|
1
|
Zhao Y, Xia S, Zhao X, Song Z, Wang F, Mao L, He Z, Du X. DNA ploidy combined with tumor stroma as a biomarker for predicting the prognosis of stage II colorectal cancer patients and identifying candidates for chemotherapy. World J Surg Oncol 2025; 23:49. [PMID: 39940036 PMCID: PMC11823223 DOI: 10.1186/s12957-025-03693-6] [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: 10/01/2024] [Accepted: 01/30/2025] [Indexed: 02/14/2025] Open
Abstract
PURPOSE The efficacy of postoperative adjuvant chemotherapy in patients with stage II colorectal cancer has been a subject of debate. This study aimed to evaluate the prognostic and predictive significance of DNA ploidy and stroma ratio in patients diagnosed with stage II colorectal cancer (CRC). METHODS Clinical data and tumor tissues from 179 patients with stage II CRC were collected retrospectively. DNA ploidy (P) and stroma (S) were assessed using automatic image analysis tools powered by machine learning. RESULTS Patients were categorized into three risk groups: PS-low (diploid and low stroma, PS-L), PS-intermediate (non-diploid or high stroma, PS-M), and PS-high (non-diploid and high-stroma, PS-H). According to the univariable model, the PS-H group exhibited significantly poorer 5-year overall survival rates at 73.0% compared to 87.8%, with a hazard ratio (HR) of 2.281 (95% CI: 0.946-5.502, P = 0.066), as well as lower 5-year disease-free survival rates at 69.4% versus 86.6%, HR = 2.323 (95% CI: 1.016-5.308, P = 0.046) among stage II colorectal cancer patients. Notably, chemotherapy was associated with improved overall survival [HR = 83.460 (95% CI: 0.179-38925.833), P = 0.003] and disease-free survival [HR = 8.628 (95% CI: 1.059-70.265), P = 0 .044] in individuals within the PS-high group. CONCLUSION While ploidy and stroma alone do not possess predictive power regarding survival outcomes for stage II colorectal cancer patients, those receiving chemotherapy within the PS-H group demonstrated enhanced survival rates. Therefore, combining assessments of ploidy and stroma may serve as an adjunctive tool in clinical decision-making processes to guide chemotherapy treatment strategies for patients diagnosed with stage II colorectal cancer.
Collapse
Affiliation(s)
- Yunshan Zhao
- Department of General Surgery, First Medical Center of the Chinese PLA General Hospital, Haidian District, 28 Fuxing Road, Beijing, 100853, China
| | - Shaoyou Xia
- Department of General Surgery, First Medical Center of the Chinese PLA General Hospital, Haidian District, 28 Fuxing Road, Beijing, 100853, China
| | - Xudong Zhao
- Department of General Surgery, First Medical Center of the Chinese PLA General Hospital, Haidian District, 28 Fuxing Road, Beijing, 100853, China
| | - Zhigang Song
- Department of Pathology, First Medical Center of the Chinese PLA General Hospital, Beijing, 100853, China
| | - Fei Wang
- My-BioMed Technology (Guangzhou) Co., Ltd., Guangzhou, 510535, China
| | - Lijun Mao
- My-BioMed Technology (Guangzhou) Co., Ltd., Guangzhou, 510535, China
| | - Zufeng He
- My-BioMed Technology (Guangzhou) Co., Ltd., Guangzhou, 510535, China
| | - Xiaohui Du
- Department of General Surgery, First Medical Center of the Chinese PLA General Hospital, Haidian District, 28 Fuxing Road, Beijing, 100853, China.
| |
Collapse
|
|
2
|
Kim HM, Lee D, Song JH, Kim H, Lee S, Shin S, Park SD, Kim YW, Choi YH, Kim WJ, Moon SK. The edible ethanol extract of Rosa hybrida suppresses colon cancer progression by inhibiting the proliferation-cell signaling-metastasis axis. Nutr Res Pract 2025; 19:14-29. [PMID: 39959743 PMCID: PMC11821778 DOI: 10.4162/nrp.2025.19.1.14] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2024] [Revised: 08/31/2024] [Accepted: 09/12/2024] [Indexed: 02/18/2025] Open
Abstract
BACKGROUND/OBJECTIVES Rosa hybrida has been demonstrated to exert biological effects on several cell types. This study investigated the efficacy of the edible ethanol extract of R. hybrida (EERH) against human colorectal carcinoma cell line (HCT116) cells. MATERIALS/METHODS HCT116 cells were cultured with different concentrations of EERH (0, 400, 600, 800, and 1,000 µg/mL) in Dulbecco's modified Eagle medium. Cell viability was measured using the 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyl tetrazolium bromide and viable cell counting assays. Cell cycle pattern was observed by flow cytometry analysis. The wound-healing migration assay, invasion assay, and zymography were used to determine the migratory and invasive level of HCT116 cells treated with EERH. The protein expression and binding ability level of HCT116 cells following EERH treatment were analyzed via immunoblotting and the electrophoretic mobility shift assay. RESULTS EERH suppressed HCT116 cell proliferation, thus arresting the G1-phase cell cycle. It also reduced cyclin-dependent kinases and cyclins, which are associated with p27KIP1 expression. Additionally, EERH differentially regulated the phosphorylation of extracellular signal-regulated kinase 1/2, c-Jun NH2-terminal kinase, p38, and protein kinase B. Moreover, EERH treatment inhibited the enzymatic activity of matrix metalloproteinase-9 (MMP-9) and MMP-2, resulting in HCT116 cell migration and invasion. The EERH-induced inhibition of MMP-9 and MMP-2 was attributed to the reduced transcriptional binding of activator protein-1, specificity protein-1, and nuclear factor-κB motifs in HCT116 cells. Kaempferol was identified as the main compound contributing to EERH's antitumor activity. CONCLUSION EERH inhibits HCT116 cell proliferation and metastatic potential. Therefore, it is potentially useful as a preventive and curative nutraceutical agent against colorectal cancer.
Collapse
Affiliation(s)
- Hong-Man Kim
- Department of Food and Nutrition, Chung-Ang University, Anseong 17546, Korea
| | - Daeun Lee
- Department of Food and Nutrition, Chung-Ang University, Anseong 17546, Korea
| | - Jun-Hui Song
- Department of Food and Nutrition, Chung-Ang University, Anseong 17546, Korea
| | - Hoon Kim
- Department of Food and Nutrition, Chung-Ang University, Anseong 17546, Korea
| | - Sanghyun Lee
- Department of Plant Science and Technology, Chung-Ang University, Anseong 17546, Korea
| | - Sangah Shin
- Department of Food and Nutrition, Chung-Ang University, Anseong 17546, Korea
| | - Sun-Dong Park
- Department of Herbal Prescription, School of Korean Medicine, Dongguk University, Goyang 10326, Korea
| | - Young Woo Kim
- Department of Herbal Prescription, School of Korean Medicine, Dongguk University, Goyang 10326, Korea
| | - Yung Hyun Choi
- Department of Biochemistry, College of Oriental Medicine, Dongeui University, Busan 47340, Korea
| | | | - Sung-Kwon Moon
- Department of Food and Nutrition, Chung-Ang University, Anseong 17546, Korea
| |
Collapse
|
|
3
|
Hirano H, Kataoka K, Yamaguchi T, Wagner AD, Shimada Y, Inomata M, Hamaguchi T, Takii Y, Mizusawa J, Sano Y, Shiomi A, Shiozawa M, Ohue M, Adachi T, Ueno H, Ikeda S, Komori K, Tsukamoto S, Takashima A, Kanemitsu Y. Sex differences in toxicities and survival outcomes among Japanese patients with Stage III colorectal cancer receiving adjuvant fluoropyrimidine monotherapy: A pooled analysis of 4 randomized controlled trials (JCOG2310A). Eur J Cancer 2025; 214:115139. [PMID: 39579641 DOI: 10.1016/j.ejca.2024.115139] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2024] [Revised: 11/13/2024] [Accepted: 11/15/2024] [Indexed: 11/25/2024]
Abstract
BACKGROUND Fluoropyrimidine remains the key agent of adjuvant chemotherapy for stage III colorectal cancer (CRC). Western studies have shown that female sex is a favorable prognostic factor after surgery, but it is also a risk factor for adverse events (AEs) during adjuvant chemotherapy with fluoropyrimidine. However, little is known about whether sex differences in treatment outcomes exist in this setting in the Asian population. METHODS Patients with stage III CRC who received adjuvant fluoropyrimidine monotherapy in 4 randomized controlled trials were analyzed. Incidences of AEs and survival outcomes were compared between female and male patients. RESULTS A total of 3170 patients (female, 1516; male, 1654) were included in this analysis. Compared with males, females were less likely to have a relative dose intensity (≥90 %: female 59.1 % vs. male 67.6 %), with a higher proportion of requiring dose reduction (28.8 % vs. 20.4 %) and a lower proportion of completing adjuvant chemotherapy (77.0 % vs. 81.7 %). Multivariable analyses demonstrated that female sex was associated with a higher incidence of grade 3-4 AEs (odds ratio 1.80 [95 % CI 1.51-2.14]). Female sex was identified as a favorable prognostic factor for overall survival (hazard ratio [HR]: 0.80 [0.65-0.97]) and relapse-free survival (HR: 0.73 [0.63-0.85]) in multivariable analyses. Female patients had fewer time-to recurrence (TTR) events than male patients (5-year TTR: 17.7 % vs. 22.3 %). CONCLUSION Sex had implications for the development of AEs and survival outcomes of Japanese patients with stage III CRC who received adjuvant fluoropyrimidine monotherapy.
