, 210000, China; Department of Medical Oncology, Jinling Hospital, Nanjing Medical University, Nanjing, 210000, China; Department of Medical Oncology, Jinling Hospital, Nanjing University of Chinese Medicine, Nanjing, 210000, China.
| | - Mengxi Huang
- Department of Medical Oncology, Nanjing Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, 210000, China
| | - Xiaoming Kao
- Department of General Surgery, Jinling Hospital, Nanjing Medical University, Nanjing, 210002, China
| | - Jialong Zhu
- Department of Medical Oncology, Jinling Hospital, The First School of Clinical Medicine, Southern Medical University, Nanjing, 210000, China
| | - Zhe Dai
- Department of Medical Oncology, Nanjing Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, 210000, China
| | - Yitian Chen
- Department of Medical Oncology, Nanjing Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, 210000, China
| | - Huiyu Li
- Department of Medical Oncology, Nanjing Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, 210000, China
| | - Jie Zhou
- Department of Oncology and Southwest Cancer Center, Southwest Hospital, Army Medical University (Third Military Medical University), Chongqing, 400038, China.
| | - Xiaoyuan Chu
- Department of Medical Oncology, Nanjing Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, 210000, China; Department of Medical Oncology, Jinling Hospital, The First School of Clinical Medicine, Southern Medical University, Nanjing, 210000, China; Department of Medical Oncology, Jinling Hospital, Nanjing Medical University, Nanjing, 210000, China; Department of Medical Oncology, Jinling Hospital, Nanjing University of Chinese Medicine, Nanjing, 210000, China.
| | - Zengjie Lei
- Department of Medical Oncology, Nanjing Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, 210000, China; Department of Medical Oncology, Jinling Hospital, The First School of Clinical Medicine, Southern Medical University, Nanjing, 210000, China; Department of Medical Oncology, Jinling Hospital, Nanjing Medical University, Nanjing, 210000, China; Department of Medical Oncology, Jinling Hospital, Nanjing University of Chinese Medicine, Nanjing, 210000, China.
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11
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Mao Y, Wang X, Xi L, Dong M, Song P, Miao J, Lu C, Sun S, Li Q, Yu C, Shen X. Prediction values of tertiary lymphoid structures in the prognosis of patients with left- and right-sided colon cancer: a multicenter propensity score-matched study. Int J Surg 2023; 109:2344-2358. [PMID: 37247038 PMCID: PMC10442147 DOI: 10.1097/js9.0000000000000483] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2023] [Accepted: 05/09/2023] [Indexed: 05/30/2023]
Abstract
BACKGROUND Tertiary lymphoid structures (TLS) are the lymphocyte aggregates that play a key role in the vast majority of solid tumors including colon cancer, displaying an antitumor effect under most circumstances. The heterogeneity between left- and right-sided colon cancer (LCC and RCC) encompasses various aspects, such as clinical manifestations, pathological features, and immune responses. However, the function and prognostic significance of TLS within LCC and RCC have yet to be fully understood. METHODS A retrospective analysis was performed on 2612 patients who underwent radical resection for LCC or RCC without distant metastasis in multiple medical centers. Utilizing propensity score matching, 121 patients with LCC and 121 patients with RCC were selected for the training set. An external validation set including 64 patients with LCC and 64 patients with RCC were also employed. Hematoxylin-eosin and immunohistochemical staining were used to assess TLS and the proportion of various immune cells. Clinical characteristics and prognostic values of TLS in patients with LCC and RCC were analyzed. Nomograms were constructed for LCC and RCC to predict 3-year and 5-year overall survival (OS), respectively. RESULTS For LCC and RCC patients, TLS was located in the interstitial region or outside the tumor tissue and mainly consisted of B cells and T cells. The TLS quantity and density in RCC were higher than those of LCC. In multivariate Cox regression analysis, TLS density ( P =0.014), vascular invasion ( P =0.019), and AJCC stage ( P =0.026) were independent prognostic factors for 5-year OS of RCC. For LCC patients, AJCC stage ( P =0.024), tumor differentiation ( P =0.001), and tumor budding ( P =0.040) emerged as independent prognostic factors for 5-year OS. Similar results were obtained in the external verification set. Separate nomograms for RCC and LCC were developed, displaying improved prediction performance compared to the AJCC 8th edition TNM staging system. CONCLUSIONS Differences in TLS quantity and density were observed between LCC and RCC, suggesting that a nomogram based on TLS density could more effectively predict survival for RCC patients. Furthermore, a nomogram based on tumor budding was recommended for better prediction of LCC patient survival. Taken together, these results suggested that the immune and clinical characteristics of colon cancer at left and right side were substantially different, which may lead to the use of different prediction model and the development of individual treatment strategy.
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Affiliation(s)
- Yonghuan Mao
- Department of General Surgery, Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University
- Department of General Surgery
- Department of General Surgery, the Second Affiliated Hospital of Nanjing Medical University
| | - Xingzhou Wang
- Department of General Surgery, Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University
- Department of General Surgery
| | - Ling Xi
- Department of Gerontology, Geriatric Hospital of Nanjing Medical University
| | - Meng Dong
- Department of General Surgery
- Department of Pathology, Nanjing Drum Tower Hospital, the Affiliated Hospital of Nanjing University Medical School
| | - Peng Song
- Department of General Surgery, Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University
- Department of General Surgery
| | - Ji Miao
- Department of General Surgery, Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University
- Department of General Surgery
| | - Cheng Lu
- Department of General Surgery, Sir Run Run Hospital of Nanjing Medical University, Nanjing, China
| | - Sizheng Sun
- Department of General Surgery, the Second Affiliated Hospital of Nanjing Medical University
| | - Qiang Li
- Department of General Surgery, Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University
- Department of General Surgery
| | - Chunzhao Yu
- Department of General Surgery, the Second Affiliated Hospital of Nanjing Medical University
- Department of General Surgery, Sir Run Run Hospital of Nanjing Medical University, Nanjing, China
| | - Xiaofei Shen
- Department of General Surgery, Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University
- Department of General Surgery
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12
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de Oliveira C, Gonçalves PG, Bidinotto LT. Role of EGFL7 in human cancers: A review. J Cell Physiol 2023; 238:1756-1767. [PMID: 37490307 DOI: 10.1002/jcp.31084] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2023] [Revised: 06/26/2023] [Accepted: 07/10/2023] [Indexed: 07/26/2023]
Abstract
EGFL7 is a proangiogenic factor. It has been widely described with having a vital role in tubulogenesis and regulation of angiogenesis, mainly during embryogenesis and organogenesis. It has been mainly associated with NOTCH pathway, but there are reports showing association with MAPK and integrin pathways. Given its association with angiogenesis and these other pathways, there are several studies associating EGFL7 with carcinogenesis. In fact, most of the studies have pointed to EGFL7 as an oncogene, and some of them suggest EGFL7 expression as a possible biomarker of prognosis or use for a patient's follow-up. Here, we review the molecular pathways which EGFL7 is associated and highlight several studies describing the role of EGFL7 in tumorigenesis, separated by tumor type. Besides its role on angiogenesis, EGFL7 may act in other pathways as oncogene, which makes it a possible biomarker and a candidate to targeted therapy.
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Affiliation(s)
- Cristiane de Oliveira
- Department of Pathology, Botucatu Medical School, São Paulo State University (Unesp), Botucatu, São Paulo, Brazil
- Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos, São Paulo, Brazil
| | - Paola Gyuliane Gonçalves
- Department of Pathology, Botucatu Medical School, São Paulo State University (Unesp), Botucatu, São Paulo, Brazil
- Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos, São Paulo, Brazil
| | - Lucas Tadeu Bidinotto
- Department of Pathology, Botucatu Medical School, São Paulo State University (Unesp), Botucatu, São Paulo, Brazil
- Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos, São Paulo, Brazil
- Human and Experimental Biology Department, Barretos School of Health Sciences, Dr Paulo Prata - FACISB, Barretos, São Paulo, Brazil
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13
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Šustić I, Racetin A, Vukojević K, Benzon B, Tonkić A, Šundov Ž, Puljiz M, Glavina Durdov M, Filipović N. Expression Pattern of DAB Adaptor Protein 2 in Left- and Right-Side Colorectal Carcinoma. Genes (Basel) 2023; 14:1306. [PMID: 37510211 PMCID: PMC10379130 DOI: 10.3390/genes14071306] [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: 05/20/2023] [Revised: 06/17/2023] [Accepted: 06/20/2023] [Indexed: 07/30/2023] Open
Abstract
Left-sided and right-sided colorectal cancer (L-CRC and R-CRC) have relatively different clinical pictures and pathophysiological backgrounds. The aim of this study was to investigate the presence of DAB adapter protein 2 (DAB2) as a potential molecular mechanism that contributes to this diversity in terms of malignancy and responses to therapy. The expression of the suppressor gene DAB2 in colon cancer has already been analyzed, but its significance has not been fully elucidated. Archived samples from 34 patients who underwent colon cancer surgery were included in this study, with 13 patients with low-grade CRC and 21 with high-grade CRC. Twenty of the tumors were R-CRC, while 14 were L-CRC. DAB2 expression was analyzed immunohistochemically in the tumor tissue and the colon resection margin was used as a control. Tumors were divided into L-CRC and R-CRC, with splenic flexure as the cutoff point for each side. The results showed that R-CRC had lower DAB2 protein expression compared to L-CRC (p = 0.01). High-grade tumors had reduced DAB2 expression compared to low-grade tumors (p = 0.02). These results are consistent with the analysis of DAB2 gene expression data that we exported from the TCGA Colon and Rectal Cancer Study (COADREAD). In 736 samples of colon cancer, lower DAB2 gene expression was found in R-CRC compared to L-CRC (p < 0.0001). DAB2 gene expression was significantly higher in the sigmoid colon than in the cecum and ascending colon (p < 0.01). The analysis confirmed a lower expression of the DAB2 in tumors with positive microsatellite instability (p < 0.001). In conclusion, DAB2 has a role in the biological differences between R-CRC and L-CRC and its therapeutic and diagnostic potential needs to be further examined.
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Affiliation(s)
- Ivan Šustić
- Division of Gastroenterology, Department of Internal Medicine, University Hospital of Split, Spinčićeva 1, 21000 Split, Croatia
| | - Anita Racetin
- Department of Anatomy, Histology and Embryology, University of Split School of Medicine, Šoltanska 2, 21000 Split, Croatia
| | - Katarina Vukojević
- Department of Anatomy, Histology and Embryology, University of Split School of Medicine, Šoltanska 2, 21000 Split, Croatia
| | - Benjamin Benzon
- Department of Anatomy, Histology and Embryology, University of Split School of Medicine, Šoltanska 2, 21000 Split, Croatia
| | - Ante Tonkić
- Division of Gastroenterology, Department of Internal Medicine, University Hospital of Split, Spinčićeva 1, 21000 Split, Croatia
- University of Split School of Medicine, Šoltanska 2, 21000 Split, Croatia
| | - Željko Šundov
- Division of Gastroenterology, Department of Internal Medicine, University Hospital of Split, Spinčićeva 1, 21000 Split, Croatia
| | - Mario Puljiz
- Clinical Department of Gynaecologic Oncology, University Hospital for Tumours, Sestre Milosrdnice University Hospital Centre, 10000 Zagreb, Croatia
| | - Merica Glavina Durdov
- Department of Pathology, Forensic Medicine and Cytology, University Hospital of Split, University of Split School of Medicine, Spinčićeva 1, 21000 Split, Croatia
| | - Natalija Filipović
- Department of Anatomy, Histology and Embryology, University of Split School of Medicine, Šoltanska 2, 21000 Split, Croatia
- Laboratory for Experimental Neurocardiology, Department of Anatomy, Histology and Embryology, University of Split School of Medicine, Šoltanska 2, 21000 Split, Croatia
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14
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Long C, Li G, Meng Y, Huang X, Chen J, Liu J. Weighted gene co-expression network analysis identifies the prognosis-related models of left- and right-sided colon cancer. Medicine (Baltimore) 2023; 102:e33390. [PMID: 37144998 PMCID: PMC10158920 DOI: 10.1097/md.0000000000033390] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/08/2022] [Accepted: 03/08/2023] [Indexed: 05/06/2023] Open
Abstract
Left-sided colon cancer (LC) and right-sided colon cancer (RC) are 2 essentially different diseases, and the potential mechanisms regulating them remain unidentified. In this study, we applied weighted gene co-expression network analysis (WGCNA) to confirm a yellow module, mainly enriched in metabolism-related signaling pathways related to LC and RC. Based on the RNA-seq data of colon cancer in The Cancer Genome Atlas (TCGA) and GSE41258 dataset with their corresponding clinical information, a training set (TCGA: LC: n = 171; RC: n = 260) and a validation set (GSE41258: LC: n = 94; RC: n = 77) were divided. Least absolute shrinkage and selection operator (LASSO) penalized COX regression analysis identified 20 prognosis-related genes (PRGs) and helped constructed 2 risk (LC-R and RC-R) models in LC and RC, respectively. The model-based risk scores accurately performed in risk stratification for colon cancer patients. The high-risk group of the LC-R model showed associations with ECM-receptor interaction, focal adhesion, and PI3K-AKT signaling pathway. Interestingly, the low-risk group of the LC-R model showed associations with immune-related signaling pathways like antigen processing and presentation. On the other hand, the high-risk group of the RC-R model showed enrichment for cell adhesion molecules and axon guidance signaling pathways. Furthermore, we identified 20 differentially expressed PRGs between LC and RC. Our findings provide new insights into the difference between LC and RC, and uncover the potential biomarkers for the treatment of LC and RC.