Collapse
Affiliation(s)
- Hidekazu Hirano
- Department of Gastrointestinal Medical Oncology, National Cancer Center Hospital, Tokyo, Japan
| | - Kozo Kataoka
- Division of lower GI, department of gastroenterological surgery, Hyogo Medical University, Hyogo, Japan
| | - Toshifumi Yamaguchi
- Cancer Chemotherapy Center, Osaka Medical and Pharmaceutical University Hospital, Osaka, Japan
| | - Anna Dorothea Wagner
- Department of Oncology, Lausanne University Hospital, University of Lausanne, Lausanne, Switzerland
| | - Yasuhiro Shimada
- Clinical Oncology Division, Kochi Health Sciences Center, Kochi, Japan
| | - Masafumi Inomata
- Department of Gastroenterological and Pediatric Surgery, Oita University Hospital, Oita, Japan
| | - Tetsuya Hamaguchi
- Department of Gastroenterological Oncology, Saitama Medical University International Medical Center, Saitama, Japan
| | - Yasumasa Takii
- Department of Surgery, Niigata Cancer Center Hospital, Niigata, Japan
| | - Junki Mizusawa
- Japan Clinical Oncology Group Data Center/Operations Office, National Cancer Center Hospital, Tokyo, Japan
| | - Yusuke Sano
- Japan Clinical Oncology Group Data Center/Operations Office, National Cancer Center Hospital, Tokyo, Japan
| | - Akio Shiomi
- Division of Colon and Rectal Surgery, Shizuoka Cancer Center Hospital, Shizuoka, Japan
| | - Manabu Shiozawa
- Department of Gastrointestinal Surgery, Kanagawa Cancer Center, Yokohama, Japan
| | - Masayuki Ohue
- Department of Gastroenterological Surgery, Osaka International Cancer Institute, Osaka, Japan
| | - Tomohiro Adachi
- Department of Surgery, Hiroshima City North Medical Center Asa Citizens Hospital, Hiroshima, Japan
| | - Hideki Ueno
- Department of Surgery, National Defense Medical College, Saitama, Japan
| | - Satoshi Ikeda
- Department of Gastroenterological Surgery, Hiroshima Prefectural Hospital, Hiroshima, Japan
| | - Koji Komori
- Department of Gastroenterological Surgery, Aichi Cancer Center Hospital, Nagoya, Aichi, Japan
| | - Shunsuke Tsukamoto
- Department of Colorectal Surgery, National Cancer Center Hospital, Tokyo, Japan
| | - Atsuo Takashima
- Department of Gastrointestinal Medical Oncology, National Cancer Center Hospital, Tokyo, Japan
| | - Yukihide Kanemitsu
- Department of Colorectal Surgery, National Cancer Center Hospital, Tokyo, Japan.
| |
Collapse
|
|
4
|
Schaub D, Gunderson J, Thompson S, Saeed S, Batzli E, Mittal R, Tecle D, Pavleszek K, Nfonsam V. Mismatch repair deficiency confers worse survival in stage IV colon cancer. J Gastrointest Oncol 2024; 15:2521-2532. [PMID: 39816023 PMCID: PMC11732351 DOI: 10.21037/jgo-24-387] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/21/2024] [Accepted: 11/18/2024] [Indexed: 01/18/2025] Open
Abstract
Background Metastatic colon cancer (MCC) is a debilitating condition with a poor prognosis. Currently, there is limited data that investigates MCC in relation to mismatch repair (MMR) status. The aims of this study are to compare sociodemographic and clinicopathologic features and mortality between patients with MMR-proficient (MMR-P) and MMR-deficient (MMR-D) MCC. Methods We performed an 8-year retrospective review of the National Cancer Database (NCDB) to identify patients age ≥18 years with MCC and reported MMR status. Data collection included sociodemographic characteristics, primary tumor sites and histopathologic features, and treatment modalities. Outcomes included 90-day, 180-day, 1-year, and 2-year overall mortality. Bivariate logistic regression and multivariate Cox regression identified differences between MMR-P and MMR-D and identified predictors of mortality, respectively. Results A total of 10,922 MCC cases were identified; 8,796 (80.53%) were MMR-P and 2,126 (19.47%) were MMR-D. MMR-D was independently associated with older age at diagnosis, female sex, mucinous adenocarcinoma, medullary carcinoma, and lymph-vascular invasion. MMR-P was independently associated with perineural invasion and left-sided colonic primary tumor predominance. When adjusted for demographics, histology, and treatment modalities, MMR-D was associated with mortality at 180 days, 1 year, and 2 years. Conclusions Our study identified several key sociodemographic and clinicopathologic features of MMR-D MCC. MMR-D appears to confer increased overall mortality at 180 days, 1 year, and 2 years after diagnosis in MCC.
Collapse
Affiliation(s)
- David Schaub
- Department of Surgery, University of Arizona College of Medicine-Tucson, Tucson, Arizona, USA
| | - Joseph Gunderson
- Department of Surgery, University of Arizona College of Medicine-Tucson, Tucson, Arizona, USA
| | - Sierra Thompson
- Department of Surgery, A.T. Still University School of Osteopathic Medicine, Mesa, Arizona, USA
| | - Sabina Saeed
- Department of Surgery, University of Arizona College of Medicine-Tucson, Tucson, Arizona, USA
| | - Elisabeth Batzli
- Department of Surgery, University of Arizona College of Medicine-Tucson, Tucson, Arizona, USA
| | - Rohan Mittal
- Department of Surgery, University of Arizona College of Medicine-Tucson, Tucson, Arizona, USA
| | - Daniom Tecle
- Department of Surgery, University of Arizona College of Medicine-Tucson, Tucson, Arizona, USA
| | - Katherine Pavleszek
- Department of Surgery, Louisiana State University Health Sciences Center School of Medicine, New Orleans, LA, USA
| | - Valentine Nfonsam
- Department of Surgery, Louisiana State University Health Sciences Center School of Medicine, New Orleans, LA, USA
| |
Collapse
|
|
5
|
González A, Badiola I, Fullaondo A, Rodríguez J, Odriozola A. Personalised medicine based on host genetics and microbiota applied to colorectal cancer. ADVANCES IN GENETICS 2024; 112:411-485. [PMID: 39396842 DOI: 10.1016/bs.adgen.2024.08.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/15/2024]
Abstract
Colorectal cancer (CRC) ranks second in incidence and third in cancer mortality worldwide. This situation, together with the understanding of the heterogeneity of the disease, has highlighted the need to develop a more individualised approach to its prevention, diagnosis and treatment through personalised medicine. This approach aims to stratify patients according to risk, predict disease progression and determine the most appropriate treatment. It is essential to identify patients who may respond adequately to treatment and those who may be resistant to treatment to avoid unnecessary therapies and minimise adverse side effects. Current research is focused on identifying biomarkers such as specific mutated genes, the type of mutations and molecular profiles critical for the individualisation of CRC diagnosis, prognosis and treatment guidance. In addition, the study of the intestinal microbiota as biomarkers is being incorporated due to the growing scientific evidence supporting its influence on this disease. This article comprehensively addresses the use of current and emerging diagnostic, prognostic and predictive biomarkers in precision medicine against CRC. The effects of host genetics and gut microbiota composition on new approaches to treating this disease are discussed. How the gut microbiota could mitigate the side effects of treatment is reviewed. In addition, strategies to modulate the gut microbiota, such as dietary interventions, antibiotics, and transplantation of faecal microbiota and phages, are discussed to improve CRC prevention and treatment. These findings provide a solid foundation for future research and improving the care of CRC patients.
Collapse
Affiliation(s)
- Adriana González
- Hologenomics Research Group, Department of Genetics, Physical Anthropology, and Animal Physiology, University of the Basque Country, Spain
| | - Iker Badiola
- Department of Cell Biology and Histology, Faculty of Medicine and Nursing, University of the Basque Country (UPV/EHU), Leioa, Spain
| | - Asier Fullaondo
- Hologenomics Research Group, Department of Genetics, Physical Anthropology, and Animal Physiology, University of the Basque Country, Spain
| | | | - Adrian Odriozola
- Hologenomics Research Group, Department of Genetics, Physical Anthropology, and Animal Physiology, University of the Basque Country, Spain.
| |
Collapse
|
|
6
|
Mihailov R, Beznea A, Popazu C, Voicu D, Toma A, Tudorașcu I, Rebegea L, Mihailov OM, Lutenco V, Constantin GB, Țocu G, Niculeț E, Bîrlă R, Georgescu DE, Șerban C. The pathological and immunohistochemical profile of tumor angiogenesis in perforated sigmoid carcinoma–Case report and short literature review. ELECTRONIC JOURNAL OF GENERAL MEDICINE 2024; 21:em600. [DOI: 10.29333/ejgm/14847] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
Abstract
<b>Background:</b> Little is known about the physiopathological factors or mechanisms that underlie tumor invasion of the serosa and lead to perforation in the peritoneal cavity. The aim of the work was to analyze the pathological and immunohistochemical factors of tumor neoangiogenesis which could influence tumor perforation in colorectal cancer.<br />
<b>Results and discussions:</b> 451 cases of complicated colorectal carcinomas were statistically analyzed, of which 19 cases were perforated sigmoid tumors. The immunohistochemical detection of mutant p53 proteins was the first molecular parameter examined in the context of the search for markers predicting the natural evolution mode in colorectal carcinomas.<br />
<b>Conclusions</b>: Both loss of p53 and overexpression of bcl-2 proteins confer immortalization on cancer cells by inhibiting the processes leading to apoptosis. The paper proposes a review of the specialized literature, but also the presentation of a clinical case.
Collapse
Affiliation(s)
- Raul Mihailov
- Surgery Clinic, “Sf. Ap. Andrei” Emergency Clinical Hospital, Galati, ROMANIA
- Faculty of Medicine and Pharmacy, “Dunarea de Jos” University, Galati, ROMANIA
| | - Adrian Beznea
- Surgery Clinic, “Sf. Ap. Andrei” Emergency Clinical Hospital, Galati, ROMANIA
- Faculty of Medicine and Pharmacy, “Dunarea de Jos” University, Galati, ROMANIA
| | - Constantin Popazu
- Faculty of Medicine and Pharmacy, “Dunarea de Jos” University, Galati, ROMANIA
| | - Dragoș Voicu
- Faculty of Medicine and Pharmacy, “Dunarea de Jos” University, Galati, ROMANIA
| | - Alexandra Toma
- Faculty of Medicine and Pharmacy, “Dunarea de Jos” University, Galati, ROMANIA
| | - Iulia Tudorașcu
- University of Medicine and Pharmacy of Craiova, Craiova, ROMANIA
| | - Laura Rebegea
- Faculty of Medicine and Pharmacy, “Dunarea de Jos” University, Galati, ROMANIA
| | | | - Valerii Lutenco
- Surgery Clinic, “Sf. Ap. Andrei” Emergency Clinical Hospital, Galati, ROMANIA
- Faculty of Medicine and Pharmacy, “Dunarea de Jos” University, Galati, ROMANIA
| | | | - George Țocu
- Faculty of Medicine and Pharmacy, “Dunarea de Jos” University, Galati, ROMANIA
| | - Elena Niculeț
- Faculty of Medicine and Pharmacy, “Dunarea de Jos” University, Galati, ROMANIA
| | - Rodica Bîrlă
- “Carol Davila” University of Medicine and Pharmacy, Bucharest, ROMANIA
| | - Dragoș Eugen Georgescu
- “Carol Davila” University of Medicine and Pharmacy, Bucharest, ROMANIA
- Department of General Surgery, Dr. Ion Cantacuzino Hospital, Bucharest, ROMANIA
| | - Cristina Șerban
- Surgery Clinic, “Sf. Ap. Andrei” Emergency Clinical Hospital, Galati, ROMANIA
- Faculty of Medicine and Pharmacy, “Dunarea de Jos” University, Galati, ROMANIA
| |
Collapse
|
|
7
|
Cayún JP, Cerpa LC, Colombo A, Cáceres DD, Leal JL, Reyes F, Gutiérrez-Cáceres C, Calfunao S, Varela NM, Quiñones LA. Genetic Polymorphisms and Tumoral Mutational Profiles over Survival in Advanced Colorectal Cancer Patients: An Exploratory Study. Curr Oncol 2024; 31:274-295. [PMID: 38248103 PMCID: PMC10814806 DOI: 10.3390/curroncol31010018] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2023] [Revised: 12/23/2023] [Accepted: 12/27/2023] [Indexed: 01/23/2024] Open
Abstract
Colorectal cancer is a common disease, both in Chile and worldwide. The most widely used chemotherapy schemes are based on 5-fluorouracil (5FU) as the foundational drug (FOLFOX, CapeOX). Genetic polymorphisms have emerged as potential predictive biomarkers of response to chemotherapy, but conclusive evidence is lacking. This study aimed to investigate the role of genetic variants associated with 5FU-based chemotherapy on therapeutic response, considering their interaction with oncogene mutations (KRAS, NRAS, PI3KCA, AKT1, BRAF). In a retrospective cohort of 63 patients diagnosed with metastatic colorectal cancer, a multivariate analysis revealed that liver metastases, DPYD, ABCB1, and MTHFR polymorphisms are independent indicators of poor prognosis, irrespective of oncogene mutations. BRAF wild-type status and high-risk drug-metabolism polymorphisms correlated with a poor prognosis in this Chilean cohort. Additionally, findings from the genomics of drug sensitivity (GDSC) project demonstrated that cell lines with wild-type BRAF have higher IC50 values for 5-FU compared to BRAF-mutated cell lines. In conclusion, the genetic polymorphisms DPYDrs1801265, ABCB1rs1045642, and MTHFRrs180113 may serve as useful biomarkers for predicting a poor prognosis in patients undergoing 5-fluorouracil chemotherapy, regardless of oncogene mutations.
Collapse
Affiliation(s)
- Juan Pablo Cayún
- Laboratory of Chemical Carcinogenesis and Pharmacogenetics, Department of Basic-Clinical Oncology (DOBC), Faculty of Medicine, University of Chile, Santiago 8350499, Chile; (J.P.C.); (L.C.C.); (C.G.-C.); (S.C.)
- Latin American Network for Implementation and Validation of Clinical Pharmacogenomics Guidelines (RELIVAF-CYTED), Santiago 8350499, Chile
| | - Leslie Carol Cerpa
- Laboratory of Chemical Carcinogenesis and Pharmacogenetics, Department of Basic-Clinical Oncology (DOBC), Faculty of Medicine, University of Chile, Santiago 8350499, Chile; (J.P.C.); (L.C.C.); (C.G.-C.); (S.C.)
- Latin American Network for Implementation and Validation of Clinical Pharmacogenomics Guidelines (RELIVAF-CYTED), Santiago 8350499, Chile
| | - Alicia Colombo
- Anatomy Pathology Service, Hospital Clínico de la Universidad de Chile, Santiago 8350499, Chile;
- Department of Basic-Clinical Oncology (DOBC), Faculty of Medicine, University of Chile, Santiago 8350499, Chile
| | - Dante Daniel Cáceres
- Institute of Population Health, School of Public Health, Faculty of Medicine, University of Chile, Santiago 8350499, Chile;
| | - José Luis Leal
- Cancer Research Department, Instituto Oncológico Fundación Arturo López Pérez, Santiago 8350499, Chile; (J.L.L.); (F.R.)
| | - Felipe Reyes
- Cancer Research Department, Instituto Oncológico Fundación Arturo López Pérez, Santiago 8350499, Chile; (J.L.L.); (F.R.)
| | - Carolina Gutiérrez-Cáceres
- Laboratory of Chemical Carcinogenesis and Pharmacogenetics, Department of Basic-Clinical Oncology (DOBC), Faculty of Medicine, University of Chile, Santiago 8350499, Chile; (J.P.C.); (L.C.C.); (C.G.-C.); (S.C.)
- Department of Pharmaceutical Sciences and Technology, Faculty of Chemical and Pharmaceutical Sciences, University of Chile, Santiago 8350499, Chile
| | - Susan Calfunao
- Laboratory of Chemical Carcinogenesis and Pharmacogenetics, Department of Basic-Clinical Oncology (DOBC), Faculty of Medicine, University of Chile, Santiago 8350499, Chile; (J.P.C.); (L.C.C.); (C.G.-C.); (S.C.)
- Latin American Network for Implementation and Validation of Clinical Pharmacogenomics Guidelines (RELIVAF-CYTED), Santiago 8350499, Chile
- Laboratory Pathological Anatomy, Hospital Luis Calvo Mackenna, Santiago 8350499, Chile
| | - Nelson Miguel Varela
- Laboratory of Chemical Carcinogenesis and Pharmacogenetics, Department of Basic-Clinical Oncology (DOBC), Faculty of Medicine, University of Chile, Santiago 8350499, Chile; (J.P.C.); (L.C.C.); (C.G.-C.); (S.C.)
- Latin American Network for Implementation and Validation of Clinical Pharmacogenomics Guidelines (RELIVAF-CYTED), Santiago 8350499, Chile
| | - Luis Abel Quiñones
- Laboratory of Chemical Carcinogenesis and Pharmacogenetics, Department of Basic-Clinical Oncology (DOBC), Faculty of Medicine, University of Chile, Santiago 8350499, Chile; (J.P.C.); (L.C.C.); (C.G.-C.); (S.C.)
- Latin American Network for Implementation and Validation of Clinical Pharmacogenomics Guidelines (RELIVAF-CYTED), Santiago 8350499, Chile
- Department of Pharmaceutical Sciences and Technology, Faculty of Chemical and Pharmaceutical Sciences, University of Chile, Santiago 8350499, Chile
| |
Collapse
|
|
8
|
Chakraborty B, Agarwal S, Kori S, Das R, Kashaw V, Iyer AK, Kashaw SK. Multiple Protein Biomarkers and Different Treatment Strategies for Colorectal Carcinoma: A Comprehensive Prospective. Curr Med Chem 2024; 31:3286-3326. [PMID: 37151060 DOI: 10.2174/0929867330666230505165031] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2022] [Revised: 02/20/2023] [Accepted: 02/24/2023] [Indexed: 05/09/2023]
Abstract
In this review, we emphasized important biomarkers, pathogenesis, and newly developed therapeutic approaches in the treatment of colorectal cancer (CRC). This includes a complete description of small-molecule inhibitors, phytopharmaceuticals with antiproliferative potential, monoclonal antibodies for targeted therapy, vaccinations as immunotherapeutic agents, and many innovative strategies to intervene in the interaction of oncogenic proteins. Many factors combine to determine the clinical behavior of colorectal cancer and it is still difficult to comprehend the molecular causes of a person's vulnerability to CRC. It is also challenging to identify the causes of the tumor's onset, progression, and responsiveness or resistance to antitumor treatment. Current recommendations for targeted medications are being updated by guidelines throughout the world in light of the growing number of high-quality clinical studies. So, being concerned about the aforementioned aspects, we have tried to present a summarized pathogenic view, including a brief description of biomarkers and an update of compounds with their underlying mechanisms that are currently under various stages of clinical testing. This will help to identify gaps or shortfalls that can be addressed in upcoming colorectal cancer research.
Collapse
Affiliation(s)
- Biswadip Chakraborty
- Integrated Drug Discovery Research Laboratory, Department of Pharmaceutical Sciences, Dr. Harisingh Gour University (A Central University), Sagar (MP), India
| | - Shivangi Agarwal
- Integrated Drug Discovery Research Laboratory, Department of Pharmaceutical Sciences, Dr. Harisingh Gour University (A Central University), Sagar (MP), India
| | - Shivam Kori
- Integrated Drug Discovery Research Laboratory, Department of Pharmaceutical Sciences, Dr. Harisingh Gour University (A Central University), Sagar (MP), India
| | - Ratnesh Das
- Department of Chemistry, ISF College of Pharmacy, Moga-Punjab, India
| | - Varsha Kashaw
- Sagar Institute of Pharmaceutical Sciences, Sagar (M.P.), India
| | - Arun K Iyer
- Use-inspired Biomaterials & Integrated Nano Delivery (U-BiND) Systems Laboratory, Department of Pharmaceutical Sciences, Wayne State University, Detroit, Michigan, USA
- Molecular Imaging Program, Karmanos Cancer Institute, Detroit, Michigan, USA
| | - Sushil Kumar Kashaw
- Integrated Drug Discovery Research Laboratory, Department of Pharmaceutical Sciences, Dr. Harisingh Gour University (A Central University), Sagar (MP), India
| |
Collapse
|
|
9
|
Hassan S, Miles A, Rachet B, Morris M. Variations in the Type of Adjuvant Chemotherapy Among Stage III Colon Cancer Patients in England. J Gastrointest Cancer 2023; 54:1193-1201. [PMID: 36602753 DOI: 10.1007/s12029-022-00899-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/15/2022] [Indexed: 01/06/2023]
Abstract
PURPOSE Treatment with any adjuvant chemotherapy for stage III colon cancer has been shown to differ between population groups. Few studies, however, explore variations in the type of adjuvant chemotherapy received, none of which are from the UK. The aim of this study is to explore variation in the type of chemotherapy received by stage III colon cancer patients in England. METHODS Data from the national cancer registry was linked to the Systemic Anti-Cancer Therapy database, which provides detailed information on treatment of malignant diseases from all NHS England chemotherapy providers. Demographic and clinical characteristics were compared between those who received monotherapy (fluoropyrimidine) or combination chemotherapy (fluoropyrimidine and oxaliplatin) among stage III colon cancer patients between 2012 and 2017. RESULTS Of 8750 patients who received adjuvant chemotherapy, 22.3% (n = 2359) received monotherapy and 60.4% (n = 6391) received combination therapy. The odds of receiving combination therapy decreased with age. Those from the most deprived group had half the odds (OR: 0.5, CI: 0.42, 0.59, p < 0.001) of receiving combination therapy compared to the least deprived group. Women were 14% less likely to get combined therapy (OR: 0.86, CI: 0.77, 0.95, p = 0.005). Those with the largest tumour size (T4) and those with more than three lymph nodes involved (N2) had 30% (OR: 1.30; CI: 1.07, 1.59; p = 0.008) and 50% (OR: 1.50; 1.34, 1.69; p < 0.001) higher odds of receiving combination therapy compared to T1 or T2 and N1, respectively. CONCLUSION There is variation in the type of chemotherapy received for stage III colon cancer patients by sociodemographic factors, despite clear clinical guidelines.
Collapse
Affiliation(s)
- Syreen Hassan
- Department of Health Services Research and Policy, London School of Hygiene and Tropical Medicine, 15-17 Tavistock Place, London, WC1H 9SH, UK.