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Affiliation(s)
- Chenyan Long
- Division of Colorectal & Anal Surgery, Department of Gastrointestinal Surgery, Guangxi Medical University Cancer Hospital, Nanning, Guangxi Zhuang Autonomous Region, The People’s Republic of China
- Guangxi Clinical Research Center for Colorectal Cancer, Nanning, Guangxi Zhuang Autonomous Region, The People’s Republic of China
| | - Gang Li
- School of Public Health, Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region, The People’s Republic of China
| | - Yongsheng Meng
- Division of Colorectal & Anal Surgery, Department of Gastrointestinal Surgery, Guangxi Medical University Cancer Hospital, Nanning, Guangxi Zhuang Autonomous Region, The People’s Republic of China
- Guangxi Clinical Research Center for Colorectal Cancer, Nanning, Guangxi Zhuang Autonomous Region, The People’s Republic of China
| | - Xiaoliang Huang
- Division of Colorectal & Anal Surgery, Department of Gastrointestinal Surgery, Guangxi Medical University Cancer Hospital, Nanning, Guangxi Zhuang Autonomous Region, The People’s Republic of China
- Guangxi Clinical Research Center for Colorectal Cancer, Nanning, Guangxi Zhuang Autonomous Region, The People’s Republic of China
| | - Jianhong Chen
- Division of Colorectal & Anal Surgery, Department of Gastrointestinal Surgery, Guangxi Medical University Cancer Hospital, Nanning, Guangxi Zhuang Autonomous Region, The People’s Republic of China
- Guangxi Clinical Research Center for Colorectal Cancer, Nanning, Guangxi Zhuang Autonomous Region, The People’s Republic of China
| | - Jungang Liu
- Division of Colorectal & Anal Surgery, Department of Gastrointestinal Surgery, Guangxi Medical University Cancer Hospital, Nanning, Guangxi Zhuang Autonomous Region, The People’s Republic of China
- Guangxi Clinical Research Center for Colorectal Cancer, Nanning, Guangxi Zhuang Autonomous Region, The People’s Republic of China
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15
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Buckley CE, Yin X, Meltzer S, Ree AH, Redalen KR, Brennan L, O'Sullivan J, Lynam-Lennon N. Energy Metabolism Is Altered in Radioresistant Rectal Cancer. Int J Mol Sci 2023; 24:ijms24087082. [PMID: 37108244 PMCID: PMC10138551 DOI: 10.3390/ijms24087082] [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: 01/10/2023] [Revised: 03/31/2023] [Accepted: 04/03/2023] [Indexed: 04/29/2023] Open
Abstract
Resistance to neoadjuvant chemoradiation therapy is a significant clinical challenge in the management of rectal cancer. There is an unmet need to identify the underlying mechanisms of treatment resistance to enable the development of biomarkers predictive of response and novel treatment strategies to improve therapeutic response. In this study, an in vitro model of inherently radioresistant rectal cancer was identified and characterized to identify mechanisms underlying radioresistance in rectal cancer. Transcriptomic and functional analysis demonstrated significant alterations in multiple molecular pathways, including the cell cycle, DNA repair efficiency and upregulation of oxidative phosphorylation-related genes in radioresistant SW837 rectal cancer cells. Real-time metabolic profiling demonstrated decreased reliance on glycolysis and enhanced mitochondrial spare respiratory capacity in radioresistant SW837 cells when compared to radiosensitive HCT116 cells. Metabolomic profiling of pre-treatment serum samples from rectal cancer patients (n = 52) identified 16 metabolites significantly associated with subsequent pathological response to neoadjuvant chemoradiation therapy. Thirteen of these metabolites were also significantly associated with overall survival. This study demonstrates, for the first time, a role for metabolic reprograming in the radioresistance of rectal cancer in vitro and highlights a potential role for altered metabolites as novel circulating predictive markers of treatment response in rectal cancer patients.
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Affiliation(s)
- Croí E Buckley
- Department of Surgery, School of Medicine, Trinity Translational Medicine Institute, Trinity St James's Cancer Institute, Trinity College Dublin, D08 NHY1 Dublin, Ireland
| | - Xiaofei Yin
- UCD School of Agriculture and Food Science, UCD Institute of Food and Health, Conway Institute, University College Dublin, D04 V1W8 Dublin, Ireland
| | - Sebastian Meltzer
- Department of Oncology, Akershus University Hospital, 1478 Lørenskog, Norway
| | - Anne Hansen Ree
- Department of Oncology, Akershus University Hospital, 1478 Lørenskog, Norway
| | - Kathrine Røe Redalen
- Department of Physics, Norwegian University of Science and Technology, 7491 Trondheim, Norway
| | - Lorraine Brennan
- UCD School of Agriculture and Food Science, UCD Institute of Food and Health, Conway Institute, University College Dublin, D04 V1W8 Dublin, Ireland
| | - Jacintha O'Sullivan
- Department of Surgery, School of Medicine, Trinity Translational Medicine Institute, Trinity St James's Cancer Institute, Trinity College Dublin, D08 NHY1 Dublin, Ireland
| | - Niamh Lynam-Lennon
- Department of Surgery, School of Medicine, Trinity Translational Medicine Institute, Trinity St James's Cancer Institute, Trinity College Dublin, D08 NHY1 Dublin, Ireland
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16
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Li Z, Zhang J, Zhong Q, Feng Z, Shi Y, Xu L, Zhang R, Yu F, Lv B, Yang T, Huang C, Cui F, Chen F. Development and external validation of a multiparametric MRI-based radiomics model for preoperative prediction of microsatellite instability status in rectal cancer: a retrospective multicenter study. Eur Radiol 2023; 33:1835-1843. [PMID: 36282309 DOI: 10.1007/s00330-022-09160-0] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2022] [Revised: 07/27/2022] [Accepted: 08/29/2022] [Indexed: 11/30/2022]
Abstract
OBJECTIVES To establish and validate a radiomics model based on multiparametric magnetic resonance imaging (MRI), and to predict microsatellite instability (MSI) status in rectal cancer patients. METHODS A total of 199 patients with pathologically confirmed rectal cancer were included. The MSI status was confirmed by immunohistochemistry (IHC) staining. Clinical factors and laboratory data associated with MSI status were analyzed. The imaging data of 100 patients from one of the hospitals were used as the training set. The remaining 99 patients from the other two hospitals were used as the external validation set. The regions of interest (ROIs) were delineated from T1-weighted imaging (T1WI), T2-weighted imaging (T2WI), diffusion-weighted imaging (DWI), and contrast-enhanced T1WI (CE-T1WI) sequence to extract the radiomics features. The Tree-based approach was used for feature selection. The models were constructed based on the four single sequences and a combination of the four sequences using the random forest (RF) algorithm. The external validation set was used to verify the generalization ability of each model. The receiver operating characteristic (ROC) curves and the area under the curve (AUC) were plotted to evaluate and compare the predictive performance of each model. RESULTS In the four single-series models, the CE-T1WI model performed the best. The AUCs of the T1WI, T2WI, DWI, and CE-T1WI prediction models in the training set were 0.74, 0.71, 0.71, and 0.78, respectively, while in the external validation set, the corresponding AUCs were 0.67, 0.66, 0.70, and 0.77. The prediction and generalization performance of the combined model of multi-sequences was comparable to that of the CE-T1WI model and it was better than that of the remaining three single-series models, with AUC values of 0.78 and 0.78 in the training and validation sets, respectively. CONCLUSION The established radiomics models based on CE-T1WI or multiparametric MRI have similar predictive performance. They have the potential to predict MSI status in rectal cancer patients. KEY POINTS • A radiomics model for the prediction of MSI status in patients with rectal cancer was established and validated using external validation. • The models based on CE-T1WI or multiparametric MRI have better predictive performance than those based on single unenhanced sequence images. • The radiomics model has the potential to suggest MSI status in rectal cancer patients; however, it is not yet a substitute for histological confirmation.
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Affiliation(s)
- Zhi Li
- Department of Radiology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Jing Zhang
- Department of Radiology, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Qi Zhong
- Department of Radiology, Hangzhou Hospital of Traditional Chinese Medicine, Hangzhou, Zhejiang, China
| | - Zhan Feng
- Department of Radiology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Yushu Shi
- Department of Radiology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Ligong Xu
- Department of Radiology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Rui Zhang
- Department of Radiology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Fang Yu
- Department of Pathology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Biao Lv
- Department of Radiology, The 903 Hospital of Joint Logistics Support Force of PLA, Hangzhou, Zhejiang, China
| | - Tian Yang
- Department of Radiology, Shulan (Hangzhou) Hospital, Hangzhou, Zhejiang, China
| | - Chencui Huang
- Department of Research Collaboration, R&D Center, Beijing Deepwise & League of PHD Technology Co., Ltd, Beijing, China
| | - Feng Cui
- Department of Radiology, Hangzhou Hospital of Traditional Chinese Medicine, Hangzhou, Zhejiang, China
| | - Feng Chen
- Department of Radiology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
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Chang JS, Cheng HH, Huang SC, Lin HH, Chang SC, Lin CC. The impact of inflammatory markers on prognosis of stage II colon cancers depends on tumour sidedness. ANZ J Surg 2023; 93:182-195. [PMID: 36097407 DOI: 10.1111/ans.18014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2022] [Revised: 08/10/2022] [Accepted: 08/16/2022] [Indexed: 12/24/2022]
Abstract
BACKGROUNDS Accumulating evidence has reported a high correlation between inflammatory markers and oncological outcomes in colorectal cancer. In the present study, we aimed to assess the prognostic values of five inflammatory markers in stage II colon cancer patients with different tumour locations. METHODS The consecutive stage II colon adenocarcinoma patients undergoing curative resection were analysed retrospectively. ROC curves and the area under the curve (AUCs) via bootstrap method were used to analyse the prognostic impact of various inflammatory markers, including neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), lymphocyte-to-monocyte ratio (LMR), systemic immune-inflammation index (SII) and prognostic nutrition index (PNI). RESULTS A total of 768 patients were enrolled for analysis. In univariate analysis, right-sided colon cancer (RCC) patients have significantly higher mean levels of all inflammatory markers than left-sided colon cancer (LCC) patients. In multivariate analyses, high NLR in LCC (P = 0.025) and low PNI in both RCC (P = 0.049) and LCC (P = 0.027) were significantly associated with a worse OS while none of the inflammatory markers was found to have a significant impact on DFS or CSS. CONCLUSIONS The profiles and prognostic impact of inflammatory markers are significantly different between stage II RCC and LCC patients. Researchers should take sidedness into consideration when addressing survival analysis of inflammatory markers.
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Affiliation(s)
- Jui-Shen Chang
- Department of Surgery, Veterans General Hospital, Taipei, Taiwan
| | - Hou-Hsuan Cheng
- Division of Colon and Rectal Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan.,Department of Surgery, School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Sheng-Chieh Huang
- Division of Colon and Rectal Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan.,Department of Surgery, School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Hung-Hsin Lin
- Division of Colon and Rectal Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan.,Department of Surgery, School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Shih-Ching Chang
- Division of Colon and Rectal Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan.,Department of Surgery, School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Chun-Chi Lin
- Division of Colon and Rectal Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan.,Department of Surgery, School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
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18
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Mokhtari Z, Rezaei M, Sanei MH, Dehghanian A, Faghih Z, Heidari Z, Tavana S. Tim3 and PD-1 as a therapeutic and prognostic targets in colorectal cancer: Relationship with sidedness, clinicopathological parameters, and survival. Front Oncol 2023; 13:1069696. [PMID: 37035199 PMCID: PMC10076872 DOI: 10.3389/fonc.2023.1069696] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2022] [Accepted: 03/08/2023] [Indexed: 04/11/2023] Open
Abstract
Background Colorectal cancer (CRC) is a heterogeneous disease that complicates predicting patients' prognosis and their response to treatment. CRC prognosis is influenced by the tumor microenvironment (TME). The immune system is a critical component of the TME. Programmed cell death receptor 1 (PD-1) and T-cell immunoglobulin and mucin-domain containing-3 (Tim3) are inhibitory immune checkpoints that regulate immune response and may provide prognostic power. However, the effect of their expressions and co-expressions on the CRC prognosis remains unclear. Accordingly, this study aimed to investigate the prognostic value of the CD8, CD3, PD-1, Tim3 expression, and PD-1/Tim3 co-expression in patients with CRC. Materials and Methods One hundred and thirty six patients with CRC who underwent curative surgery were enrolled in the study. Immunohistochemical staining was performed for PD-1, Tim3, CD8, and CD3, and the expression of each marker was evaluated in the center of the tumor (CT), invasive margin (IM), and adjacent normal-like tissue. Result Our results indicated that high expression of PD-1 in IM was significantly associated with lower TNM stage, T-stage, M-stage, lack of metastasis, the presence of tertiary lymphoid structure (TLS), lack of recurrence (in the left-sided tumors), and larger tumor size (in right-sided tumors) (P<0.05). High expression of PD-1 in IM was also associated with improved overall survival (OS) in a subgroup of patients with high CD8 expression. High Tim3 expression in CT was associated with higher M-stage (M1) (in left-sided CRCs) (P<0.05). It was also associated with decreased OS in total cohort and left-sided CRCs and represented an independent prognostic factor for CRC patients in multivariate analysis. PD-1 and Tim3 co-expression had no synergistic effects on predicting OS. Conclusion Our findings suggest that the clinicopathological and prognostic significance of immune system-related markers such as CD8, PD-1, and Tim3 depends on the primary tumor sides. We also showed that Tim3 could act as a prognostic factor and therapeutic target in CRC. This marker is probably a more preferred target for immunotherapy than PD-1, especially in left-sided CRCs.
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Affiliation(s)
- Zahra Mokhtari
- Department of Immunology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Marzieh Rezaei
- Department of Immunology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
- *Correspondence: Marzieh Rezaei,
| | - Mohammad Hossein Sanei
- Department of Pathology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Amirreza Dehghanian
- Department of Pathology, School of Medicine, Shiraz University of Medical Science, Shiraz, Iran
| | - Zahra Faghih
- Institute for Cancer Research (ICR), School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Zahra Heidari
- Department of Biostatistics & Epidemiologyt, School of Public Health, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Shirin Tavana
- Department of Immunology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
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19
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Arai J, Suzuki N, Niikura R, Ooki D, Kawahara T, Honda T, Hasatani K, Yoshida N, Nishida T, Sumiyoshi T, Kiyotoki S, Ikeya T, Arai M, Ishibashi R, Aoki T, Tsuji Y, Yamamichi N, Hayakawa Y, Fujishiro M. Chemoprevention for Colorectal Cancers: Are Chemopreventive Effects Different Between Left and Right Sided Colorectal Cancers? Dig Dis Sci 2022; 67:5227-5238. [PMID: 35230578 DOI: 10.1007/s10620-022-07431-w] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/16/2021] [Accepted: 01/30/2022] [Indexed: 01/05/2023]
Abstract
BACKGROUND AND AIMS Recent studies have suggested that right- and left-sided colorectal cancers (CRCs) are molecularly distinct. In this study, we examined the association between the risk of right- and left-sided CRC and drug use to estimate their chemopreventive effects METHODS: This multicenter retrospective cohort study was conducted using the data of hospitalized patients between 2014 and 2019 from nine hospital databases. The primary outcomes were right- and left-sided CRC. We evaluated the association of CRCs with drug use and clinical factors. Odds ratios adjusted for age, sex, Charlson Comorbidity Index scores, and smoking status were calculated. We also compared the transcriptional profiling in precancerous lesions, including sessile serrated lesions (SSLs) RESULTS: A total of 307,938 patients, including 2745 with right-sided CRC and 4819 with left-sided CRC, were analyzed. The use of nonsteroidal anti-inflammatory drugs (NSAIDs), aspirin, cyclooxygenase-2 inhibitors, and steroids was associated with a lower risk of both right- and left-sided CRCs. In contrast, statins, other lipid-lowering agents, and metformin were associated with a lower risk of left-sided CRC. Transcriptomic analysis showed that SSL, which predominantly develops in the right colon, was associated with a lower expression of lipid metabolism-related genes. CONCLUSIONS Targeting lipid metabolism may be useful for chemoprevention of left-sided CRCs, while development of right-sided CRCs may be independent of this pathway.