- Department of Psychological Sciences, Birkbeck, University of London, Malet Street, London, WC1E 7HX, United Kingdom.
| | - Anne Miles
- Department of Psychological Sciences, Birkbeck, University of London, Malet Street, London, WC1E 7HX, United Kingdom
| | - Bernard Rachet
- Department of Non-communicable Disease Epidemiology, London School of Hygiene and Tropical Medicine, Keppel Street, London, WC1E 7HT, United Kingdom
| | - Melanie Morris
- Department of Health Services Research and Policy, London School of Hygiene and Tropical Medicine, 15-17 Tavistock Place, London, WC1H 9SH, UK
| |
Collapse
|
|
10
|
Brandt VP, Holland H, Wallenborn M, Koschny R, Frydrychowicz C, Richter M, Holland L, Nestler U, Sander C. SNP array genomic analysis of matched pairs of brain and liver metastases in primary colorectal cancer. J Cancer Res Clin Oncol 2023; 149:18173-18183. [PMID: 38010391 PMCID: PMC10725338 DOI: 10.1007/s00432-023-05505-4] [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: 07/24/2023] [Accepted: 10/31/2023] [Indexed: 11/29/2023]
Abstract
PURPOSE Brain metastasis formation is a rare and late event in colorectal cancer (CRC) patients and associated with poor survival. In contrast to other metastatic sites, the knowledge on chromosomal aberrations in brain metastases is very limited. METHODS Therefore, we carried out single nucleotide polymorphism (SNP) array analyses on matched primary CRC and brain metastases of four patients as well as on liver metastases of three patients. RESULTS Brain metastases showed more chromosomal aberrations than primary tumors or liver metastases. Commonly occurring aberrations were gain of 8q11.1-q24.3 (primary CRC), gain of 13q12.13-q12.3 (liver metastases), and gain of 20q11.1-q13.33 (brain metastases). Furthermore, we found one copy-neutral loss of heterozygosity (cn-LOH) region on chromosome 3 in primary CRC, three cn-LOH regions in liver metastases and 23 cn-LOH regions in brain metastases, comprising 26 previously undescribed sites. CONCLUSION The more frequent occurrence of cn-LOHs and subsequently affected genes in brain metastases shed light on the pathophysiology of brain metastasis formation. Further pairwise genetic analyses between primary tumors and their metastases will help to define the role of affected genes in cn-LOH regions.
Collapse
Affiliation(s)
- Vivian-Pascal Brandt
- Department of Neurosurgery, University Hospital Leipzig, Leipzig, Saxony, Germany.
- Saxonian Incubator for Clinical Translation (SIKT), University of Leipzig, Leipzig, Saxony, Germany.
| | - Heidrun Holland
- Saxonian Incubator for Clinical Translation (SIKT), University of Leipzig, Leipzig, Saxony, Germany
| | - Marco Wallenborn
- Department of Neurosurgery, University Hospital Leipzig, Leipzig, Saxony, Germany
- Saxonian Incubator for Clinical Translation (SIKT), University of Leipzig, Leipzig, Saxony, Germany
| | - Ronald Koschny
- Interdisciplinary Endoscopy Center (IEZ), Department of Gastroenterology and Hepatology, University Hospital Heidelberg, Heidelberg, Baden-Wuerttemberg, Germany
| | - Clara Frydrychowicz
- Paul Flechsig Institute of Neuropathology, University Medicine Leipzig, Leipzig, Saxony, Germany
| | - Mandy Richter
- Saxonian Incubator for Clinical Translation (SIKT), University of Leipzig, Leipzig, Saxony, Germany
| | - Lydia Holland
- Saxonian Incubator for Clinical Translation (SIKT), University of Leipzig, Leipzig, Saxony, Germany
| | - Ulf Nestler
- Department of Neurosurgery, University Hospital Leipzig, Leipzig, Saxony, Germany
| | - Caroline Sander
- Department of Neurosurgery, University Hospital Leipzig, Leipzig, Saxony, Germany
| |
Collapse
|
|
11
|
Ye T, Lin A, Qiu Z, Hu S, Zhou C, Liu Z, Cheng Q, Zhang J, Luo P. Microsatellite instability states serve as predictive biomarkers for tumors chemotherapy sensitivity. iScience 2023; 26:107045. [PMID: 37448561 PMCID: PMC10336167 DOI: 10.1016/j.isci.2023.107045] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2022] [Revised: 03/17/2023] [Accepted: 06/01/2023] [Indexed: 07/15/2023] Open
Abstract
There is an urgent need for markers to predict the efficacy of different chemotherapy drugs. Herein, we examined whether microsatellite instability (MSI) status can predict tumor multidrug sensitivity and explored the underlying mechanisms. We downloaded data from several public databases. Drug sensitivity was compared between the high microsatellite instability (MSI-H) and microsatellite-stable/low microsatellite instability (MSS/MSI-L) groups. In addition, we performed pathway enrichment analysis and cellular chemosensitivity assays to explore the mechanisms by which MSI status may affect drug sensitivity and assessed the differences between drug-treated and control cell lines. We found that multiple MSI-H tumors were more sensitive to a variety of chemotherapy drugs than MSS/MSI-L tumors, and especially for CRC, chemosensitivity is enhanced through the downregulation of DDR pathways such as NHEJ. Additional DNA damage caused by chemotherapeutic drugs results in further downregulation of DDR pathways and enhances drug sensitivity, forming a cycle of increasing drug sensitivity.
Collapse
Affiliation(s)
- Taojun Ye
- Department of Oncology, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China
- The First Clinical Medical School, Southern Medical University, Guangzhou, Guangdong, China
| | - Anqi Lin
- Department of Oncology, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China
- The First Clinical Medical School, Southern Medical University, Guangzhou, Guangdong, China
| | - Zhengang Qiu
- The First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi, China
| | - Shulu Hu
- Department of Oncology, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China
- The First Clinical Medical School, Southern Medical University, Guangzhou, Guangdong, China
| | - Chaozheng Zhou
- Department of Oncology, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China
- The First Clinical Medical School, Southern Medical University, Guangzhou, Guangdong, China
| | - Zaoqu Liu
- The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Quan Cheng
- Xiangya Hospital, Central South University, Changsha, Hunan, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Jian Zhang
- Department of Oncology, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China
- The First Clinical Medical School, Southern Medical University, Guangzhou, Guangdong, China
| | - Peng Luo
- Department of Oncology, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China
- The First Clinical Medical School, Southern Medical University, Guangzhou, Guangdong, China
| |
Collapse
|
|
12
|
Wosiak A, Szmajda-Krygier D, Pietrzak J, Boncela J, Balcerczak E. Assessment of the Influence of 5-Fluorouracil on SMAD4 and TGFB1 Gene Expression, Apoptosis Induction and DNA Damage in Human Cell Lines. Bioengineering (Basel) 2023; 10:bioengineering10050570. [PMID: 37237640 DOI: 10.3390/bioengineering10050570] [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: 03/21/2023] [Revised: 04/18/2023] [Accepted: 04/20/2023] [Indexed: 05/28/2023] Open
Abstract
PURPOSE Suppressor of mothers against decapentaplegic homolog 4 (SMAD family member 4, SMAD4) is involved in the adenoma-carcinoma pathway, leading to the development of colon cancer. The encoded protein is a key downstream signaling mediator in the TGFβ pathway. This pathway has tumor-suppressor functions, including cell-cycle arrest and apoptosis. Its activation in late-stage cancer can promote tumorigenesis, including metastasis and chemoresistance. Most colorectal cancer patients receive chemotherapy based on 5-FU as an adjuvant treatment. However, the success of therapy is hampered by multidrug resistance by neoplastic cells. In colorectal cancer, resistance to 5-FU-based therapy is influenced by SMAD4 gene expression, as patients with decreased SMAD4 gene expression probably have a higher risk of developing 5-FU-induced resistance. The mechanism leading to the development of this phenomenon is not fully understood. Therefore, the present study assesses the possible influence of 5-FU on changes in the expression of the SMAD4 and TGFB1 genes. PATIENTS AND METHODS The effect of 5-FU on the expression of SMAD4 and TGFB1 in colorectal cancer cells derived from the CACO-2, SW480 and SW620 cell lines was evaluated using real-time PCR. The cytotoxicity of 5-FU on colon cancer cells was assessed by the MTT method, and its effect on the induction of cell apoptosis and the initiation of DNA damage using a flow cytometer. RESULTS Significant changes in the level of SMAD4 and TGFB1 gene expression were noted in the CACO-2, SW480 and SW620 cells treated with 5-FU at various concentrations during 24 h and 48 h exposure. The use of 5-FU at a concentration of 5 µmol/L resulted in a decrease in the expression of the SMAD4 gene in all cell lines at both exposure times, while the concentration of 100 µmol/L increased the expression of the SMAD4 gene in CACO-2 cells. The level of expression of the TGFB1 gene was higher for all cells treated with 5-FU at the highest concentrations, while the exposure time was extended to 48 h. CONCLUSION The observed in vitro changes in CACO-2 cells caused by 5-FU may be of clinical relevance when choosing the drug concentration for treating patients with colorectal cancer. It is possible that 5-FU has a stronger effect on colorectal cancer cells at the higher concentrations. Low concentrations of 5-FU may not have a therapeutic effect and may also influence drug resistance in cancer cells. Higher concentrations and prolonged exposure time may affect SMAD4 gene expression, which may increase the effectiveness of therapy.
Collapse
Affiliation(s)
- Agnieszka Wosiak
- Laboratory of Molecular Diagnostics and Pharmacogenomics, Department of Pharmaceutical Biochemistry and Molecular Diagnostics, Medical University of Lodz, 1 Muszynskiego, 90-151 Lodz, Poland
| | - Dagmara Szmajda-Krygier
- Laboratory of Molecular Diagnostics and Pharmacogenomics, Department of Pharmaceutical Biochemistry and Molecular Diagnostics, Medical University of Lodz, 1 Muszynskiego, 90-151 Lodz, Poland
| | - Jacek Pietrzak
- Laboratory of Molecular Diagnostics and Pharmacogenomics, Department of Pharmaceutical Biochemistry and Molecular Diagnostics, Medical University of Lodz, 1 Muszynskiego, 90-151 Lodz, Poland
| | - Joanna Boncela
- Institute of Medical Biology, Polish Academy of Science, 106 Lodowa, 93-232 Lodz, Poland
| | - Ewa Balcerczak
- Laboratory of Molecular Diagnostics and Pharmacogenomics, Department of Pharmaceutical Biochemistry and Molecular Diagnostics, Medical University of Lodz, 1 Muszynskiego, 90-151 Lodz, Poland
| |
Collapse
|
|
13
|
Wang T, Wu L, Wang S, Shi X, Liu H, Deng W. Chang Wei Qing Decoction enhances the anti-tumor effect of PD-1 inhibitor therapy by regulating the immune microenvironment and gut microbiota in colorectal cancer. Chin J Nat Med 2023; 21:333-345. [PMID: 37245872 DOI: 10.1016/s1875-5364(23)60451-0] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2022] [Indexed: 05/30/2023]
Abstract
The anti-tumor effect of anti-PD-1 antibody has long been shown to be strongly related to the tumor immune microenvironment (TIME). This study aimed to mechanistically assess whether Chang Wei Qing (CWQ) Decoction can enhance the anti-tumor effect of PD-1 inhibitor therapy. PD-1 inhibitor therapy showed the significant anti-tumor effect in patients with mismatch repair-deficient/microsatellite instability-high (dMMR/MSI-H) colorectal cancer (CRC), rather than those with mismatch repair-proficient/microsatellite stable (pMMR/MSS) CRC. Hence, immunofluorescence double-label staining was utilized to explore the difference in the TIME between dMMR/MSI-H and pMMR/MSS CRC patients. Flow cytometry was used to analyze T-lymphocytes in tumors from mice. Western blot was used to measure the expression of PD-L1 protein in mouse tumors. The intestinal mucosal barrier of mice was evaluated by hematoxylin-eosin staining and immunohistochemistry. 16S rRNA-gene sequencing was used to examine the structure of the gut microbiota in mice. Subsequently, Spearmanapos;s correlation analysis was used to analyze the relationship between the gut microbiota and tumor-infiltrating T-lymphocytes. The results showed that dMMR/MSI-H CRC patients had more CD8+T cells and higher expression of PD-1 and PD-L1 proteins. In vivo, CWQ enhanced the anti-tumor effect of anti-PD-1 antibody and increased the infiltration of CD8+ and PD-1+CD8+ T cells in tumors. Additionally, the combination of CWQ with anti-PD-1 antibody resulted in lower inflammation in the intestinal mucosa than that induced by anti-PD-1 antibody alone. CWQ and anti-PD-1 antibody co-treatment upregulated PD-L1 protein and reduced the abundance of Bacteroides in the gut microbiota but increased the abundance of Akkermansia,Firmicutes, andActinobacteria. Additionally, the proportion of infiltrated CD8+PD-1+, CD8+, and CD3+ T cells were found to be positively correlated with the abundance of Akkermansia. Accordingly, CWQ may modulate the TIME by modifying the gut microbiota and consequently enhance the anti-tumor effect of PD-1 inhibitor therapy.
Collapse
Affiliation(s)
- Ting Wang
- Department of Oncology, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200062, China; Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
| | - Linguangjin Wu
- Department of Oncology, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200062, China; Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Shuyun Wang
- Department of Oncology, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200062, China; Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Xiaolan Shi
- Department of Oncology, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200062, China.
| | - Hui Liu
- Department of Oncology, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200062, China.
| | - Wanli Deng
- Department of Oncology, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200062, China.
| |
Collapse
|
|
14
|
Kim S, Lee JH, Park EJ, Lee HS, Baik SH, Jeon TJ, Lee KY, Ryu YH, Kang J. Prediction of Microsatellite Instability in Colorectal Cancer Using a Machine Learning Model Based on PET/CT Radiomics. Yonsei Med J 2023; 64:320-326. [PMID: 37114635 PMCID: PMC10151228 DOI: 10.3349/ymj.2022.0548] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/20/2022] [Revised: 03/11/2023] [Accepted: 03/20/2023] [Indexed: 04/29/2023] Open
Abstract
PURPOSE We investigated the feasibility of preoperative 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT) radiomics with machine learning to predict microsatellite instability (MSI) status in colorectal cancer (CRC) patients. MATERIALS AND METHODS Altogether, 233 patients with CRC who underwent preoperative FDG PET/CT were enrolled and divided into training (n=139) and test (n=94) sets. A PET-based radiomics signature (rad_score) was established to predict the MSI status in patients with CRC. The predictive ability of the rad_score was evaluated using the area under the receiver operating characteristic curve (AUROC) in the test set. A logistic regression model was used to determine whether the rad_score was an independent predictor of MSI status in CRC. The predictive performance of rad_score was compared with conventional PET parameters. RESULTS The incidence of MSI-high was 15 (10.8%) and 10 (10.6%) in the training and test sets, respectively. The rad_score was constructed based on the two radiomic features and showed similar AUROC values for predicting MSI status in the training and test sets (0.815 and 0.867, respectively; p=0.490). Logistic regression analysis revealed that the rad_score was an independent predictor of MSI status in the training set. The rad_score performed better than metabolic tumor volume when assessed using the AUROC (0.867 vs. 0.794, p=0.015). CONCLUSION Our predictive model incorporating PET radiomic features successfully identified the MSI status of CRC, and it also showed better performance than the conventional PET image parameters.
Collapse
Affiliation(s)
- Soyoung Kim
- Department of Nuclear Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Jae-Hoon Lee
- Department of Nuclear Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea.
| | - Eun Jung Park
- Department of Surgery, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Hye Sun Lee
- Biostatistics Collaboration Unit, Yonsei University College of Medicine, Seoul, Korea
| | - Seung Hyuk Baik
- Department of Surgery, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Tae Joo Jeon
- Department of Nuclear Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Kang Young Lee
- Department of Surgery, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Young Hoon Ryu
- Department of Nuclear Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Jeonghyun Kang
- Department of Surgery, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea.
| |
Collapse
|
|
15
|
Gmeiner WH, Okechukwu CC. Review of 5-FU resistance mechanisms in colorectal cancer: clinical significance of attenuated on-target effects. CANCER DRUG RESISTANCE (ALHAMBRA, CALIF.) 2023; 6:257-272. [PMID: 37457133 PMCID: PMC10344727 DOI: 10.20517/cdr.2022.136] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 11/30/2022] [Revised: 04/01/2023] [Accepted: 04/17/2023] [Indexed: 07/18/2023]
Abstract
The emergence of chemoresistant disease during chemotherapy with 5-Fluorouracil-based (5-FU-based) regimens is an important factor in the mortality of metastatic CRC (mCRC). The causes of 5-FU resistance are multi-factorial, and besides DNA mismatch repair deficiency (MMR-D), there are no widely accepted criteria for determining which CRC patients are not likely to be responsive to 5-FU-based therapy. Thus, there is a need to systematically understand the mechanistic basis for 5-FU treatment failure and an urgent need to develop new approaches for circumventing the major causes of 5-FU resistance. In this manuscript, we review mechanisms of 5-FU resistance with an emphasis on: (1) altered anabolic metabolism limiting the formation of the primary active metabolite Fluorodeoxyuridylate (5-Fluoro-2'-deoxyuridine-5'-O-monophosphate; FdUMP); (2) elevated expression or activity of the primary enzymatic target thymidylate synthase (TS); and (3) dysregulated programmed cell death as important causes of 5-FU resistance. Importantly, these causes of 5-FU resistance can potentially be overcome through the use of next-generation fluoropyrimidine (FP) polymers (e.g., CF10) that display reduced dependence on anabolic metabolism and more potent TS inhibitory activity.
Collapse
Affiliation(s)
- William H. Gmeiner
- Department of Cancer Biology and Comprehensive Cancer Center, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA
- Integrative Physiology and Pharmacology Graduate Program, Institution, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA
| | - Charles Chidi Okechukwu
- Department of Cancer Biology and Comprehensive Cancer Center, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA
| |
Collapse
|
|
16
|
Balaji AK, Saha S, Deshpande S, Poola D, Sengupta K. Nuclear envelope, chromatin organizers, histones, and DNA: The many achilles heels exploited across cancers. Front Cell Dev Biol 2022; 10:1068347. [PMID: 36589746 PMCID: PMC9800887 DOI: 10.3389/fcell.2022.1068347] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2022] [Accepted: 12/05/2022] [Indexed: 12/23/2022] Open
Abstract
In eukaryotic cells, the genome is organized in the form of chromatin composed of DNA and histones that organize and regulate gene expression. The dysregulation of chromatin remodeling, including the aberrant incorporation of histone variants and their consequent post-translational modifications, is prevalent across cancers. Additionally, nuclear envelope proteins are often deregulated in cancers, which impacts the 3D organization of the genome. Altered nuclear morphology, genome organization, and gene expression are defining features of cancers. With advances in single-cell sequencing, imaging technologies, and high-end data mining approaches, we are now at the forefront of designing appropriate small molecules to selectively inhibit the growth and proliferation of cancer cells in a genome- and epigenome-specific manner. Here, we review recent advances and the emerging significance of aberrations in nuclear envelope proteins, histone variants, and oncohistones in deregulating chromatin organization and gene expression in oncogenesis.
Collapse
Affiliation(s)
| | | | | | | | - Kundan Sengupta
- Chromosome Biology Lab (CBL), Indian Institute of Science Education and Research, Pune, Maharashtra, India
| |
Collapse
|
|
17
|
Gogoi P, Kaur G, Singh NK. Nanotechnology for colorectal cancer detection and treatment. World J Gastroenterol 2022; 28:6497-6511. [PMID: 36569271 PMCID: PMC9782835 DOI: 10.3748/wjg.v28.i46.6497] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/13/2022] [Revised: 10/28/2022] [Accepted: 11/18/2022] [Indexed: 12/08/2022] Open
Abstract
Colorectal cancer (CRC) is the third most diagnosed cancer and the second leading cause of cancer-related mortality in the United States. Across the globe, people in the age group older than 50 are at a higher risk of CRC. Genetic and environmental risk factors play a significant role in the development of CRC. If detected early, CRC is preventable and treatable. Currently, available screening methods and therapies for CRC treatment reduce the incidence rate among the population, but the micrometastasis of cancer may lead to recurrence. Therefore, the challenge is to develop an alternative therapy to overcome this complication. Nanotechnology plays a vital role in cancer treatment and offers targeted chemotherapies directly and selectively to cancer cells, with enhanced therapeutic efficacy. Additionally, nanotechnology elevates the chances of patient survival in comparison to traditional chemotherapies. The potential of nanoparticles includes that they may be used simultaneously for diagnosis and treatment. These exciting properties of nanoparticles have enticed researchers worldwide to unveil their use in early CRC detection and as effective treatment. This review discusses contemporary methods of CRC screening and therapies for CRC treatment, while the primary focus is on the theranostic approach of nanotechnology in CRC treatment and its prospects. In addition, this review aims to provide knowledge on the advancement of nanotechnology in CRC and as a starting point for researchers to think about new therapeutic approaches using nanotechnology.
Collapse
Affiliation(s)
- Purnima Gogoi
- Integrative Biosciences Center, OVAS, Wayne State University School of Medicine, Detroit, MI 48202, United States
| | - Geetika Kaur
- Integrative Biosciences Center, OVAS, Wayne State University School of Medicine, Detroit, MI 48202, United States
| | - Nikhlesh K Singh
- Integrative Biosciences Center, OVAS, Wayne State University School of Medicine, Detroit, MI 48202, United States
| |
Collapse
|
|
18
|
Association of microsatellite instability (MSI) status with the 5-year outcome and genetic ancestry in a large Brazilian cohort of colorectal cancer. Eur J Hum Genet 2022; 30:824-832. [PMID: 35474354 PMCID: PMC9259739 DOI: 10.1038/s41431-022-01104-y] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2021] [Revised: 02/04/2022] [Accepted: 04/12/2022] [Indexed: 12/22/2022] Open
Abstract
Colorectal cancer (CRC) has a high incidence and mortality worldwide. Microsatellite instability (MSI) is crucial in CRC, with distinct molecular and clinicopathological features in patients. Nowadays, it is a predictive marker for immunotherapy. We proposed to evaluate the 5-year outcome of MSI status in 1002 Brazilian CRC, and associate it with genetic ancestry, molecular and clinicopathological features. MSI evaluation was performed using molecular markers. MSI+ tumors were analyzed for alterations in 23 MSI-targeted genes. Genetic ancestry was evaluated using an Ancestry-Informative markers panel. MSI status was analyzed in relation to CRC specific survival and other clinical and genetic variables. MSI+ status was observed in 10.5% of cases. MSI+ status was significantly associated with the anatomic site right colon, mucinous histological type, clinical stage II, histological grade III/undifferentiated, no recurrence of disease, and live cases without cancer. No association of MSI status with genetic ancestry components was observed. MSI-targeted genes analyses showed the most frequently altered genes: ATM, EGFR, MRE11, ROCK1, and TGFBRII. There was a statistically significant difference in cancer-specific survival between cases according to MSI status. This study constitutes the most comprehensive analyses of the MSI impact on the Brazilian CRC. MSI+ frequency in Brazilian CRC agreed with the literature and was associated with several clinicopathological features related with less aggressive tumors, independently of their genetic ancestry.