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Affiliation(s)
- Junya Arai
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan
| | - Nobumi Suzuki
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan
| | - Ryota Niikura
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan
| | - Daisuke Ooki
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan
| | - Takuya Kawahara
- Clinical Research Promotion Center, The University of Tokyo Hospital, Tokyo, Japan
| | - Tetsuro Honda
- Department of Gastroenterology, Nagasaki Harbor Medical Center, Nagasaki-shi, Nagasaki, Japan
| | - Kenkei Hasatani
- Department of Gastroenterology, Fukui Prefectural Hospital, Fukui-shi, Fukui, Japan
| | - Naohiro Yoshida
- Department of Gastroenterology, Ishikawa Prefectural Central Hospital, Kanazawa-shi, Ishikawa, Japan
| | - Tsutomu Nishida
- Department of Gastroenterology, Toyonaka Municipal Hospital, Toyonaka-shi, Osaka, Japan
| | - Tetsuya Sumiyoshi
- Department of Gastroenterology, Tonan Hospital, Sapporo-shi, Hokkaido, Japan
| | - Shu Kiyotoki
- Department of Gastroenterology, Shuto General Hospital, Yanai-shi, Yamaguchi, Japan
| | - Takashi Ikeya
- Department of Gastroenterology, St. Luke's International Hospital, Chuo-ku, Tokyo, Japan
| | - Masahiro Arai
- Department of Gastroenterology, Nerima Hikarigaoka Hospital, Nerima-ku, Tokyo, Japan
| | - Rei Ishibashi
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan
| | - Tomonori Aoki
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan
| | - Yosuke Tsuji
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan
| | - Nobutake Yamamichi
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan
| | - Yoku Hayakawa
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan.
| | - Mitsuhiro Fujishiro
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan
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20
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Bairi KE, Trapani D, Page CL, Saad A, Jarroudi OA, Afqir S. Exploring the prognostic impact of tumor sidedness in ovarian cancer: A population-based survival analysis of over 10,000 patients. Cancer Treat Res Commun 2022; 33:100625. [PMID: 36057142 DOI: 10.1016/j.ctarc.2022.100625] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2022] [Revised: 08/14/2022] [Accepted: 08/16/2022] [Indexed: 12/14/2022]
Abstract
Very recently, emerging evidence demonstrated that laterality might be an independent prognostic factor in patients with advanced ovarian cancer (OC). Based on preliminary provocative observations, our study aimed to investigate the prognostic impact of sidedness in a large cohort of women with OC. Survival was estimated based on Kaplan-Meier method and survival curves were compared using Log-rank test. Cox proportional-hazards model was used to study the association between survival and covariates. A total of 10,177 women with OC were included. Mean age at diagnosis was 59.58 years (±13.5); 36.7% OC right-sided, 36.9% were left- sided, and 26.4% had bilateral OC. The median overall survival (OS) for the entire population was 77 months, with the lowest median OS observed in bilateral OC (median OS: 34 months). The prognostic value of OC sidedness was not confirmed at the univariable analysis (HR = 0.958; 95% CI: 0.888-1.033, p = 0.268). However, women with bilateral OC has a 45% higher risk of death as compared with unilateral diagnosis (HR = 1.453; 95% CI: 1.410-1.497; p< 0.001). The independent prognostic value was further confirmed on multivarible analysis after adjusting for covariates including age, marital status, histological type, CA-125 at diagnosis, grade, stage, chemotherapy and surgery (HR = 1.087; 95% CI: 1.043-1.136, p = 0.02). However, the ultimate prognostic significance appeared less prominent, with bilateral OC conferring a relative increase of 8.7% of mortality. Our real-world study demonstrated that impact of tumor sidedness has no prognostic implication (right vs left OC) but bilateral OCs might be marginally more prognostically unfavorable. Prospective validation might be warranted, to confirm the prognostic significance of OC sidedness, including for the presence of key genetic alterations and lymph nodes asymmetry, to better stratify patients with OC and predict outcomes according to tumor sidedness at diagnosis.
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Affiliation(s)
- Khalid El Bairi
- Department of Medical Oncology, Mohammed VI University Hospital, Oujda, Morocco; Faculty of Medicine and Pharmacy, Mohammed Ist University, Oujda, Morocco.
| | - Dario Trapani
- Division of Early Drug Development for Innovative Therapies, IEO, European Institute of Oncology IRCCS, Milan, Italy
| | - Cécile Le Page
- Research Institute of McGill University Health Center (RI-MUHC), Montréal, QC, Canada
| | - Anas Saad
- Cleveland Clinic Foundation, Cleveland, Ohio, United States of America
| | - Ouissam Al Jarroudi
- Department of Medical Oncology, Mohammed VI University Hospital, Oujda, Morocco; Faculty of Medicine and Pharmacy, Mohammed Ist University, Oujda, Morocco
| | - Said Afqir
- Department of Medical Oncology, Mohammed VI University Hospital, Oujda, Morocco; Faculty of Medicine and Pharmacy, Mohammed Ist University, Oujda, Morocco
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21
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Zhou E, Chen J, Peng S, Chen J, Fei T, Wang X, Qi C, Huang Q. Evaluating the value of tumor length times width in colorectal adenocarcinoma with different tumor locations. Medicine (Baltimore) 2022; 101:e29845. [PMID: 35777036 PMCID: PMC9239658 DOI: 10.1097/md.0000000000029845] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
Abstract
The T classification, which reflects the vertical growth pattern of the tumor, is one of the most important prognostic factors in colorectal cancer. We aimed to investigate the prognostic value of tumor length and width in patients with colorectal cancer (CRC). A total of 259 patients with stage I-III CRC who underwent curative resection were reevaluated according to tumor location. One-way ANOVA analysis was conducted to investigate the relationship between the tumor length times width (TLTW) and clinical parameters. Univariate and multivariate analyses were conducted to analyze the potential prognostic factors affecting overall survival (OS) of patients with stage I-III CRC. In the entire cohort, the TLTW was analyzed as a continuous variable. The results suggested that TLTW (P = .003) and tumor location (P = .04) could be independent prognostic factors for patients with CRC. In addition, TLTW had an intimate relationship with tumor location (P < 0.001) and differentiation (P = .003). The mean TLTW of the right colon was significantly larger than mean TLTW of the left colon and rectal cancers. However, the mean TLTW of the left colon cancer was similar to that of the rectal cancer TLTW (P > 0.05, not shown). Subgroup analysis of TLTW according to tumor location suggested that TLTW was an independent prognostic factor for patients with right colon cancer (RCC) (P = .007) rather than left colon cancer (LCC) (P = .49) or rectal cancer (P = .16). Kaplan-Meier (K-M) analysis based on tumor location suggested that the survival rate of RCC patients had a distinctly higher trend rate than LCC patients and RECC patients in the long-term rather than in the short-term. TLTW is closely associated with tumor location in CRC. In addition, TLTW may be an independent prognostic factor for patients with RCC.
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Affiliation(s)
- Encheng Zhou
- Department of Gastrointestinal Surgery of The Affiliated Hospital of Medical School, Ningbo University, Ningbo, Zhejiang, China
| | - Jianhui Chen
- Department of Gastrointestinal Surgery, Taizhou Hospital, Wenzhou Medical University, Linhai, Zhejiang, China
| | - Shuwang Peng
- Department of General Surgery of the First Hospital of Hunan University of Chinese Medicine, Changsha, Hunan, China
| | - Jingfeng Chen
- Anus and intestine surgery department of Central Hospital of Lishui, Lishui, Zhejiang, China
| | - Ting Fei
- Department of Gastrointestinal Surgery of The Affiliated Hospital of Medical School, Ningbo University, Ningbo, Zhejiang, China
| | - Xiaojun Wang
- Department of Gastrointestinal Surgery of The Affiliated Hospital of Medical School, Ningbo University, Ningbo, Zhejiang, China
| | - Changlei Qi
- Department of Gastrointestinal Surgery of The Affiliated Hospital of Medical School, Ningbo University, Ningbo, Zhejiang, China
| | - Qing Huang
- Emergency Department of The Affiliated Hospital of Medical School, Ningbo University, Ningbo, Zhejiang, China
- *Correspondence: Qing Huang, Emergency Department of The Affiliated Hospital of Medical School, Ningbo University, 247 Renmin Road, Ningbo, 315000, Zhejiang, China (e-mail: )
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22
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La Salvia A, Persano I, Siciliani A, Verrico M, Bassi M, Modica R, Audisio A, Zanata I, Trabalza Marinucci B, Trevisi E, Puliani G, Rinzivillo M, Parlagreco E, Baldelli R, Feola T, Sesti F, Razzore P, Mazzilli R, Mancini M, Panzuto F, Volante M, Giannetta E, Romero C, Appetecchia M, Isidori A, Venuta F, Ambrosio MR, Zatelli MC, Ibrahim M, Colao A, Brizzi MP, García-Carbonero R, Faggiano A. Prognostic significance of laterality in lung neuroendocrine tumors. Endocrine 2022; 76:733-746. [PMID: 35301675 PMCID: PMC9156515 DOI: 10.1007/s12020-022-03015-w] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/21/2021] [Accepted: 02/06/2022] [Indexed: 12/23/2022]
Abstract
PURPOSE Well-differentiated lung neuroendocrine tumors (Lu-NET) are classified as typical (TC) and atypical (AC) carcinoids, based on mitotic counts and necrosis. However, prognostic factors, other than tumor node metastasis (TNM) stage and the histopathological diagnosis, are still lacking. The current study is aimed to identify potential prognostic factors to better stratify lung NET, thus, improving patients' treatment strategy and follow-up. METHODS A multicentric retrospective study, including 300 Lung NET, all surgically removed, from Italian and Spanish Institutions. RESULTS Median age 61 years (13-86), 37.7% were males, 25.0% were AC, 42.0% were located in the lung left parenchyma, 80.3% presented a TNM stage I-II. Mitotic count was ≥2 per 10 high-power field (HPF) in 24.7%, necrosis in 13.0%. Median overall survival (OS) was 46.1 months (0.6-323), median progression-free survival (PFS) was 36.0 months (0.3-323). Female sex correlated with a more indolent disease (T1; N0; lower Ki67; lower mitotic count and the absence of necrosis). Left-sided primary tumors were associated with higher mitotic count and necrosis. At Cox-multivariate regression model, age, left-sided tumors, nodal (N) positive status and the diagnosis of AC resulted independent negative prognostic factors for PFS and OS. CONCLUSIONS This study highlights that laterality is an independent prognostic factors in Lu-NETs, with left tumors being less frequent but showing a worse prognosis than right ones. A wider spectrum of clinical and pathological prognostic factors, including TNM stage, age and laterality is suggested. These parameters could help clinicians to personalize the management of Lu-NET.
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Affiliation(s)
- Anna La Salvia
- Department of Oncology, 12 de Octubre University Hospital, Madrid, Spain
| | - Irene Persano
- Department of Oncology, San Luigi Gonzaga Hospital, Orbassano, Italy
| | | | - Monica Verrico
- Department of Radiological, Oncological, and Pathological Sciences, Sapienza University of Rome, Rome, Italy
| | - Massimiliano Bassi
- Department of Thoracic Surgery, Policlinico Umberto I, "Sapienza" University of Rome, Rome, Italy
| | - Roberta Modica
- Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy
| | | | - Isabella Zanata
- Department of Medical Sciences, Section of Endocrinology and Internal Medicine, University of Ferrara, Ferrara, Italy
| | | | - Elena Trevisi
- Department of Oncology, San Luigi Gonzaga Hospital, Orbassano, Italy
| | - Giulia Puliani
- Oncological Endocrinology Unit, Regina Elena National Cancer Institute, Rome, Italy
- Department of Experimental Medicine, "Sapienza" University of Roma, Rome, Italy
| | - Maria Rinzivillo
- Digestive Disease Unit, ENETS Center of Excellence, Sant'Andrea University Hospital, Rome, Italy
| | - Elena Parlagreco
- Department of Oncology, San Luigi Gonzaga Hospital, Orbassano, Italy
| | - Roberto Baldelli
- Endocrinology Unit, Department of Oncology and Medical Specialities, A.O. San Camillo-Forlanini, Rome, Italy
| | - Tiziana Feola
- Department of Experimental Medicine, "Sapienza" University of Roma, Rome, Italy
- Neuroendocrinology, Neuromed Institute, IRCCS, Pozzilli, Italy
| | - Franz Sesti
- Department of Experimental Medicine, "Sapienza" University of Roma, Rome, Italy
| | - Paola Razzore
- Endocrinology Unit, Mauriziano Hospital, Turin, Italy
| | - Rossella Mazzilli
- Endocrinology Unit, Department of Clinical and Molecular Medicine, Sant'Andrea Hospital, Sapienza University of Rome, ENETS Center of Excellence, Rome, Italy
| | | | - Francesco Panzuto
- Digestive Disease Unit, ENETS Center of Excellence, Sant'Andrea University Hospital, Rome, Italy
| | - Marco Volante
- Department of Oncology, Pathology Unit of San Luigi Hospital, University of Turin, Orbassano, Turin, Italy
| | - Elisa Giannetta
- Department of Experimental Medicine, "Sapienza" University of Roma, Rome, Italy
| | - Carmen Romero
- Scientific Support, 12 de Octubre University Hospital, Madrid, Spain
| | | | - Andrea Isidori
- Department of Experimental Medicine, "Sapienza" University of Roma, Rome, Italy
| | - Federico Venuta
- Department of Thoracic Surgery, Policlinico Umberto I, "Sapienza" University of Rome, Rome, Italy
| | - Maria Rosaria Ambrosio
- Department of Medical Sciences, Section of Endocrinology and Internal Medicine, University of Ferrara, Ferrara, Italy
| | - Maria Chiara Zatelli
- Department of Medical Sciences, Section of Endocrinology and Internal Medicine, University of Ferrara, Ferrara, Italy
| | - Mohsen Ibrahim
- Department of Thoracic Surgery, Sant'Andrea University Hospital, Rome, Italy
| | - Annamaria Colao
- Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy
| | - Maria Pia Brizzi
- Department of Oncology, San Luigi Gonzaga Hospital, Orbassano, Italy
| | | | - Antongiulio Faggiano
- Endocrinology Unit, Department of Clinical and Molecular Medicine, Sant'Andrea Hospital, Sapienza University of Rome, ENETS Center of Excellence, Rome, Italy.