Collapse
|
|
19
|
Bottom-Up Approach to the Discovery of Clinically Relevant Biomarker Genes: The Case of Colorectal Cancer. Cancers (Basel) 2022; 14:cancers14112654. [PMID: 35681633 PMCID: PMC9179423 DOI: 10.3390/cancers14112654] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2022] [Revised: 05/26/2022] [Accepted: 05/26/2022] [Indexed: 12/07/2022] Open
Abstract
Traditional approaches to genome-wide marker discovery often follow a common top-down strategy, where a large scale ‘omics’ investigation is followed by the analysis of functional pathways involved, to narrow down the list of identified putative biomarkers, and to deconvolute gene expression networks, or to obtain an insight into genetic alterations observed in cancer. We set out to investigate whether a reverse approach would allow full or partial reconstruction of the transcriptional programs and biological pathways specific to a given cancer and whether the full or substantially expanded list of putative markers could thus be identified by starting with the partial knowledge of a few disease-specific markers. To this end, we used 10 well-documented differentially expressed markers of colorectal cancer (CRC), analyzed their transcription factor networks and biological pathways, and predicted the existence of 193 new putative markers. Incredibly, the use of a validation marker set of 10 other completely different known CRC markers and the same procedure resulted in a very similar set of 143 predicted markers. Of these, 138 were identical to those found using the training set, confirming our main hypothesis that a much-expanded set of disease markers can be predicted by starting with just a small subset of validated markers. Further to this, we validated the expression of 42 out of 138 top-ranked predicted markers experimentally using qPCR in surgically removed CRC tissues. We showed that 41 out of 42 mRNAs tested have significantly altered levels of mRNA expression in surgically excised CRC tissues. Of the markers tested, 36 have been reported to be associated with aspects of CRC in the past, whilst only limited published evidence exists for another three genes (BCL2, PDGFRB and TSC2), and no published evidence directly linking genes to CRC was found for CCNA1, SHC1 and TGFB3. Whilst we used CRC to test and validate our marker discovery strategy, the reported procedures apply more generally to cancer marker discovery.
Collapse
|
|
20
|
Kang SY, Kim DG, Ahn S, Ha SY, Jang KT, Kim KM. Comparative analysis of microsatellite instability by next-generation sequencing, MSI PCR and MMR immunohistochemistry in 1942 solid cancers. Pathol Res Pract 2022; 233:153874. [PMID: 35405622 DOI: 10.1016/j.prp.2022.153874] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/08/2021] [Revised: 03/15/2022] [Accepted: 03/30/2022] [Indexed: 11/25/2022]
Abstract
Checkpoint inhibitor approval for microsatellite instability-high (MSI-H) tumours has made MSI as a therapeutically important biomarker. Next-generation sequencing (NGS)-based MSI detection is being widely used for assessing MSI. However, MSI tumours detected using NGS and their relevance to MSI-polymerase chain reaction (PCR) and mismatch repair deficiency (dMMR) are unclear. In 1942 solid cancer cases tested using NGS-based comprehensive cancer panel with 523 genes (1.94 mb), the MSI score, tumour mutation burden (TMB; ≥ 10 mutations/mb), and frameshift mutations were analysed. GeneScan analyses of five mononucleotide markers (MSI-PCR) and MMR protein immunohistochemistry (IHC) were compared with the NGS-MSI results. With a ≥ 12% MSI score as a cut-off for MSI-H, two MSS cases were classified as MSI-H. With a ≥ 20% cut-off, 10 cases categorised as MSS by NGS were MSI-H/dMMR by MSI-PCR and MMR IHC. To avoid discrepant cases, we adopted a high MSI cut-off and a borderline MSI category. Finally, MSI-H (≥ 20%), borderline MSI (≥ 7% and < 20%), and MSS (< 7%) were found in 35 (1.8%), 24 (1.2%), and 1883 (97%) cases, respectively. All MSI-H cases by NGS were MSI-H/dMMR by MSI-PCR and MMR IHC. Of the 24 borderline MSI cases by NGS, MSI-H/dMMR was 9 (37.5%) cases, MSS/dMMR was 1 (4.2%) case, and 11 (45.8%) of them had high TMB. All MSS cases by NGS were MSS/pMMR by MSI-PCR/IHC, and 257 (13.6%) had high TMB. With those arbitrary cut-off points, 10 (0.5%) MSS cases using NGS were discrepant with MSI-PCR or MMR IHC, and all were borderline MSI cases. The mean number of frameshift mutations was significantly higher in the MSI-H group (28.3) than in the borderline MSI (7.7) or MSS (1.3) groups (p < 0.001). In conclusion, to facilitate therapeutic decision-making for NGS, cut-off points for MSI can be defined based on MSI-PCR/dMMR confirmation.
Collapse
Affiliation(s)
- So Young Kang
- Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Deok Geun Kim
- Department of Clinical Genomic Center, Samsung Medical Center, Seoul, Republic of Korea; Department of Digital Health, Samsung Advanced Institute of Health Science and Technology, Sungkyunkwan University, Seoul, Republic of Korea
| | - Soomin Ahn
- Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Sang Yun Ha
- Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Kee-Taek Jang
- Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Kyoung-Mee Kim
- Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea; Department of Clinical Genomic Center, Samsung Medical Center, Seoul, Republic of Korea; Center of Companion Diagnostics, Samsung Medical Center, Seoul, Republic of Korea.
| |
Collapse
|
|
21
|
Rogers MP, Mi Z, Li NY, Wai PY, Kuo PC. Tumor: Stroma Interaction and Cancer. EXPERIENTIA SUPPLEMENTUM (2012) 2022; 113:59-87. [PMID: 35165860 DOI: 10.1007/978-3-030-91311-3_2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/14/2023]
Abstract
The understanding of how normal cells transform into tumor cells and progress to invasive cancer and metastases continues to evolve. The tumor mass is comprised of a heterogeneous population of cells that include recruited host immune cells, stromal cells, matrix components, and endothelial cells. This tumor microenvironment plays a fundamental role in the acquisition of hallmark traits, and has been the intense focus of current research. A key regulatory mechanism triggered by these tumor-stroma interactions includes processes that resemble epithelial-mesenchymal transition, a physiologic program that allows a polarized epithelial cell to undergo biochemical and cellular changes and adopt mesenchymal cell characteristics. These cellular adaptations facilitate enhanced migratory capacity, invasiveness, elevated resistance to apoptosis, and greatly increased production of ECM components. Indeed, it has been postulated that cancer cells undergo epithelial-mesenchymal transition to invade and metastasize.In the following discussion, the physiology of chronic inflammation, wound healing, fibrosis, and tumor invasion will be explored. The key regulatory cytokines, transforming growth factor β and osteopontin, and their roles in cancer metastasis will be highlighted.
Collapse
Affiliation(s)
- Michael P Rogers
- Department of Surgery, University of South Florida Morsani College of Medicine, Tampa, FL, USA
| | - Zhiyong Mi
- Department of Surgery, University of South Florida Morsani College of Medicine, Tampa, FL, USA
| | - Neill Y Li
- Department of Surgery, University of South Florida Morsani College of Medicine, Tampa, FL, USA
| | - Philip Y Wai
- Department of Surgery, University of South Florida Morsani College of Medicine, Tampa, FL, USA
| | - Paul C Kuo
- Department of Surgery, University of South Florida Morsani College of Medicine, Tampa, FL, USA.
| |
Collapse
|
|
22
|
Kotake M, Bando H, Kaneko M, Takemura H, Minamoto T, Kawakami K. Thymidylate synthase locus LOH in combination with genotype has prognostic and predictive significance in colorectal cancer. Mol Clin Oncol 2021; 15:235. [PMID: 34650802 PMCID: PMC8506693 DOI: 10.3892/mco.2021.2398] [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: 09/29/2020] [Accepted: 07/22/2021] [Indexed: 11/06/2022] Open
Abstract
The aim of the current study was to investigate the prognostic and predictive significance of polymorphisms in the thymidylate synthase (TS) gene, alongside the loss of heterozygocity (LOH) at this gene locus in patients with colorectal cancer. Genotyping was carried out for a variable number tandem repeat (VNTR) polymorphism in the TS 5'-untranslated region, a G/C single nucleotide polymorphism (SNP) located within this VNTR, and for TS LOH status in 246 colorectal cancer and paired normal DNA samples. The results were analyzed in relation to clinicopathological features, including the prognostic and predictive significance of TS genotype in patients who underwent curative surgery. Complete VNTR, SNP and LOH information for TS was obtained in 226 cases. No significant associations were observed between normal tissue TS genotype status and clinicopathological features. LOH of TS was observed in 58% of tumor samples and was associated with poor prognosis independently of clinical stage. Cases exhibiting TS LOH were classified into the three groups of 2R/loss, 3G/loss and 3C/loss. Patients with 3C/loss genotype status had poor outcomes when treated by surgery alone, but their survival was similar to patients with other genotypes following Fluorouracil (5-FU)-based adjuvant chemotherapy. The results suggested that LOH of the TS locus may be a significant prognostic factor in colorectal cancer, with the genotype of the residual allele also demonstrating an influence on prognosis. In conclusion, LOH status should be considered when TS genotype is explored as a potential prognostic and predictive marker for 5-FU-based adjuvant chemotherapy in colorectal cancer.
Collapse
Affiliation(s)
- Masanori Kotake
- Department of General and Cardiothoracic Surgery, Graduate School of Medical Science, Kanazawa University, Kanazawa, Ishikawa 920-8641, Japan.,Department of Gastrointestinal Surgery, Ishikawa Prefectural Central Hospital, Kanazawa, Ishikawa 920-8530, Japan.,Department of Surgery, Kouseiren Takaoka Hospital, Takaoka, Toyama 933-8555, Japan.,Division of Translational and Clinical Oncology, Cancer Research Institute, Kanazawa University, Kanazawa, Ishikawa 920-0934, Japan
| | - Hiroyuki Bando
- Department of Gastrointestinal Surgery, Ishikawa Prefectural Central Hospital, Kanazawa, Ishikawa 920-8530, Japan
| | - Mami Kaneko
- Department of General and Cardiothoracic Surgery, Graduate School of Medical Science, Kanazawa University, Kanazawa, Ishikawa 920-8641, Japan.,Department of Gastrointestinal Surgery, Ishikawa Prefectural Central Hospital, Kanazawa, Ishikawa 920-8530, Japan.,Division of Translational and Clinical Oncology, Cancer Research Institute, Kanazawa University, Kanazawa, Ishikawa 920-0934, Japan
| | - Hirofumi Takemura
- Department of General and Cardiothoracic Surgery, Graduate School of Medical Science, Kanazawa University, Kanazawa, Ishikawa 920-8641, Japan
| | - Toshinari Minamoto
- Division of Translational and Clinical Oncology, Cancer Research Institute, Kanazawa University, Kanazawa, Ishikawa 920-0934, Japan
| | - Kazuyuki Kawakami
- Division of Translational and Clinical Oncology, Cancer Research Institute, Kanazawa University, Kanazawa, Ishikawa 920-0934, Japan.,Department of Chemotherapy and Palliative Care, Tokyo Women's Medical University, Tokyo 162-8666, Japan
| |
Collapse
|
|
23
|
Baidoun F, Saad AM, Abdel-Rahman O. Prognostic and predictive value of microsatellite instability status among patients with colorectal cancer. J Comp Eff Res 2021; 10:1197-1214. [PMID: 34608819 DOI: 10.2217/cer-2021-0013] [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: 11/21/2022] Open
Abstract
Objectives: Compare overall survival (OS) between microsatellite instability (MSI) high and MSI-stable and analyze the effect of chemotherapy on OS. Methods: National cancer database was queried for patients diagnosed with colorectal adenocarcinoma between 2010 and 2016. We evaluated the OS and the chemotherapy effect using Kaplan-Meier estimates and multivariate Cox regression analyses. Results: Total of 30,436 stage II patients and 30,302 stage III patients were included. In stage II with high-risk features and MSI-high, patients who received chemotherapy had better OS compared to patients who didn't receive chemotherapy. The same was found in stage II with no high-risk features and MSI-high group. Conclusion: Stage II colorectal cancer patients with high-risk features and MSI-high who received chemotherapy have better OS compared to patients who didn't receive chemotherapy.
Collapse
Affiliation(s)
- Firas Baidoun
- Department of Hospital Medicine, Cleveland Clinic Foundation, Cleveland, OH 44195, USA
| | - Anas M Saad
- Heart & Vascular Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA
| | - Omar Abdel-Rahman
- Department of Oncology, University of Alberta, Cross Cancer Institute, Edmonton, AB, T6G 1Z2, Canada
| |
Collapse
|
|
24
|
Huo X, Feng D, Zhang S, Li Z, Li X, Li C, Guo M, Wang J, Zhang Z, Lu Q, Du X, Bai Z, Chen Z. Characterization and clinical evaluation of microsatellite instability and loss of heterozygosity within tumor-related genes in colorectal cancer. BMC Med Genomics 2021; 14:235. [PMID: 34563193 PMCID: PMC8466986 DOI: 10.1186/s12920-021-01051-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2020] [Accepted: 08/05/2021] [Indexed: 11/30/2022] Open
Abstract
BACKGROUND Microsatellite instability (MSI) is a biomarker for better outcomes in colorectal cancer (CRC). However, this conclusion is controversial. In addition, MSs can be a useful marker for loss of heterozygosity (LOH) of genes, but this finding has not been well studied. Here, we aimed to clarify the predictive value of MSI/LOH within tumor-related genes in CRC. METHODS We detected MSI/LOH of MSs in tumor-related genes and the Bethesda (B5) panel by STR scanning and cloning/sequencing. We further analyzed the relationship between MSI/LOH status and clinical features or outcomes by Pearson's Chi-square test, Fisher's exact test and the Kaplan-Meier method. RESULTS The findings indicated that the MSI rates of B5 loci were all higher than those of loci in tumor-related genes. Interestingly, MSI/LOH of 2 loci in the B5 panel and 12 loci in tumor-related genes were associated with poorer outcomes, while MSI/LOH of the B5 panel failed to predict outcomes in CRC. MSI of BAT25, MSI/LOH of BAT26 and MSI of the B5 panel showed closer relationships with mucinous carcinoma. In addition, LOH-H of the B5 panel was associated with increased lymphatic metastasis. CONCLUSIONS In summary, MSI/LOH of certain loci or the whole panel of B5 is related to clinical features, and several loci within tumor-related genes showed prognostic value in the outcomes of CRC.
Collapse
Affiliation(s)
- Xueyun Huo
- School of Basic Medical Sciences, Capital Medical University, Beijing Key Laboratory of Cancer Invasion & Metastasis Research, Beijing, 100069, China
| | - Dandan Feng
- School of Basic Medical Sciences, Capital Medical University, Beijing Key Laboratory of Cancer Invasion & Metastasis Research, Beijing, 100069, China
| | - Shuangyue Zhang
- Institute of Laboratory Animal Sciences, Chinese Academy of Medical Sciences and Comparative Medicine Center, Peking Union Medical Collage, Beijing, 100021 , China
| | - Zhenkun Li
- School of Basic Medical Sciences, Capital Medical University, Beijing Key Laboratory of Cancer Invasion & Metastasis Research, Beijing, 100069, China
| | - Xiaohong Li
- School of Basic Medical Sciences, Capital Medical University, Beijing Key Laboratory of Cancer Invasion & Metastasis Research, Beijing, 100069, China
| | - Changlong Li
- School of Basic Medical Sciences, Capital Medical University, Beijing Key Laboratory of Cancer Invasion & Metastasis Research, Beijing, 100069, China
| | - Meng Guo
- School of Basic Medical Sciences, Capital Medical University, Beijing Key Laboratory of Cancer Invasion & Metastasis Research, Beijing, 100069, China
| | - Jin Wang
- Department of General Surgery, Beijing Friendship Hospital, Capital Medical University, Beijing Key Laboratory of Cancer Invasion & Metastasis Research & National Clinical Research Center for Digestive Diseases, Beijing, 100050, China
| | - Zhongtao Zhang
- Department of General Surgery, Beijing Friendship Hospital, Capital Medical University, Beijing Key Laboratory of Cancer Invasion & Metastasis Research & National Clinical Research Center for Digestive Diseases, Beijing, 100050, China
| | - Qingxian Lu
- Department of Ophthalmology and Visual Sciences, University of Louisville School of Medicine, Louisville, KY, 40202, USA
| | - Xiaoyan Du
- School of Basic Medical Sciences, Capital Medical University, Beijing Key Laboratory of Cancer Invasion & Metastasis Research, Beijing, 100069, China
| | - Zhigang Bai
- Department of General Surgery, Beijing Friendship Hospital, Capital Medical University, Beijing Key Laboratory of Cancer Invasion & Metastasis Research & National Clinical Research Center for Digestive Diseases, Beijing, 100050, China.
| | - Zhenwen Chen
- School of Basic Medical Sciences, Capital Medical University, Beijing Key Laboratory of Cancer Invasion & Metastasis Research, Beijing, 100069, China.
| |
Collapse
|
|
25
|
Toh JWT, Phan K, Reza F, Chapuis P, Spring KJ. Rate of dissemination and prognosis in early and advanced stage colorectal cancer based on microsatellite instability status: systematic review and meta-analysis. Int J Colorectal Dis 2021; 36:1573-1596. [PMID: 33604737 DOI: 10.1007/s00384-021-03874-1] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 01/27/2021] [Indexed: 02/04/2023]
Abstract
INTRODUCTION For the past two decades, microsatellite instability (MSI) has been reported as a robust clinical biomarker associated with survival advantage attributed to its immunogenicity. However, MSI is also associated with high-risk adverse pathological features (poorly differentiated, mucinous, signet cell, higher grade) and exhibits a double-edged sword phenomenon. We performed a systematic review and meta-analysis to evaluate the rate of dissemination and the prognosis of early and advanced stage colorectal cancer based on MSI status. METHODS A systematic literature search of original studies was performed on Ovid searching MEDLINE, Embase, Cochrane Database of Systematic Reviews, American College of Physicians ACP Journal Club, Database of Abstracts of Reviews of Effects DARE, Clinical Trials databases from inception of database to June 2019. Colorectal cancer, microsatellite instability, genomic instability and DNA mismatch repair were used as key words or MeSH terms. The Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline was followed. Data were pooled using a random-effects model with odds ratio (OR) as the effect size. Statistical analysis was performed using RevMan ver 5.3 Cochrane Collaboration. RESULTS From 5288 studies, 136 met the inclusion criteria (n = 92,035; MSI-H 11,746 (13%)). Overall, MSI-H was associated with improved OS (OR, 0.81; 95% CI 0.73-0.90), DFS (OR, 0.73; 95% CI 0.66-0.81) and DSS (OR, 0.69; 95% CI 0.52-0.90). Importantly, MSI-H had a protective effect against dissemination with a significantly lower rate of lymph node and distant metastases. By stage, the protective effect of MSI-H in terms of OS and DFS was observed clearly in stage II and stage III. Survival in stage I CRC was excellent irrespective of MSI status. In stage IV CRC, without immunotherapy, MSI-H was not associated with any survival benefit. CONCLUSIONS MSI-H CRC was associated with an overall survival benefit with a lower rate of dissemination. Survival benefit was clearly evident in both stage II and III CRC, but MSI-H was neither a robust prognostic marker in stage I nor stage IV CRC without immunotherapy.
Collapse
Affiliation(s)
- James W T Toh
- Department of Surgery, Division of Colorectal Surgery, Westmead Hospital, Sydney, NSW, Australia. .,Discipline of Surgery, Sydney Medical School, University of Sydney, Sydney, NSW, Australia. .,Discipline of Surgery, The University of New South Wales, Sydney, NSW, Australia. .,Medical Oncology, Ingham Institute for Applied Medical Research, School of Medicine Western Sydney University and South Western Clinical School, University of New South Wales, NSW, Sydney, Australia.
| | - Kevin Phan
- Department of Surgery, Division of Colorectal Surgery, Westmead Hospital, Sydney, NSW, Australia
| | - Faizur Reza
- Department of Surgery, Division of Colorectal Surgery, Westmead Hospital, Sydney, NSW, Australia
| | - Pierre Chapuis
- Discipline of Surgery, Sydney Medical School, University of Sydney, Sydney, NSW, Australia
| | - Kevin J Spring
- Medical Oncology, Ingham Institute for Applied Medical Research, School of Medicine Western Sydney University and South Western Clinical School, University of New South Wales, NSW, Sydney, Australia
| |
Collapse
|
|
26
|
Hinoi T. Cancer Genomic Profiling in Colorectal Cancer: Current Challenges in Subtyping Colorectal Cancers Based on Somatic and Germline Variants. J Anus Rectum Colon 2021; 5:213-228. [PMID: 34395933 PMCID: PMC8321592 DOI: 10.23922/jarc.2021-009] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/31/2021] [Accepted: 03/17/2021] [Indexed: 11/30/2022] Open
Abstract
Colorectal cancer (CRC) is a heterogeneous disease caused by the accumulation of multistep genetic alterations under the influence of genomic instability. Different backgrounds of genomic instability, such as chromosomal instability, microsatellite instability, hypermutated-single nucleotide variants, and genome stable-induced transformation in the colonic epithelium, can result in adenomas, adenocarcinomas, and metastatic tumors. Characterization of molecular subtypes and establishment of treatment policies based on each subtype will lead to better treatment outcomes and an improved selection of molecularly targeted agents. In Japan, cancer precision medicine has been introduced in the National Health Insurance program through the addition of the cancer genomic profiling (CGP) examination. It has also become possible to access a large amount of genomic information, including information on pathogenic somatic and germline variants, incomparable to conventional diagnostic tests. This information enables us to apply research data to clinical decision-making, benefiting patients and their healthy family members. In this article, we discuss the important molecules and signaling pathways presumed to be the driver genes of CRC progression and the signal transduction system in which they are involved. Molecular subtypes of CRC based on CGP examinations and gene expression profiles have been established in The Cancer Genome Atlas Network with the advent of next-generation sequencing technology. We will also discuss the recommended management of secondary/germline findings, pathogenic germline variants, and presumed germline pathogenic variants obtained from CGP examination and review the current challenges to better understand these data in a new era of cancer genomic medicine.