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23
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Newland R, Ng KS, Chapuis P, Chan C, Dent O. The Association Between Tumour Sub-site and Local Nodal and/or Distant Metastasis at the Time of Resection of Colorectal Cancer: A prospective study of 3,360 consecutive cases. Hum Pathol 2022; 126:121-128. [DOI: 10.1016/j.humpath.2022.05.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/07/2022] [Revised: 05/01/2022] [Accepted: 05/03/2022] [Indexed: 11/04/2022]
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24
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Filippini Velázquez G, Schiele S, Gerken M, Neumaier S, Hackl C, Mayr P, Klinkhammer-Schalke M, Illerhaus G, Schlitt HJ, Anthuber M, Kröncke T, Messmann H, Märkl B, Schmid C, Trepel M, Müller G, Claus R, Hackanson B. Predictive preoperative clinical score for patients with liver-only oligometastatic colorectal cancer. ESMO Open 2022; 7:100470. [PMID: 35461024 PMCID: PMC9271475 DOI: 10.1016/j.esmoop.2022.100470] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2021] [Revised: 03/10/2022] [Accepted: 03/11/2022] [Indexed: 12/03/2022] Open
Abstract
Background Resection of liver metastases from colorectal cancer (CRC) in the oligometastatic stage improves survival and is a potentially curative treatment. Thus, predictive scores that reliably identify those patients who especially benefit from surgery are essential. Patients and methods In this multicenter analysis, 512 patients had undergone surgery for liver metastases from CRC. We investigated distinct cancer-specific risk factors that are routinely available in clinical practice and developed a predictive preoperative score using a training cohort (TC), which was thereafter tested in a validation cohort (VC). Results Inflammatory response to the tumor, a right-sided primary tumor, multiple liver metastases, and node-positive primary tumor were significant adverse variables for overall survival (OS). Patients were stratified in five groups according to the cumulative score given by the presence of these risk factors. Median OS for patients without risk factors was 133.8 months [95% confidence interval (CI) 81.2-not reached (nr)] in the TC and was not reached in the VC. OS decreased significantly for each subsequent group with increasing number of risk factors. Median OS was significantly shorter (P < 0.0001) for patients presenting all four risk factors: 14.3 months (95% CI 10.5 months-nr) in the TC and 16.6 months (95% CI 14.6 months-nr) in the VC. Conclusions Including easily obtainable variables, this preoperative score identifies oligometastatic CRC patients with prolonged survival rates that may be cured, and harbors potential to be implemented in daily clinical practice.
We identified four variables of adverse outcome for patients treated with surgical resection of liver metastases from CRC. Adverse variables were inflammatory response to the tumor, multiple metastases, right-sided primary tumor, node-positive primary tumor. We developed a preoperative clinical score according to the number of risk factors present. Using easily obtainable variables, this score identified patients with oligometastatic CRC with good prognosis. Patients without risk factors should strongly be considered for surgical resection of their metastases.
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Affiliation(s)
- G Filippini Velázquez
- Comprehensive Cancer Center Augsburg (CCCA), University Medical Center Augsburg, Augsburg, Germany
| | - S Schiele
- Faculty of Applied Mathematics and Statistics, University of Augsburg, Augsburg, Germany
| | - M Gerken
- Tumor Center Regensburg, Institute for Quality Assurance and Health Service Research, University of Regensburg, Regensburg, Germany
| | - S Neumaier
- Department of Haematology and Oncology, Katharinen Hospital Stuttgart, Stuttgart, Germany
| | - C Hackl
- Department of Surgery, University Medical Center Regensburg, Regensburg, Germany
| | - P Mayr
- Comprehensive Cancer Center Augsburg (CCCA), University Medical Center Augsburg, Augsburg, Germany
| | - M Klinkhammer-Schalke
- Tumor Center Regensburg, Institute for Quality Assurance and Health Service Research, University of Regensburg, Regensburg, Germany
| | - G Illerhaus
- Department of Haematology and Oncology, Katharinen Hospital Stuttgart, Stuttgart, Germany
| | - H J Schlitt
- Department of Surgery, University Medical Center Regensburg, Regensburg, Germany
| | - M Anthuber
- Comprehensive Cancer Center Augsburg (CCCA), University Medical Center Augsburg, Augsburg, Germany
| | - T Kröncke
- Comprehensive Cancer Center Augsburg (CCCA), University Medical Center Augsburg, Augsburg, Germany
| | - H Messmann
- Comprehensive Cancer Center Augsburg (CCCA), University Medical Center Augsburg, Augsburg, Germany
| | - B Märkl
- Comprehensive Cancer Center Augsburg (CCCA), University Medical Center Augsburg, Augsburg, Germany
| | - C Schmid
- Comprehensive Cancer Center Augsburg (CCCA), University Medical Center Augsburg, Augsburg, Germany
| | - M Trepel
- Comprehensive Cancer Center Augsburg (CCCA), University Medical Center Augsburg, Augsburg, Germany
| | - G Müller
- Faculty of Applied Mathematics and Statistics, University of Augsburg, Augsburg, Germany
| | - R Claus
- Comprehensive Cancer Center Augsburg (CCCA), University Medical Center Augsburg, Augsburg, Germany; General Pathology and Molecular Diagnostics, Faculty of Medicine, University of Augsburg, Augsburg, Germany; Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - B Hackanson
- Comprehensive Cancer Center Augsburg (CCCA), University Medical Center Augsburg, Augsburg, Germany; Faculty of Medicine, University of Freiburg, Freiburg, Germany.
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25
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Zhang YF, Ma C, Qian XP. Development and external validation of a novel nomogram for predicting cancer-specific survival in patients with ascending colon adenocarcinoma after surgery: a population-based study. World J Surg Oncol 2022; 20:126. [PMID: 35439983 PMCID: PMC9020108 DOI: 10.1186/s12957-022-02576-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2021] [Accepted: 03/17/2022] [Indexed: 11/23/2022] Open
Abstract
BACKGROUND This study aimed to develop and validate a novel nomogram to predict the cancer-specific survival (CSS) of patients with ascending colon adenocarcinoma after surgery. METHODS Patients with ascending colon adenocarcinoma were enrolled from the Surveillance, Epidemiology, and End Results (SEER) database from 1973 to 2015 and randomly divided into a training set (5930) and a validation set (2540). The cut-off values for age, tumour size and lymph node ratio (LNR) were calculated via X-tile software. In the training set, independent prognostic factors were identified using univariate and multivariate Cox analyses, and a nomogram incorporating these factors was subsequently built. Data from the validation set were used to assess the reliability and accuracy of the nomogram and then compared with the 8th edition of the American Joint Committee on Cancer (AJCC) tumour-node-metastasis (TNM) staging system. Furthermore, external validation was performed from a single institution in China. RESULTS A total of 8470 patients were enrolled from the SEER database, 5930 patients were allocated to the training set, 2540 were allocated to the internal validation set and a separate set of 473 patients was allocated to the external validation set. The optimal cut-off values of age, tumour size and lymph node ratio were 73 and 85, 33 and 75 and 4.9 and 32.8, respectively. Univariate and multivariate Cox multivariate regression revealed that age, AJCC 8th edition T, N and M stage, carcinoembryonic antigen (CEA), tumour differentiation, chemotherapy, perineural invasion and LNR were independent risk factors for patient CSS. The nomogram showed good predictive ability, as indicated by discriminative ability and calibration, with C statistics of 0.835 (95% CI, 0.823-0.847) and 0.848 (95% CI, 0.830-0.866) in the training and validation sets and 0.732 (95% CI, 0.664-0.799) in the external validation set. The nomogram showed favourable discrimination and calibration abilities and performed better than the AJCC TNM staging system. CONCLUSIONS A novel validated nomogram could effectively predict patients with ascending colon adenocarcinoma after surgery, and this predictive power may guide clinicians in accurate prognostic judgement.
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Affiliation(s)
- Yi Fan Zhang
- Comprehensive Cancer Center, Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University, Nanjing, 210000, China
- Department of Radiotherapy, The Xuzhou School of Clinical Medicine of Nanjing Medical University, Xuzhou, 221000, China
| | - Cheng Ma
- Department of Gastrointestinal Surgery, The Xuzhou School of Clinical Medicine of Nanjing Medical University, Xuzhou, 221000, China
| | - Xiao Ping Qian
- Comprehensive Cancer Center, Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University, Nanjing, 210000, China.
- Comprehensive Cancer Center, Nanjing Drum Tower Hospital, Medical School of Nanjing University, Clinical Cancer Institute of Nanjing University, Nanjing, 210000, China.
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Yan H, Yu TN. Radiomics-clinical nomogram for response to chemotherapy in synchronous liver metastasis of colorectal cancer: Good, but not good enough. World J Gastroenterol 2022; 28:973-975. [PMID: 35317054 PMCID: PMC8908283 DOI: 10.3748/wjg.v28.i9.973] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/31/2021] [Revised: 01/03/2022] [Accepted: 01/29/2022] [Indexed: 02/06/2023] Open
Abstract
There remains a persistent unmet need to detect the disease nonresponse (nonDR) subgroup before adjuvant therapy in synchronous liver metastasis patients with colorectal cancer. Ma’s radiomics-clinical nomogram shows potential for the early detection of nonDR subgroups, but it is not good enough owing to at least three limitaions, which we address in this letter to the editor. First, the study did not explore RAS/BRAF mutations, HER2 amplifications, etc. to complement the current nomogram. Second, the nomogram was not validated in left- and right-sided tumors separately. Third, the most critical factor for determining the success of adjuvant therapy should be resectability rather than tumor size shrinkage, which was used in the study.
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Affiliation(s)
- Han Yan
- Department of Colorectal Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou 310016, Zhejiang Province, China
| | - Tu-Nan Yu
- Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou 310016, Zhejiang Province, China
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27
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Sofía M, Sebastián R, Emanuel C, Branham MT, Marzese DM, Matthew S, De Blas G, Rodolfo A, Michael L, María R. When left does not seem right: epigenetic and bioelectric differences between left- and right-sided breast cancer. Mol Med 2022; 28:15. [PMID: 35123413 PMCID: PMC8817536 DOI: 10.1186/s10020-022-00440-5] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2021] [Accepted: 01/18/2022] [Indexed: 01/22/2023] Open
Abstract
Background During embryogenesis lateral symmetry is broken, giving rise to Left/Right (L/R) breast tissues with distinct identity. L/R-sided breast tumors exhibit consistently-biased incidence, gene expression, and DNA methylation. We postulate that a differential L/R tumor-microenvironment crosstalk generates different tumorigenesis mechanisms. Methods We performed in-silico analyses on breast tumors of public datasets, developed xenografted tumors, and conditioned MDA-MB-231 cells with L/R mammary extracts. Results We found L/R differential DNA methylation involved in embryogenic and neuron-like functions. Focusing on ion-channels, we discovered significant L/R epigenetic and bioelectric differences. Specifically, L-sided cells presented increased methylation of hyperpolarizing ion channel genes and increased Ca2+ concentration and depolarized membrane potential, compared to R-ones. Functional consequences were associated with increased proliferation in left tumors, assessed by KI67 expression and mitotic count. Conclusions Our findings reveal considerable L/R asymmetry in cancer processes, and suggest specific L/R epigenetic and bioelectric differences as future targets for cancer therapeutic approaches in the breast and many other paired organs. Supplementary Information The online version contains supplementary material available at 10.1186/s10020-022-00440-5.
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Arai J, Hayakawa Y, Koike K. The Colorectal Cancer Lipidome: Are There Any Differences in Lipid Species Between Right and Left Colorectal Cancers? Gastroenterology 2022; 162:658. [PMID: 34087183 DOI: 10.1053/j.gastro.2021.05.052] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/22/2021] [Accepted: 05/31/2021] [Indexed: 12/02/2022]
Affiliation(s)
- Junya Arai
- Department of Gastroenterology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan
| | - Yoku Hayakawa
- Department of Gastroenterology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan
| | - Kazuhiko Koike
- Department of Gastroenterology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan
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Golas MM, Gunawan B, Cakir M, Cameron S, Enders C, Liersch T, Füzesi L, Sander B. Evolutionary patterns of chromosomal instability and mismatch repair deficiency in proximal and distal colorectal cancer. Colorectal Dis 2022; 24:157-176. [PMID: 34623739 DOI: 10.1111/codi.15946] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/31/2021] [Revised: 07/04/2021] [Accepted: 09/28/2021] [Indexed: 12/27/2022]
Abstract
AIM Colorectal carcinomas (CRCs) progress through heterogeneous pathways. The aim of this study was to analyse whether or not the cytogenetic evolution of CRC is linked to tumour site, level of chromosomal imbalance and metastasis. METHOD A set of therapy-naïve pT3 CRCs comprising 26 proximal and 49 distal pT3 CRCs was studied by combining immunohistochemistry of mismatch repair (MMR) proteins, microsatellite analyses and molecular karyotyping as well as clinical parameters. RESULTS A MMR deficient/microsatellite-unstable (dMMR/MSI-H) status was associated with location of the primary tumour proximal to the splenic flexure, and dMMR/MSI-H tumours presented with significantly lower levels of chromosomal imbalances compared with MMR proficient/microsatellite-stable (pMMR/MSS) tumours. Oncogenetic tree modelling suggested two evolutionary clusters characterized by dMMR/MSI-H and chromosomal instability (CIN), respectively, for both proximal and distal CRCs. In CIN cases, +13q, -18q and +20q were predicted as preferentially early events, and -1p, -4 -and -5q as late events. Separate oncogenetic tree models of proximal and distal cases indicated similar early events independent of tumour site. However, in cases with high CIN defined by more than 10 copy number aberrations, loss of 17p occurred earlier in cytogenetic evolution than in cases showing low to moderate CIN. Differences in the oncogenetic trees were observed for CRCs with lymph node and distant metastasis. Loss of 8p was modelled as an early event in node-positive CRC, while +7p and +8q comprised early events in CRC with distant metastasis. CONCLUSION CRCs characterized by CIN follow multiple, interconnected genetic pathways in line with the basic 'Vogelgram' concept proposed for the progression of CRC that places the accumulation of genetic changes at centre of tumour evolution. However, the timing of specific genetic events may favour metastatic potential.
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Affiliation(s)
- Mariola Monika Golas
- Department of Hematology and Medical Oncology, Comprehensive Cancer Center Augsburg, University Medical Center Augsburg, Augsburg, Germany
| | - Bastian Gunawan
- Institute of Pathology, University Medical Center Göttingen, Göttingen, Germany
| | - Meliha Cakir
- Institute of Pathology, University Medical Center Göttingen, Göttingen, Germany
| | - Silke Cameron
- Department of Gastroenterology and Gastrointestinal Oncology, University Medical Center Göttingen, Göttingen, Germany
| | - Christina Enders
- Institute of Pathology, University Medical Center Göttingen, Göttingen, Germany
| | - Torsten Liersch
- Department of General, Visceral and Pediatric Surgery, University Medical Center Göttingen, Göttingen, Germany
| | - Laszlo Füzesi
- Institute of Pathology, University Medical Center Göttingen, Göttingen, Germany.,Institute of Pathology and Molecular Diagnostics, University Medical Center Augsburg, Augsburg, Germany
| | - Bjoern Sander
- Institute of Pathology, University Medical Center Göttingen, Göttingen, Germany.,Institute of Pathology, Hannover Medical School, Hannover, Germany
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30
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Yan S, Guo W, Liu Y, Li K, Wang W. The role of folate receptor-positive circulating tumor cell analysis in the diagnosis of colorectal cancer: a retrospective cohort study. Int J Clin Oncol 2022; 27:538-544. [PMID: 35043284 DOI: 10.1007/s10147-021-02097-2] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2021] [Accepted: 11/24/2021] [Indexed: 11/30/2022]
Abstract
OBJECTIVE To explore the application value of folate receptor-positive circulating tumor cell analysis (FR+-CTC analysis) in the diagnosis of colorectal cancer (CRC). METHODS Clinical data of CRC patients and healthy subjects admitted to our hospital from January 2019 to October 2019 were retrospectively collected. CTC result and serological and pathological outcomes of the study patients were collected and analyzed. Receiver operating characteristic curve (ROC curve) was drawn. RESULTS The CTC levels of cancer patients (9.34 ± 3.53 FU/3 ml) were significantly higher than those of healthy subjects (7.00 ± 2.33 FU/3 ml). CTC levels could be related to cancer stage and metastasis in patients. ROC curves were drawn and the area under the ROC curve (AUC) was 0.702. The cutoff value was determined to be 8.87 FU/3 ml. At this cutoff value, the sensitivity and specificity of FR+-CTC analysis in the diagnosis of colorectal cancer were 61.8% and 82.6%, respectively. The diagnostic efficiency of FR+-CTCs in advanced CRC was significantly higher than that in the early stage. And the cutoff value of early and advanced stage CRC was determined to be 9.66 FU/3 ml. CONCLUSION FR+-CTC analysis has high potential in recurrence diagnosis and decision of adjuvant chemotherapy for CRC.
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Affiliation(s)
- Su Yan
- Department of General Surgery, Renmin Hospital of Wuhan University, Wuhan, 430060, China
| | - Wenyi Guo
- Department of General Surgery, Renmin Hospital of Wuhan University, Wuhan, 430060, China.,Department of Gastrointestinal Surgery, Renmin Hospital of Wuhan University, Wuhan, 430060, China
| | - Yanliang Liu
- Department of General Surgery, Renmin Hospital of Wuhan University, Wuhan, 430060, China.,Department of Gastrointestinal Surgery, Renmin Hospital of Wuhan University, Wuhan, 430060, China
| | - Kai Li
- Department of General Surgery, Renmin Hospital of Wuhan University, Wuhan, 430060, China.,Department of Gastrointestinal Surgery, Renmin Hospital of Wuhan University, Wuhan, 430060, China
| | - Weixing Wang
- Department of General Surgery, Renmin Hospital of Wuhan University, Wuhan, 430060, China.
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31
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Alterations of circulating lymphocyte subsets in patients with colorectal carcinoma. Cancer Immunol Immunother 2021; 71:1937-1947. [PMID: 34928423 PMCID: PMC9293872 DOI: 10.1007/s00262-021-03127-8] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2021] [Accepted: 12/06/2021] [Indexed: 12/25/2022]
Abstract
Introduction Cellular immune response to cancer is known to be of great importance for tumor control. Moreover, solid tumors influence circulating lymphocytes, which has been shown for several types of cancer. In our prospective study we elucidate changes in lymphocyte subsets in patients with colorectal carcinoma compared to healthy volunteers. Methods Flow cytometry was performed at diagnosis of colon carcinoma to analyze B cells, T cells and NK cells including various subtypes of each group. Univariate and multivariate analyses including age, gender, tumor stage, sidedness and microsatellite instability status (MSI) were performed. Results Forty-seven patients and 50 healthy volunteers were included. Median age was 65 years in patients and 43 years in the control group. Univariate analysis revealed lower total lymphocyte counts, lower CD4 + cells, CD8 + cells, B cells and NKs including various of their subsets in patients. In multivariate analysis patients had inferior values of B cells, CD4 + cells and NK cells and various subsets, regardless of age and gender. Naïve, central memory and HLADR + CD8 + cells showed an increase in patients whereas all other altered subsets declined. MSI status had no influence on circulating lymphocytes except for higher effector memory CD8 + cells in MSI-high patients. Localization in the left hemicolon led to higher values of total cytotoxic T cells and various T cell subsets. Conclusion We found significant changes in circulating lymphocyte subsets in colon carcinoma patients, independent of physiological alterations due to gender or age. For some lymphocyte subsets significant differences according to tumor localization or MSI-status could be seen. Supplementary Information The online version contains supplementary material available at 10.1007/s00262-021-03127-8.
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Sultan A, Sahar NE, Riaz SK, Qadir J, Waqar SH, Haq F, Khaliq T, Malik MFA. Metadherin (MTDH) overexpression significantly correlates with advanced tumor grade and stages among colorectal cancer patients. Mol Biol Rep 2021; 48:7999-8007. [PMID: 34741710 DOI: 10.1007/s11033-021-06834-8] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2021] [Accepted: 10/12/2021] [Indexed: 10/19/2022]
Abstract
BACKGROUND Colorectal cancer is the 4th leading cause of cancer related deaths affecting both men and women worldwide. In the present study, any probable role of MTDH mRNA expression in CRC tumorigenesis was explored using both discovery and validation cohorts. METHODS AND RESULTS After prior ethical and biosafety approvals, tumor tissue samples along with their adjacent controls were collected for this study from Pakistani patients diagnosed with colorectal cancer. RNA was isolated using Trizol reagent, followed by cDNA synthesis. Transcript analysis of MTDH was performed by using qPCR. Moreover, genome-wide expression of MTDH was also determined through micro-array data analysis using BRB-array tools software. MTDH expression was significantly high in tumor tissue samples (p < 0.05) compared to their respective controls. Likewise, results of microarray analysis also revealed overamplification of MTDH in tumor samples as compared to controls. Expression of MTDH was also found to be positively correlated with KI-67 index (p < 0.05) and were observed to be significantly upregulated in advance tumor grade (p < 0.05) and stage (p < 0.05). However, no association of MTDH overexpression with age and gender could be established. CONCLUSION Hence, it can be concluded that MTDH is a core element that plays a pivotal role in colorectal tumorigenesis irrespective of patient's age and gender. Molecular insight into the tumor microenvironment revealed MTDH as a niche, representing distinctive framework for cancer progression, thus, making it an innovative target strategy for colorectal cancer treatment.
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Affiliation(s)
- Aimen Sultan
- Department of Biosciences, COMSATS University Islamabad, Park Road, Islamabad, Pakistan
| | - Namood-E Sahar
- Department of Biosciences, COMSATS University Islamabad, Park Road, Islamabad, Pakistan.,College of Medicine, University of Nebraska, Medical Center, Omaha, USA
| | - Syeda Kiran Riaz
- Department of Molecular Biology, Shaheed Zulfiqar Ali Bhutto Medical University, Islamabad, Pakistan
| | - Javeria Qadir
- Department of Biosciences, COMSATS University Islamabad, Park Road, Islamabad, Pakistan.,Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada
| | - Shahzad Hussain Waqar
- Department of General Surgery, Shaheed Zulfiqar Ali Bhutto Medical University, Islamabad, Pakistan
| | - Farhan Haq
- Department of Biosciences, COMSATS University Islamabad, Park Road, Islamabad, Pakistan
| | - Tanwir Khaliq
- Department of General Surgery, Shaheed Zulfiqar Ali Bhutto Medical University, Islamabad, Pakistan
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Jin M, Shang F, Wu J, Fan Q, Chen C, Fan J, Liu L, Nie X, Zhang T, Cai K, Ogino S, Liu H. Tumor-Associated Microbiota in Proximal and Distal Colorectal Cancer and Their Relationships With Clinical Outcomes. Front Microbiol 2021; 12:727937. [PMID: 34650531 PMCID: PMC8506159 DOI: 10.3389/fmicb.2021.727937] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2021] [Accepted: 08/17/2021] [Indexed: 12/21/2022] Open
Abstract
The proximal and distal subsites of colorectal cancer (CRC) have distinct differences in their embryonic origin, epidemiology, and prognosis. Therefore, they are not considered as the same disease. However, the possible difference in microbial characterization of the two subsites of CRC is still unclear. In this study, we explored tumor microbiota diversity and composition difference in patients with proximal (N = 187) and distal CRCs (N = 142). This was carried out on cancer tissues and adjacent tissues using bacterial 16S rRNA sequencing. The Kaplan-Meier method was used to analyze the correlation between differential flora and overall survival rate of the patients. It was found that there were significant differences in tumor microbial characteristics between the proximal and distal CRC tissues. The microbiota communities were distinctly richer in the proximal colon tumor tissues than in the distal CRC tissues. Microbial diversity and structure were relatively constant in the paracancerous normal tissues of the proximal and distal colorectum. Generally, microbial communities of CRC tumor tissues were composed of Proteobacteria, Firmicutes, Actinobacteria, and Bacteroidetes. Alpha diversity in the proximal and distal CRC tumor tissues was closely related to specific microflora. The abundance of Fusobacteria was associated with age of patient, tumor diameter, and tumor microsatellite instability (MSI) status of the patients. Moreover, Fusobacteria enrichment was associated with poor prognosis especially in patients with proximal colon cancers, but not in patients with distal CRC. In conclusion, proximal and distal subsites of the CRC present distinct microbiota diversity and community structures. The differences indicate that there are different risk factors across anatomical subsites of CRC, which may provide a new strategy for precise prevention and treatment of CRC in the future.
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Affiliation(s)
- Min Jin
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Fumei Shang
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Department of Medical Oncology, Nanyang Central Hospital, Nanyang, China
| | - Jingjing Wu
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Qilin Fan
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Chen Chen
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jun Fan
- Department of Pathology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Li Liu
- Department of Epidemiology and Biostatistics, The Ministry of Education Key Lab of Environment and Health, School of Public Health, Huazhong University of Science and Technology, Wuhan, China
| | - Xiu Nie
- Department of Pathology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Tao Zhang
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Kailin Cai
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Shuji Ogino
- Program in Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, United States
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, United States
- Broad Institute of MIT and Harvard, Cambridge, MA, United States
- Cancer Immunology and Cancer Epidemiology Programs, Dana–Farber Harvard Cancer Center, Boston, MA, United States
| | - Hongli Liu
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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Advances in radiological staging of colorectal cancer. Clin Radiol 2021; 76:879-888. [PMID: 34243943 DOI: 10.1016/j.crad.2021.06.005] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2021] [Accepted: 06/08/2021] [Indexed: 12/12/2022]
Abstract
The role of imaging in clinically staging colorectal cancer has grown substantially in the 21st century with more widespread availability of multi-row detector computed tomography (CT), high-resolution magnetic resonance imaging (MRI) with diffusion weighted imaging (DWI), and integrated positron-emission tomography (PET)/CT. In contrast to staging many other cancers, increasing colorectal cancer stage does not highly correlate with survival. As has been the case previously, clinical practice incorporates advances in staging and it is used to guide therapy before adoption into international staging guidelines. Emerging imaging techniques show promise to become part of future staging standards.
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35
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Yi T, Zhang Y, Ng DM, Xi Y, Ye M, Cen L, Li J, Fan X, Li Y, Hu S, Rong H, Xie Y, Zhao G, Chen L, Chen C, Ni S, Mi J, Dai X, Liao Q. Regulatory Network Analysis of Mutated Genes Based on Multi-Omics Data Reveals the Exclusive Features in Tumor Immune Microenvironment Between Left-Sided and Right-Sided Colon Cancer. Front Oncol 2021; 11:685515. [PMID: 34211853 PMCID: PMC8239301 DOI: 10.3389/fonc.2021.685515] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2021] [Accepted: 04/29/2021] [Indexed: 01/11/2023] Open
Abstract
Left-sided colon cancer (LCC) and right-sided colon cancer (RCC) have distinct characteristics in tumor immune microenvironment (TIME). Although existing studies have shown a strong association between gene mutations and TIME, whether the regulatory mechanisms between gene mutations and TIME are different between RCC and LCC is still unclear. In this study, we showed the fractions of CD8+ T cells were higher while those of regulatory T cells were lower in RCC. Besides, a stronger association between gene mutations and TIME was observed in RCC. Specifically, using multi-omics data, we demonstrated the mutations of most top mutated genes (TMGs) including BRAF, PCLO, MUC16, LRP2, ANK3, KMT2D, RYR2 made great contributions to elevated fraction of immune cells by up-regulating immune-related genes directly or indirectly through miRNA and DNA methylation, whereas the effects of APC, TP53 and KRAS mutations on TIME were reversed in RCC. Remarkably, we found the expression levels of several immune checkpoint molecules such as PD-1 and LAG3 were correlated with corresponding DNA methylation levels, which were associated with the mutations of TMGs in RCC. In contrast, the associations between gene mutations and TIME were less significant in LCC. Besides, survival analyses showed APC mutation had adverse impact on immunotherapy while patients with BRAF mutation were more suitable for immunotherapy in colon cancer. We hope that our results will provide a deeper insight into the sophisticated mechanism underlying the regulation between mutations and TIME, and thus boost the discovery of differential immunotherapeutic strategies for RCC and LCC.
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Affiliation(s)
- Tianfei Yi
- The Affiliated Hospital of Medical School of Ningbo University, Ningbo, China.,Department of Preventative Medicine, Zhejiang Provincial Key Laboratory of Pathophysiology, School of Medicine, Ningbo University, Ningbo, China.,Department of Biochemistry and Molecular Biology, Zhejiang Provincial Key Laboratory of Pathophysiology, School of Medicine, Ningbo University, Ningbo, China
| | - Yuwei Zhang
- Department of Preventative Medicine, Zhejiang Provincial Key Laboratory of Pathophysiology, School of Medicine, Ningbo University, Ningbo, China.,Department of Biochemistry and Molecular Biology, Zhejiang Provincial Key Laboratory of Pathophysiology, School of Medicine, Ningbo University, Ningbo, China
| | - Derry Minyao Ng
- Department of Preventative Medicine, Zhejiang Provincial Key Laboratory of Pathophysiology, School of Medicine, Ningbo University, Ningbo, China.,Department of Biochemistry and Molecular Biology, Zhejiang Provincial Key Laboratory of Pathophysiology, School of Medicine, Ningbo University, Ningbo, China
| | - Yang Xi
- Department of Biochemistry and Molecular Biology, Zhejiang Provincial Key Laboratory of Pathophysiology, School of Medicine, Ningbo University, Ningbo, China
| | - Meng Ye
- The Affiliated Hospital of Medical School of Ningbo University, Ningbo, China
| | - Lvjun Cen
- The Affiliated Hospital of Medical School of Ningbo University, Ningbo, China
| | - Jianjiong Li
- Hua Mei Hospital, University of Chinese Academy of Sciences, Ningbo, China.,Ningbo Institute of Life and Health Industry, University of Chinese Academy of Sciences, Ningbo, China.,Key Laboratory of Diagnosis and Treatment of Digestive System Tumors of Zhejiang Province, Ningbo, China
| | - Xiaoxiang Fan
- Hua Mei Hospital, University of Chinese Academy of Sciences, Ningbo, China.,Ningbo Institute of Life and Health Industry, University of Chinese Academy of Sciences, Ningbo, China.,Key Laboratory of Diagnosis and Treatment of Digestive System Tumors of Zhejiang Province, Ningbo, China
| | - Yanguo Li
- Institute of Drug Discovery Technology, Ningbo University, Ningbo, China
| | - Shiyun Hu
- The Affiliated Hospital of Medical School of Ningbo University, Ningbo, China.,Department of Preventative Medicine, Zhejiang Provincial Key Laboratory of Pathophysiology, School of Medicine, Ningbo University, Ningbo, China.,Department of Biochemistry and Molecular Biology, Zhejiang Provincial Key Laboratory of Pathophysiology, School of Medicine, Ningbo University, Ningbo, China
| | - Hao Rong
- The Affiliated Hospital of Medical School of Ningbo University, Ningbo, China.,Department of Preventative Medicine, Zhejiang Provincial Key Laboratory of Pathophysiology, School of Medicine, Ningbo University, Ningbo, China.,Department of Biochemistry and Molecular Biology, Zhejiang Provincial Key Laboratory of Pathophysiology, School of Medicine, Ningbo University, Ningbo, China
| | - Yangyang Xie
- Hua Mei Hospital, University of Chinese Academy of Sciences, Ningbo, China.,Ningbo Institute of Life and Health Industry, University of Chinese Academy of Sciences, Ningbo, China.,Key Laboratory of Diagnosis and Treatment of Digestive System Tumors of Zhejiang Province, Ningbo, China
| | - Guofang Zhao
- Hua Mei Hospital, University of Chinese Academy of Sciences, Ningbo, China.,Ningbo Institute of Life and Health Industry, University of Chinese Academy of Sciences, Ningbo, China
| | - Leyi Chen
- Department of Preventative Medicine, Zhejiang Provincial Key Laboratory of Pathophysiology, School of Medicine, Ningbo University, Ningbo, China.,Department of Biochemistry and Molecular Biology, Zhejiang Provincial Key Laboratory of Pathophysiology, School of Medicine, Ningbo University, Ningbo, China
| | - Chen Chen
- Department of Preventative Medicine, Zhejiang Provincial Key Laboratory of Pathophysiology, School of Medicine, Ningbo University, Ningbo, China.,Department of Biochemistry and Molecular Biology, Zhejiang Provincial Key Laboratory of Pathophysiology, School of Medicine, Ningbo University, Ningbo, China
| | - Shujing Ni
- Department of Preventative Medicine, Zhejiang Provincial Key Laboratory of Pathophysiology, School of Medicine, Ningbo University, Ningbo, China.,Department of Biochemistry and Molecular Biology, Zhejiang Provincial Key Laboratory of Pathophysiology, School of Medicine, Ningbo University, Ningbo, China
| | - Jiaying Mi
- Hua Mei Hospital, University of Chinese Academy of Sciences, Ningbo, China.,Ningbo Institute of Life and Health Industry, University of Chinese Academy of Sciences, Ningbo, China
| | - Xiaoyu Dai
- Hua Mei Hospital, University of Chinese Academy of Sciences, Ningbo, China.,Ningbo Institute of Life and Health Industry, University of Chinese Academy of Sciences, Ningbo, China.,Key Laboratory of Diagnosis and Treatment of Digestive System Tumors of Zhejiang Province, Ningbo, China
| | - Qi Liao
- The Affiliated Hospital of Medical School of Ningbo University, Ningbo, China.,Department of Preventative Medicine, Zhejiang Provincial Key Laboratory of Pathophysiology, School of Medicine, Ningbo University, Ningbo, China.,Department of Biochemistry and Molecular Biology, Zhejiang Provincial Key Laboratory of Pathophysiology, School of Medicine, Ningbo University, Ningbo, China
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36
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Bergen ES, Scherleitner P, Ferreira P, Kiesel B, Müller C, Widhalm G, Dieckmann K, Prager G, Preusser M, Berghoff AS. Primary tumor side is associated with prognosis of colorectal cancer patients with brain metastases. ESMO Open 2021; 6:100168. [PMID: 34098230 PMCID: PMC8190486 DOI: 10.1016/j.esmoop.2021.100168] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2021] [Revised: 05/07/2021] [Accepted: 05/11/2021] [Indexed: 01/05/2023] Open
Abstract
Background Brain metastases (BM) are a rare complication in colorectal cancer (CRC) patients and associated with an unfavorable survival prognosis. Primary tumor side (PTS) was shown to act as a prognostic and predictive biomarker in several trials including metastatic CRC (mCRC) patients. Here, we aim to investigate whether PTS is also associated with the outcome of CRC patients with BM. Methods Patients treated for CRC BM between 1988 and 2017 at an academic care center were included. Right-sided CRC was defined as located in the appendix, cecum and ascending colon and left-sided CRC was defined as located in the descending colon, sigma and rectum. Results Two hundred and eighty-one CRC BM patients were available for this analysis with 239/281 patients (85.1%) presenting with a left-sided and 42/281 patients (14.9%) with a right-sided primary CRC. BM-free survival (BMFS) was significantly longer in left-sided compared with right-sided CRC patients (33 versus 20 months, P = 0.009). Overall survival from CRC diagnosis as well as from diagnosis of BM was significantly longer in patients with a left-sided primary (42 versus 25 months, P = 0.002 and 5 versus 4 months, P = 0.005, respectively). In a multivariate analysis including graded prognostic assessment, PTS remained significantly associated with prognosis after BM (hazard ratio 0.65; 95% confidence interval: 0.46-0.92 months, P = 0.0016). Conclusions PTS was associated with survival times after the rare event of BM development in CRC patients. Therefore, its prognostic value remains significant even thereafter.
Primary tumor side is a relevant and independent prognostic factor in mCRC. Left-sided CRC was associated with a significantly longer BMFS compared with right-sided CRC. OS from initial diagnosis of CRC as well as from BM was significantly longer in patients with left-sided primaries.
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Affiliation(s)
- E S Bergen
- Department of Medicine I, Division of Oncology, Medical University of Vienna, Vienna, Austria
| | - P Scherleitner
- Department of Medicine I, Division of Oncology, Medical University of Vienna, Vienna, Austria
| | - P Ferreira
- Department of Medicine I, Division of Oncology, Medical University of Vienna, Vienna, Austria
| | - B Kiesel
- Department of Neurosurgery, Medical University of Vienna, Vienna, Austria
| | - C Müller
- Department of Surgery, Medical University of Vienna, Vienna, Austria
| | - G Widhalm
- Department of Neurosurgery, Medical University of Vienna, Vienna, Austria
| | - K Dieckmann
- Department of Radiooncology, Medical University of Vienna, Vienna, Austria
| | - G Prager
- Department of Medicine I, Division of Oncology, Medical University of Vienna, Vienna, Austria
| | - M Preusser
- Department of Medicine I, Division of Oncology, Medical University of Vienna, Vienna, Austria
| | - A S Berghoff
- Department of Medicine I, Division of Oncology, Medical University of Vienna, Vienna, Austria.
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Zhou J, Ge X, Fan X, Wang J, Miao L, Hang D. Associations of vitamin D status with colorectal cancer risk and survival. Int J Cancer 2021; 149:606-614. [PMID: 33783821 DOI: 10.1002/ijc.33580] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2020] [Revised: 03/23/2021] [Accepted: 03/24/2021] [Indexed: 12/11/2022]
Abstract
Biological evidence suggests that vitamin D has numerous anticancer functions, but the associations between vitamin D status and colorectal cancer (CRC) risk and survival remain inconclusive. Based on UK Biobank, we prospectively evaluated the associations of season-standardized 25-hydroxyvitamin D (25(OH)D) concentrations with CRC risk among 360 061 participants, and with survival among 2509 CRC cases. We observed an inverse linear relationship between 25(OH)D concentrations and CRC risk (P for linearity = .01; HR per 1-SD increment, 0.95; 95% CI, 0.91-0.99). Compared to the lowest quartile of 25(OH)D, the highest quartile was associated with a 13% (HR, 0.87; 95% CI, 0.77-0.98) lower risk of CRC. For CRC survival, compared to those in the lowest quartile of 25(OH)D, cases in the highest quartile had a 20% (HR, 0.80; 95% CI, 0.65-0.99) lower risk for overall death. Our findings indicate that higher concentrations of serum 25(OH)D are associated with lower incidence and improved survival of CRC, suggesting a role of vitamin D in the pathogenesis of CRC.
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Affiliation(s)
- Jian Zhou
- Medical Center for Digestive Diseases, Second Affiliated Hospital, Nanjing Medical University, Nanjing, China
| | - Xianxiu Ge
- Medical Center for Digestive Diseases, Second Affiliated Hospital, Nanjing Medical University, Nanjing, China
| | - Xikang Fan
- Department of Epidemiology and Biostatistics, International Joint Research Center on Environment and Human Health, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Jiayu Wang
- Department of Epidemiology and Biostatistics, International Joint Research Center on Environment and Human Health, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Lin Miao
- Medical Center for Digestive Diseases, Second Affiliated Hospital, Nanjing Medical University, Nanjing, China
| | - Dong Hang
- Department of Epidemiology and Biostatistics, International Joint Research Center on Environment and Human Health, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China.,Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Medicine, Nanjing Medical University, Nanjing, China
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HomeoboxC6 promotes metastasis by orchestrating the DKK1/Wnt/β-catenin axis in right-sided colon cancer. Cell Death Dis 2021; 12:337. [PMID: 33795652 PMCID: PMC8016886 DOI: 10.1038/s41419-021-03630-x] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2020] [Revised: 03/14/2021] [Accepted: 03/16/2021] [Indexed: 12/30/2022]
Abstract
Patients with right-sided colon cancer (RCC) generally have a poorer prognosis than those with left-sided colon cancer (LCC). We previously found that homeobox C6 (HOXC6) was the most significantly upregulated gene in RCC compared to LCC. However, it remains unclear whether HOXC6 plays a role in tumor proliferation and metastasis. Our study aimed to explore the potential oncogenic role and the detailed molecular mechanism of HOXC6 in RCC. In this study, HOXC6 was validated to be overexpressed in RCC and associated with poor prognosis. Furthermore, overexpression of HOXC6 promoted the migration and invasion of colon cancer cells through inducing EMT by activating the Wnt/β-catenin signaling pathway and inhibition of DKK1 secretion. Lastly, we preliminary explored the translational effect of HOXC6 and found that silencing of HOXC6 made HCT116 and HT29 cells more sensitive to irinotecan.
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Devall M, Sun X, Yuan F, Cooper GS, Willis J, Weisenberger DJ, Casey G, Li L. Racial Disparities in Epigenetic Aging of the Right vs Left Colon. J Natl Cancer Inst 2020; 113:1779-1782. [PMID: 33377907 PMCID: PMC8634501 DOI: 10.1093/jnci/djaa206] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2020] [Revised: 08/27/2020] [Accepted: 12/08/2020] [Indexed: 12/15/2022] Open
Abstract
There are well-documented racial differences in age-of-onset and laterality of colorectal cancer. Epigenetic age acceleration is postulated to be an underlying factor. However, comparative studies of side-specific colonic tissue epigenetic aging are lacking. Here, we performed DNA methylation analysis of matched right and left biopsies of normal colon from 128 individuals. Among African Americans (n = 88), the right colon showed accelerated epigenetic aging as compared with individual-matched left colon (1.51 years; 95% confidence interval [CI] = 0.62 to 2.40 years; 2-sided P = .001). In contrast, among European Americans (n = 40), the right colon shows remarkable age deceleration (1.93 years; 95% CI = 0.65 to 3.21 years; 2-sided P = .004). Further, epigenome-wide analysis of DNA methylation identifies a unique pattern of hypermethylation in African American right colon. Our study is the first to report such race and side-specific differences in epigenetic aging of normal colon, providing novel insight into the observed younger age-of-onset and relative preponderance of right-side colon neoplasia in African Americans.
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Affiliation(s)
- Matthew Devall
- Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA
| | - Xiangqing Sun
- Department of Family Medicine, University of Virginia, Charlottesville, VA, USA
| | - Fangcheng Yuan
- Department of Family Medicine, University of Virginia, Charlottesville, VA, USA
| | - Gregory S Cooper
- Department of Medicine, Case Western Reserve University/University Hospitals Cleveland Medical Center, Cleveland, OH, USA
| | - Joseph Willis
- Department of Pathology, Case Western Reserve University/University Hospitals Cleveland Medical Center, Cleveland, OH, USA
| | - Daniel J Weisenberger
- Department of Biochemistry and Molecular Medicine, University of Southern California, Los Angeles, CA, USA
| | - Graham Casey
- Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA,University of Virginia Cancer Center, University of Virginia, Charlottesville, VA, USA
| | - Li Li
- Department of Family Medicine, University of Virginia, Charlottesville, VA, USA,University of Virginia Cancer Center, University of Virginia, Charlottesville, VA, USA,Correspondence to: Li Li, MD, PhD, Department of Family Medicine, University of Virginia School of Medicine, McKim Hall, Room 3156, 1415 Jefferson Park Avenue, PO Box 800729, Charlottesville, VA 22908 ()
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Árnadóttir SS, Mattesen TB, Vang S, Madsen MR, Madsen AH, Birkbak NJ, Bramsen JB, Andersen CL. Transcriptomic and proteomic intra-tumor heterogeneity of colorectal cancer varies depending on tumor location within the colorectum. PLoS One 2020; 15:e0241148. [PMID: 33332369 PMCID: PMC7746197 DOI: 10.1371/journal.pone.0241148] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2020] [Accepted: 10/08/2020] [Indexed: 02/07/2023] Open
Abstract
Background Intra-tumor heterogeneity (ITH) of colorectal cancer (CRC) complicates molecular tumor classification, such as transcriptional subtyping. Differences in cellular states, biopsy cell composition, and tumor microenvironment may all lead to ITH. Here we analyze ITH at the transcriptomic and proteomic levels to ascertain whether subtype discordance between multiregional biopsies reflects relevant biological ITH or lack of classifier robustness. Further, we study the impact of tumor location on ITH. Methods Multiregional biopsies from stage II and III CRC tumors were analyzed by RNA sequencing (41 biopsies, 14 tumors) and multiplex immune protein analysis (89 biopsies, 29 tumors). CRC subtyping was performed using consensus molecular subtypes (CMS), CRC intrinsic subtypes (CRIS), and TUMOR types. ITH-scores and network maps were defined to determine the origin of heterogeneity. A validation cohort was used with one biopsy per tumor (162 tumors). Results Overall, inter-tumor transcriptional variation exceeded ITH, and subtyping calls were frequently concordant between multiregional biopsies. Still, some tumors had high transcriptional ITH and were classified discordantly. Subtyping of proximal MSS tumors were discordant for 50% of the tumors, this ITH was related to differences in the microenvironment. Subtyping of distal MSS tumors were less discordant, here the ITH was more cancer-cell related. The subtype discordancy reflected actual molecular ITH within the tumors. The relevance of the subtypes was reflected at protein level where several inflammation markers were significantly increased in immune related transcriptional subtypes, which was verified in an independent cohort (Wilcoxon rank sum test; p<0.05). Unsupervised hierarchical clustering of the protein data identified large ITH at protein level; as the multiregional biopsies clustered together for only 9 out of 29 tumors. Conclusion Our transcriptomic and proteomic analyses show that the tumor location along the colorectum influence the ITH of CRC, which again influence the concordance of subtyping.
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Affiliation(s)
- Sigrid Salling Árnadóttir
- Department of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark
- Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
| | - Trine Block Mattesen
- Department of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark
- Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
| | - Søren Vang
- Department of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark
- Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
| | - Mogens Rørbæk Madsen
- Surgical Research Unit, Department of Surgery, Herning Regional Hospital, Herning, Denmark
| | - Anders Husted Madsen
- Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
- Surgical Research Unit, Department of Surgery, Herning Regional Hospital, Herning, Denmark
| | - Nicolai Juul Birkbak
- Department of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark
- Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
| | - Jesper Bertram Bramsen
- Department of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark
- Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
| | - Claus Lindbjerg Andersen
- Department of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark
- Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
- * E-mail:
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De Renzi G, Gaballo G, Gazzaniga P, Nicolazzo C. Molecular Biomarkers according to Primary Tumor Location in Colorectal Cancer: Current Standard and New Insights. Oncology 2020; 99:135-143. [PMID: 33130682 DOI: 10.1159/000510944] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2020] [Accepted: 08/12/2020] [Indexed: 11/19/2022]
Abstract
According to the 2018 GLOBOCAN database, colorectal cancer is one of the most common malignancies and leading causes of cancer-related death worldwide. During the last decades, considerable progress has been made in understanding the complex pathogenetic mechanisms involved in this neoplastic disease. Due to the need to improve treatment responses and clinical outcomes of colorectal cancer patients, the identification of new molecular biomarkers became a crucial spot in clinical oncology. As biological indicators of a specific pathological or physiological process, molecular markers play a central role in cancer detection, diagnosis, outcome prediction, and treatment choice. Considering the existing evidence that malignancies originating from distinct colonic regions behave differently, it is clear that specific biomarkers can be associated to right- or left-sided colon carcinomas, reflecting the distinct molecular signatures of these different tumor entities. The aim of this review is to summarize the main differences among tumors arising from proximal and distal colon in terms of current and emerging biomarkers.
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Affiliation(s)
- Gianluigi De Renzi
- Department of Molecular Medicine, Cancer Liquid Biopsy Unit, Sapienza University of Rome, Rome, Italy
| | - Giulio Gaballo
- Department of Molecular Medicine, Cancer Liquid Biopsy Unit, Sapienza University of Rome, Rome, Italy
| | - Paola Gazzaniga
- Department of Molecular Medicine, Cancer Liquid Biopsy Unit, Sapienza University of Rome, Rome, Italy
| | - Chiara Nicolazzo
- Department of Molecular Medicine, Cancer Liquid Biopsy Unit, Sapienza University of Rome, Rome, Italy,
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Kim HS, Kim NK. ASO Author Reflections: Poorest Survival Outcomes in Patients with Right Colon Cancer with KRAS Mutation After Simultaneous Curative-Intent Surgery for Colorectal Cancer Liver Metastases. Ann Surg Oncol 2020; 27:5159-5160. [PMID: 32813206 DOI: 10.1245/s10434-020-09047-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2020] [Accepted: 07/10/2020] [Indexed: 11/18/2022]
Affiliation(s)
- Ho Seung Kim
- Department of Surgery, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Nam Kyu Kim
- Department of Surgery, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea.
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Kim HS, Lee JM, Kim HS, Yang SY, Han YD, Cho MS, Hur H, Min BS, Lee KY, Kim NK. Prognosis of Synchronous Colorectal Liver Metastases After Simultaneous Curative-Intent Surgery According to Primary Tumor Location and KRAS Mutational Status. Ann Surg Oncol 2020; 27:5150-5158. [PMID: 32812112 DOI: 10.1245/s10434-020-09041-0] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2020] [Accepted: 06/24/2020] [Indexed: 11/18/2022]
Abstract
BACKGROUND Tumor location and KRAS mutational status have emerged as prognostic factors of colorectal cancer. We aimed to define the prognostic impact of primary tumor location and KRAS mutational status among synchronous colorectal liver metastases (CRLM) patients who underwent simultaneous curative-intent surgery (SCIS). METHODS We compared the clinicopathologic characteristics and long-term outcomes of 227 patients who underwent SCIS for synchronous CRLM, according to tumor location and KRAS mutational status. We cross-classified tumor location and KRAS mutational status and compared survival outcomes between the four resulting patient groups. RESULTS Forty-one patients (18.1%) had right-sided (RS) tumors and 186 (81.9%) had left-sided (LS) tumors. One-third of tumors (78/227) harbored KRAS mutations. The KRAS mutant-type (KRAS-mt) was more commonly observed among RS tumors than among LS tumors [21/41 (51.2%) vs. 57/186 (30.6%), p = 0.012]. Median follow-up time was 43.4 months. Patients with RS tumors had shorter survival times than those with LS tumors [median disease-free survival (DFS): RS, 9.9 months vs. LS, 12.1 months, p = 0.003; median overall survival (OS): RS, 49.7 months vs. LS, 88.8 months, p = 0.039]. RS tumors were a negative prognostic factor for DFS [hazard ratio (HR) 1.878, p = 0.001] and OS (HR 1.660, p = 0.060). RS KRAS-mt and LS KRAS wild-type (KRAS-wt) tumors had the worst and best oncological outcomes, respectively. CONCLUSION Tumor location has a prognostic impact in patients who underwent SCIS for CRLM, and RS KRAS-mt tumors yielded the worst oncological outcome. These results may allow for more tailored multimodality treatments.
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Affiliation(s)
- Ho Seung Kim
- Department of Surgery, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Jong Min Lee
- Department of Surgery, Yongin Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Han Sang Kim
- Department of Internal Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Seung Yoon Yang
- Department of Surgery, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Yoon Dae Han
- Department of Surgery, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Min Soo Cho
- Department of Surgery, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Hyuk Hur
- Department of Surgery, Yongin Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Byung Soh Min
- Department of Surgery, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Kang Young Lee
- Department of Surgery, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Nam Kyu Kim
- Department of Surgery, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea.
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Dalla Libera LS, de Siqueira T, Santos IL, Porto Ramos JE, Milhomen AX, de Alencar RDCG, Rabelo Santos SH, dos Santos Carneiro MA, Figueiredo Alves RR, Saddi VA. Detection of Human papillomavirus and the role of p16INK4a in colorectal carcinomas. PLoS One 2020; 15:e0235065. [PMID: 32584870 PMCID: PMC7316293 DOI: 10.1371/journal.pone.0235065] [Citation(s) in RCA: 4] [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: 02/14/2020] [Accepted: 06/08/2020] [Indexed: 12/11/2022] Open
Abstract
INTRODUCTION Human papillomavirus (HPV) infection is associated with the development of anogenital and head and neck cancers. In recent years a potential role of HPV in colorectal cancer (CRC) has been suggested. OBJECTIVE To investigate the presence of HPV in colorectal carcinomas and to study the role of p16INK4a as a marker of transcriptionally active HPV infection. In addition, to investigate the correlation between these findings and the CRC prognostic factors. METHODS Case control study with 92 cases of colorectal cancers, 75 controls of normal tissue adjacent to the tumor, and 30 controls of precursor lesions, including polyps and colorectal adenomas. Paraffinized samples were used, HPV detection and genotyping were performed by PCR and reverse hybridization by using the INNO LIPA kit, with SPF10 plus primers. The expression of the p16INK4a protein was investigated using immunohistochemistry. Data analysis was performed using descriptive, univariate statistics and survival curves were calculated by using the Kaplan Meier and log-rank method. RESULTS HPV was detected in 13% of the cases and the most prevalent genotype was HPV 16. HPV DNA was not detected in either control groups. The high expression of p16INK4a was observed in 30% of the cases, but it was not associated to the presence of HPV. The overall survival was 53.3% and was influenced by prognostic factors such as later stage, lymph node and distant metastasis. CONCLUSIONS Based on these results, HPV is unlikely to be involved in colorectal carcinogenesis and p16INK4a expression is not a relevant marker of transcriptionally active HPV infection in CRC.
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Affiliation(s)
- Larisse Silva Dalla Libera
- Universidade Federal de Goiás (UFG), Programa de Pós-Graduação em Ciências da Saúde (PPGCS), Faculdade de Medicina (FM) e Instituto de Patologia Tropical e Saúde Pública (IPTSP), Goiânia, GO, Brasil
| | - Thalita de Siqueira
- Pontifícia Universidade Católica de Goiás (PUC/GO), Programa de Pós-Graduação em Ciências Ambientais e Saúde (MCAS) e Escola de Ciências Médicas, Farmacêuticas e Biomédicas (ECMFB), Goiânia, GO, Brasil
| | - Igor Lopes Santos
- Pontifícia Universidade Católica de Goiás (PUC/GO), Programa de Pós-Graduação em Ciências Ambientais e Saúde (MCAS) e Escola de Ciências Médicas, Farmacêuticas e Biomédicas (ECMFB), Goiânia, GO, Brasil
| | - Jéssica Enocencio Porto Ramos
- Pontifícia Universidade Católica de Goiás (PUC/GO), Programa de Pós-Graduação em Ciências Ambientais e Saúde (MCAS) e Escola de Ciências Médicas, Farmacêuticas e Biomédicas (ECMFB), Goiânia, GO, Brasil
| | - Amanda Xavier Milhomen
- Pontifícia Universidade Católica de Goiás (PUC/GO), Programa de Pós-Graduação em Ciências Ambientais e Saúde (MCAS) e Escola de Ciências Médicas, Farmacêuticas e Biomédicas (ECMFB), Goiânia, GO, Brasil
| | | | - Silvia Helena Rabelo Santos
- Universidade Federal de Goiás (UFG), Programa de Pós-Graduação em Ciências da Saúde (PPGCS), Faculdade de Medicina (FM) e Instituto de Patologia Tropical e Saúde Pública (IPTSP), Goiânia, GO, Brasil
| | - Megmar Aparecida dos Santos Carneiro
- Universidade Federal de Goiás (UFG), Programa de Pós-Graduação em Ciências da Saúde (PPGCS), Faculdade de Medicina (FM) e Instituto de Patologia Tropical e Saúde Pública (IPTSP), Goiânia, GO, Brasil
| | - Rosane Ribeiro Figueiredo Alves
- Universidade Federal de Goiás (UFG), Programa de Pós-Graduação em Ciências da Saúde (PPGCS), Faculdade de Medicina (FM) e Instituto de Patologia Tropical e Saúde Pública (IPTSP), Goiânia, GO, Brasil
| | - Vera Aparecida Saddi
- Universidade Federal de Goiás (UFG), Programa de Pós-Graduação em Ciências da Saúde (PPGCS), Faculdade de Medicina (FM) e Instituto de Patologia Tropical e Saúde Pública (IPTSP), Goiânia, GO, Brasil
- Pontifícia Universidade Católica de Goiás (PUC/GO), Programa de Pós-Graduação em Ciências Ambientais e Saúde (MCAS) e Escola de Ciências Médicas, Farmacêuticas e Biomédicas (ECMFB), Goiânia, GO, Brasil
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Chen J, Zhou L, Gao J, Lu T, Wang J, Wu H, Liang Z. Clinicopathological Characteristics and Mutation Spectrum of Colorectal Adenocarcinoma With Mucinous Component in a Chinese Cohort: Comparison With Classical Adenocarcinoma. Front Oncol 2020; 10:917. [PMID: 32582557 PMCID: PMC7296099 DOI: 10.3389/fonc.2020.00917] [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: 01/12/2020] [Accepted: 05/11/2020] [Indexed: 12/18/2022] Open
Abstract
Background: Colorectal adenocarcinoma with mucinous component (AWMC) is a special entity of colorectal cancer. The study is aimed at analyzing the clinicopathological characteristics, mutation spectrum, and prognosis of AWMC and comparing it with classical adenocarcinoma (AC) in a Chinese cohort. Methods: One hundred eight AMWC and 204 AC patients were included. Targeted next-generation sequencing (NGS) was performed on formalin-fixed paraffin-embedded (FFPE) tissues. AWMC was further divided into two groups: AWMC with signet ring cell component and AWMC without signet ring cell component. Clinicopathological features, mismatch repair protein (MMR) status, genetic alterations, and survival outcomes were analyzed after tumor location was taken into consideration. Results: AWMC had larger tumor size (p = 0.014) and showed predilection for proximal colon (p < 0.001) compared with AC. Regardless of primary sites, AWMC was associated with less metastasis (p < 0.001) and earlier AJCC stage (p < 0.001). Mismatch repair protein deficiency (dMMR) was more commonly detected in AWMC than in AC for right-sided colon (p < 0.001), but the difference was not significant for left-sided colon (p = 0.081). The five most commonly mutated genes in AWMC were KRAS (45.4%), TP53 (39.8%), APC (22.2%), PIK3CA (22.2%), and SMAD4 (10.2%). AWMC showed a significantly lower mutation rate of TP53 than AC, both in right-sided colon and in left-sided colon (p < 0.001 and p = 0.033, respectively). In left-sided colon, AWMC with signet ring cell component had a significantly smaller size than tumors with signet ring cell component (p = 0.034). No dMMR cases were detected in AWMC with signet ring cell component (n = 7). Moreover, AWMC with signet ring cell component had a significantly lower KRAS mutation rate than AWMC without signet ring cell component, both in right-sided colon and in left-sided colon (p = 0.036 and p = 0.012, respectively). The disease-specific survival (DSS) for AWMC and AC were not statistically different (p = 0.0587). Multivariate analysis showed that AWMC was not an independent predictor of prognosis. Conclusion: Regardless of primary sites, AWMC demonstrates less metastasis, earlier stages, more frequent dMMR, and lower TP53 mutation rate than AC. Our results indicate that different molecular pathogenesis might underlie mucinous morphology in colorectal carcinoma. Mucinous component is not an independent factor of outcome.
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Affiliation(s)
- Jingci Chen
- Department of Pathology, Molecular Pathology Research Center, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Liangrui Zhou
- Department of Pathology, Molecular Pathology Research Center, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Jie Gao
- Department of Pathology, Molecular Pathology Research Center, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Tao Lu
- Department of Pathology, Molecular Pathology Research Center, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Jing Wang
- Department of Pathology, Molecular Pathology Research Center, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Huanwen Wu
- Department of Pathology, Molecular Pathology Research Center, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Zhiyong Liang
- Department of Pathology, Molecular Pathology Research Center, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
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Binetti M, Lauro A, Vaccari S, Cervellera M, Tonini V. Proteogenomic biomarkers in colorectal cancers: clinical applications. Expert Rev Proteomics 2020; 17:355-363. [PMID: 32536221 DOI: 10.1080/14789450.2020.1782202] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2020] [Accepted: 06/09/2020] [Indexed: 02/06/2023]
Abstract
INTRODUCTION Colorectal cancer (CRC) is one of the leading cancers in terms of incidence and mortality, rate requiring a multidisciplinary approach. The discovery of specific CRC biomarkers has caused a paradigm shift in its clinical management. AREAS COVERED The aim is to illustrate the possible clinical applications of CRC biomarkers through an updated literature review (from 2015 to 2020) based on the PubMed database. A relationship between cancer localization and genetic profile has been identified. Nowadays, the tumor markers are largely used to select patients that could really benefit from a specific type of adjuvant therapy, in order to optimize treatment programs, especially in metastatic patients. This review highlights both CRC biomarkers' advantages and critical issues. EXPERT OPINION New biomarker discoveries allow to set noninvasive tests that could increase patient's compliance with therapy. They also permit a cost-effective early diagnosis, as well as patient-tailored treatments, improving the overall survival. The CRC biomarkers could also have a prognostic value, and usually, they are included in follow-up programs. However, despite the continuous progression of new technologies, their clinical validation is still debated. In this context, additional clinical studies are still necessary to identify, among potential markers, the most effective ones.
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Affiliation(s)
| | - Augusto Lauro
- Emergency Surgery Unit, St. Orsola University Hospital , Bologna, Italy
| | - Samuele Vaccari
- Department of Surgical Sciences, Umberto I University Hospital , Rome, Italy
| | | | - Valeria Tonini
- Emergency Surgery Unit, St. Orsola University Hospital , Bologna, Italy
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Guo D, Li X, Xie A, Cao Q, Zhang J, Zhang F, Li W, Chen J. Differences in oncological outcomes and inflammatory biomarkers between right-sided and left-sided stage I-III colorectal adenocarcinoma. J Clin Lab Anal 2020; 34:e23132. [PMID: 31755593 PMCID: PMC7171299 DOI: 10.1002/jcla.23132] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2019] [Revised: 10/16/2019] [Accepted: 11/10/2019] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND The aim of this study was to investigate the differences in oncological outcome and inflammatory biomarkers between right-sided colon cancer (RCC) and left-sided colorectal cancer (LCRC). METHODS We retrospectively analyzed 339 patients with stage I-III colorectal cancer, including 125 RCC patients and 214 LCRC patients, who underwent radical resection from January 2012 to January 2014. Comparison of neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and lymphocyte-to-monocyte ratio (LMR) between RCC and LCRC was evaluated using the Mann-Whitney U test. Overall survival (OS) and disease-free survival (DFS) were analyzed using Kaplan-Meier analysis and compared using the log-rank test. Univariate and multivariate Cox regression analyses were used to identify the prognostic value of inflammatory markers. RESULTS Patients with RCC had higher NLR (P = .002) and PLR (P < .001) but lower LMR (P = .002) compared to LCRC. In stage I-III, RCC showed poorer OS and DFS than LCRC (61.6% vs 71.5%, P = .018; 64.8% vs 76.2%, P = .006). Univariate and multivariate analyses indicated that NLR, PLR, and LMR were independent predictors for both OS and DFS in RCC, whereas only PLR was found to be an independent prognostic predictor in LCRC. CONCLUSION The prognosis and prognostic value of inflammatory biomarkers were significantly different between RCC and LCRC. Novel therapeutic strategies are needed, and proper prognostic predictors should be selected according to colorectal tumor location.
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Affiliation(s)
- Dongming Guo
- Department of Gastrointestinal SurgeryThe First Affiliated Hospital of Shantou University Medical CollegeShantouChina
| | - Xinxin Li
- Department of Gastrointestinal SurgeryThe First Affiliated Hospital of Shantou University Medical CollegeShantouChina
| | - Aosi Xie
- Department of Gastrointestinal SurgeryThe First Affiliated Hospital of Shantou University Medical CollegeShantouChina
| | - Qiangjian Cao
- Department of Gastrointestinal SurgeryThe First Affiliated Hospital of Shantou University Medical CollegeShantouChina
| | - Jinhai Zhang
- Department of Gastrointestinal SurgeryThe First Affiliated Hospital of Shantou University Medical CollegeShantouChina
| | - Feiran Zhang
- Department of Gastrointestinal SurgeryThe First Affiliated Hospital of Shantou University Medical CollegeShantouChina
| | - Wei Li
- Department of Gastrointestinal SurgeryThe First Affiliated Hospital of Shantou University Medical CollegeShantouChina
| | - Juntian Chen
- Department of Gastrointestinal SurgeryThe First Affiliated Hospital of Shantou University Medical CollegeShantouChina
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de Araujo EM, Torres US, Racy DJ, Torres LR, Chojniak R, D’Ippolito G. The "streamline phenomenon" of the portal vein flow and its influence on liver involvement by gastrointestinal diseases: current concepts and imaging-based review. Abdom Radiol (NY) 2020; 45:403-415. [PMID: 31768597 DOI: 10.1007/s00261-019-02335-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/25/2022]
Abstract
The streamline flow in the portal system is a phenomenon by which blood from superior mesenteric vein goes preferentially to the right hepatic lobe, while splenic and inferior mesenteric veins divert preferentially to the left lobe. Such a phenomenon results in different patterns of distribution of several liver diseases. The purpose of this article is to discuss the concepts behind the theory of streamline flow and to perform an imaging-based review of representative cases, demonstrating how it may influence the patterns of liver involvement in different gastrointestinal diseases.
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Tumor sidedness influences prognostic impact of lymph node metastasis in colon cancer patients undergoing curative surgery. Sci Rep 2019; 9:19892. [PMID: 31882754 PMCID: PMC6934859 DOI: 10.1038/s41598-019-56512-w] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2019] [Accepted: 12/13/2019] [Indexed: 12/20/2022] Open
Abstract
This study aimed to evaluate prognostic impacts of the number of lymph nodes (LNs) examined and LN ratio on cancer-specific mortality after surgery in patients with right-sided colon cancer (RCC) or left-sided colon cancer (LCC) using the Surveillance, Epidemiology, and End Results database. Number of LNs examined and LN ratio were treated as categorical and/or continuous. Competing risks proportional hazards regressions adjusted by propensity score were performed. All included patients had stage I, II, or III disease, and 45.1% of them had RCC. RCC and LCC patients with high level of LNs examined had better prognosis after segmental resection or hemicolectomy. RCC and LCC patients with higher LN ratio had worse prognosis regardless of surgery. Survival benefit of having high level of LNs examined was observed in RCC patients with stage I, II, or III disease, but only in LCC patients with stage II disease. Both higher LN ratio and high level of LN were negative prognostic factors for cancer-specific mortality in stage III patients regardless of tumor sidedness. In conclusion, RCC patients in various conditions had worse or comparable prognosis compared to their LCC counterparts, which reflected the severity of LN metastasis.
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Grassadonia A, Di Marino P, Ficorella C, Cortellini A, Cannita K, Parisi A, Gamucci T, Zoratto F, Vici P, Barba M, Porreca E, Neri M, Veronese A, Natoli C, De Tursi M, Tinari N. Impact of primary tumor location in patients with RAS wild-type metastatic colon cancer treated with first-line chemotherapy plus anti-EGFR or anti-VEGF monoclonal antibodies: a retrospective multicenter study. J Cancer 2019; 10:5926-5934. [PMID: 31762802 PMCID: PMC6856567 DOI: 10.7150/jca.34550] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2019] [Accepted: 07/01/2019] [Indexed: 12/24/2022] Open
Abstract
Emerging evidence supports a prognostic role of primary tumor location in metastatic colon cancer (mCC). We conducted a retrospective analysis to evaluate the effect of tumor location on prognosis and efficacy of biological agents (anti-EGFR, Cetuximab and Panitumumab, or anti-VEGF, Bevacizumab) added to first-line chemotherapy in patients with RAS wild-type (wt) mCC. Patients with newly diagnosed RAS wt mCC candidates to first-line chemotherapy with anti-EGFRs or Bevacizumab were selected. Clinical outcomes were assessed and stratified by tumor location and type of treatment. Overall, 351 patients met the inclusion criteria. Primary colon cancer was right-sided (RCC) in 105 (29.9%) patients and left-sided (LCC) in 246 (70.1%). Patients with LCC had a better OS compared to those with RCC (33.6 vs 23.5 months, HR 0.74; 95% CI, 0.55 to 0.99; p=0.049). In the overall study population, OS was not significantly different for patients treated with Cetuximab or Panitumumab as compared to those receiving Bevacizumab. However, when comparing treatment outcome according to tumor sidedness, patients with LCC treated with Cetuximab or Panitumumab had a significantly longer PFS (12.4 vs 10.7 months; HR: 0.69; 95% CI, 0.51 to 0.93; p= 0.015) and OS (40.7 vs 28.6 months; HR: 0.67; 95% CI 0.47 to 0.95; p= 0.026). No relevant differences were observed in patients with RCC. We found evidence in support of the impact of tumor location in RAS wt mCC treated with first-line chemotherapy in association with targeted therapy. More favorable outcomes were observed in LCC patients, but not in RCC patients, treated with anti-EGFR agents compared with those who received Bevacizumab. Further, prospective and adequately sized studies are warranted to confirm our findings.
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Affiliation(s)
- Antonino Grassadonia
- Department of Medical, Oral & Biotechnological Sciences and CeSI-MeT, G. D'Annunzio University, Chieti-Pescara, Italy
| | - Pietro Di Marino
- Department of Medical, Oral & Biotechnological Sciences, G. D'Annunzio University, Chieti-Pescara, Italy
| | - Corrado Ficorella
- Medical Oncology Unit, St Salvatore Hospital, Department of Biotechnological & Applied Clinical Sciences, University of L'Aquila, Via Vetoio, 67100, L'Aquila, Italy
| | - Alessio Cortellini
- Medical Oncology Unit, St Salvatore Hospital, Department of Biotechnological & Applied Clinical Sciences, University of L'Aquila, Via Vetoio, 67100, L'Aquila, Italy
| | - Katia Cannita
- Medical Oncology Unit, St Salvatore Hospital, Department of Biotechnological & Applied Clinical Sciences, University of L'Aquila, Via Vetoio, 67100, L'Aquila, Italy
| | - Alessandro Parisi
- Medical Oncology Unit, St Salvatore Hospital, Department of Biotechnological & Applied Clinical Sciences, University of L'Aquila, Via Vetoio, 67100, L'Aquila, Italy
| | - Teresa Gamucci
- Medical Oncology Unit, Sandro Pertini Hospital, Rome, Italy
| | | | - Patrizia Vici
- Division of Medical Oncology 2, IRCCS Regina Elena National Cancer Institute, Rome, Italy
| | - Maddalena Barba
- Division of Medical Oncology 2, IRCCS Regina Elena National Cancer Institute, Rome, Italy
| | - Ettore Porreca
- Department of Medical, Oral & Biotechnological Sciences, G. D'Annunzio University, Chieti-Pescara, Italy
| | - Matteo Neri
- Department of Medicine and Ageing Sciences and CeSI-MeT, G. D'Annunzio University, Chieti, Italy
| | - Angelo Veronese
- Department of Medicine and Ageing Sciences and CeSI-MeT, G. D'Annunzio University, Chieti, Italy
| | - Clara Natoli
- Department of Medical, Oral & Biotechnological Sciences and CeSI-MeT, G. D'Annunzio University, Chieti-Pescara, Italy
| | - Michele De Tursi
- Department of Medical, Oral & Biotechnological Sciences, G. D'Annunzio University, Chieti-Pescara, Italy
| | - Nicola Tinari
- Department of Medical, Oral & Biotechnological Sciences and CeSI-MeT, G. D'Annunzio University, Chieti-Pescara, Italy
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