Collapse
Affiliation(s)
- Takao Hinoi
- Department of Clinical and Molecular Genetics, Hiroshima University Hospital, Hiroshima, Japan
| |
Collapse
|
|
27
|
Abstract
Colorectal cancer has served as a genetic and biological paradigm for the evolution of solid tumors, and these insights have illuminated early detection, risk stratification, prevention, and treatment principles. Employing the hallmarks of cancer framework, we provide a conceptual framework to understand how genetic alterations in colorectal cancer drive cancer cell biology properties and shape the heterotypic interactions across cells in the tumor microenvironment. This review details research advances pertaining to the genetics and biology of colorectal cancer, emerging concepts gleaned from immune and single-cell profiling, and critical advances and remaining knowledge gaps influencing the development of effective therapies for this cancer that remains a major public health burden.
Collapse
Affiliation(s)
- Jiexi Li
- Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA
| | - Xingdi Ma
- Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA
| | - Deepavali Chakravarti
- Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA
| | - Shabnam Shalapour
- Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA
| | - Ronald A DePinho
- Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA
| |
Collapse
|
|
28
|
Gaiani F, Marchesi F, Negri F, Greco L, Malesci A, de’Angelis GL, Laghi L. Heterogeneity of Colorectal Cancer Progression: Molecular Gas and Brakes. Int J Mol Sci 2021; 22:5246. [PMID: 34063506 PMCID: PMC8156342 DOI: 10.3390/ijms22105246] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2021] [Revised: 05/11/2021] [Accepted: 05/13/2021] [Indexed: 02/06/2023] Open
Abstract
The review begins with molecular genetics, which hit the field unveiling the involvement of oncogenes and tumor suppressor genes in the pathogenesis of colorectal cancer (CRC) and uncovering genetic predispositions. Then the notion of molecular phenotypes with different clinical behaviors was introduced and translated in the clinical arena, paving the way to next-generation sequencing that captured previously unrecognized heterogeneity. Among other molecular regulators of CRC progression, the extent of host immune response within the tumor micro-environment has a critical position. Translational sciences deeply investigated the field, accelerating the pace toward clinical transition, due to its strong association with outcomes. While the perturbation of gut homeostasis occurring in inflammatory bowel diseases can fuel carcinogenesis, micronutrients like vitamin D and calcium can act as brakes, and we discuss underlying molecular mechanisms. Among the components of gut microbiota, Fusobacterium nucleatum is over-represented in CRC, and may worsen patient outcome. However, any translational knowledge tracing the multifaceted evolution of CRC should be interpreted according to the prognostic and predictive frame of the TNM-staging system in a perspective of clinical actionability. Eventually, we examine challenges and promises of pharmacological interventions aimed to restrain disease progression at different disease stages.
Collapse
Affiliation(s)
- Federica Gaiani
- Department of Medicine and Surgery, University of Parma, 43126 Parma, Italy; (F.G.); (G.L.d.)
- Gastroenterology and Endoscopy Unit, University-Hospital of Parma, via Gramsci 14, 43126 Parma, Italy
| | - Federica Marchesi
- IRCCS Humanitas Research Hospital, via Manzoni 56, 20089 Rozzano, Italy; (F.M.); (A.M.)
- Department of Medical Biotechnology and Translational Medicine, University of Milan, 20132 Milan, Italy
| | - Francesca Negri
- Medical Oncology Unit, University Hospital of Parma, 43126 Parma, Italy;
| | - Luana Greco
- Laboratory of Molecular Gastroenterology, IRCCS Humanitas Research Hospital, via Manzoni 56, 20089 Rozzano, Italy;
| | - Alberto Malesci
- IRCCS Humanitas Research Hospital, via Manzoni 56, 20089 Rozzano, Italy; (F.M.); (A.M.)
- Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, 20072 Pieve Emanuele, Italy
| | - Gian Luigi de’Angelis
- Department of Medicine and Surgery, University of Parma, 43126 Parma, Italy; (F.G.); (G.L.d.)
- Gastroenterology and Endoscopy Unit, University-Hospital of Parma, via Gramsci 14, 43126 Parma, Italy
| | - Luigi Laghi
- Department of Medicine and Surgery, University of Parma, 43126 Parma, Italy; (F.G.); (G.L.d.)
- Laboratory of Molecular Gastroenterology, IRCCS Humanitas Research Hospital, via Manzoni 56, 20089 Rozzano, Italy;
| |
Collapse
|
|
29
|
Ge Y, Xiang R, Ren J, Song W, Lu W, Fu T. A Nomogram for Predicting Multiple Metastases in Metastatic Colorectal Cancer Patients: A Large Population-Based Study. Front Oncol 2021; 11:633995. [PMID: 34055605 PMCID: PMC8155489 DOI: 10.3389/fonc.2021.633995] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2020] [Accepted: 04/15/2021] [Indexed: 12/29/2022] Open
Abstract
OBJECTIVES The present study aims to discover the risk factors of multiple metastases and develop a functional nomogram to forecast multiple metastases in metastatic colorectal cancer (mCRC) patients. METHODS mCRC cases were retrospectively collected from the Surveillance, Epidemiology, and End Results (SEER) database between 2010 and 2016. Survival times between multiple metastases and single metastasis were compared using Kaplan-Meier analysis and log-rank tests. Risk factors for multiple metastases were determined by univariate and multivariate logistic regression analyses, and a nomogram was developed to forecast the probability of multiple metastases in mCRC patients. We assessed the nomogram performance in terms of discrimination and calibration, including concordance index (C-index), area under the curve (AUC), and decision curve analysis (DCA). Bootstrap resampling was used as an internal verification method, and at the same time we select external data from Renmin Hospital of Wuhan University as independent validation sets. RESULTS A total of 5,302 cases were included in this study as training group, while 120 cases were as validation group. The patients with single metastasis and multiple metastases were 3,531 and 1,771, respectively. The median overall survival (OS) and cancer-specific survival (CSS) for patients with multiple metastases or single metastasis were 19 vs. 31 months, and 20 vs. 33 months, respectively. Based on the univariate and multivariate analyses, clinicopathological characteristics were associated with number of metastasis and were used to establish nomograms to predict the risk of multiple metastases. The C-indexes and AUC for the forecast of multiple metastases were 0.715 (95% confidence interval (CI), 0.707-0.723), which showed the nomogram had good discrimination and calibration curves of the nomogram showed no significant bias from the reference line, indicating a good degree of calibration. In the validation group, the AUC was 0.734 (95% CI, 0.653-0.834), and calibration curve also showed no significant bias, indicating the favorable effects of our nomogram. CONCLUSIONS We developed a new nomogram to predict the risk of multiple metastases. The nomogram shows the good prediction effect and can provide assistance for clinical diagnosis and treatment.
Collapse
Affiliation(s)
| | | | | | | | | | - Tao Fu
- Department of Gastrointestinal Surgery II, Renmin Hospital of Wuhan University, Wuhan, China
| |
Collapse
|
|
30
|
A cytokine in turmoil: Transforming growth factor beta in cancer. Biomed Pharmacother 2021; 139:111657. [PMID: 34243626 DOI: 10.1016/j.biopha.2021.111657] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2021] [Revised: 04/09/2021] [Accepted: 04/21/2021] [Indexed: 12/11/2022] Open
Abstract
Cancer remains one of the debilitating health threats to mankind in view of its incurable nature. Many factors are complicit in the initiation, progression and establishment of cancers. Early detection of cancer is the only window of hope that allows for appreciable management and possible limited survival. However, understanding of cancer biology and knowledge of the key factors that interplay at multi-level in the initiation and progression of cancer may hold possible avenues for cancer treatment and management. In particular, dysregulation of growth factor signaling such as that of transforming growth factor beta (TGF-β) and its downstream mediators play key roles in various cancer subtypes. Expanded understanding of the context/cell type-dependent roles of TGF-β and its downstream signaling mediators in cancer may provide leads for cancer pharmacotherapy. Reliable information contained in original articles, reviews, mini-reviews and expert opinions on TGF-β, cancer and the specific roles of TGF-β signaling in various cancer subtypes were retrieved from major scientific data bases including PubMed, Scopus, Medline, Web of Science core collections just to mention but a sample by using the following search terms: TGF-β in cancer, TGF-β and colorectal cancer, TGF-β and brain cancer, TGF-β in cancer initiation, TGF-β and cell proliferation, TGF-β and cell invasion, and TGF-β-based cancer therapy. Retrieved information and reports were carefully examined, contextualized and synchronized into a coherent scientific content to highlight the multiple roles of TGF-β signaling in normal and cancerous cells. From a conceptual standpoint, development of pharmacologically active agents that exert non-specific inhibitory effects on TGF-β signaling on various cell types will undoubtedly lead to a plethora of serious side effects in view of the multi-functionality and pleiotropic nature of TGF-β. Such non-specific targeting of TGF-β could derail any beneficial therapeutic intention associated with TGF-β-based therapy. However, development of pharmacologically active agents designed specifically to target TGF-β signaling in cancer cells may improve cancer pharmacotherapy. Similarly, specific targeting of downstream mediators of TGF-β such as TGF-β type 1 and II receptors (TβRI and TβRII), receptor-mediated Smads, mitogen activated protein kinase (MAPK) and importing proteins in cancer cells may be crucial for cancer pharmacotherapy.
Collapse
|
|
31
|
Michel M, Kaps L, Maderer A, Galle PR, Moehler M. The Role of p53 Dysfunction in Colorectal Cancer and Its Implication for Therapy. Cancers (Basel) 2021; 13:2296. [PMID: 34064974 PMCID: PMC8150459 DOI: 10.3390/cancers13102296] [Citation(s) in RCA: 67] [Impact Index Per Article: 16.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Revised: 04/28/2021] [Accepted: 05/03/2021] [Indexed: 02/06/2023] Open
Abstract
Colorectal cancer (CRC) is one of the most common and fatal cancers worldwide. The carcinogenesis of CRC is based on a stepwise accumulation of mutations, leading either to an activation of oncogenes or a deactivation of suppressor genes. The loss of genetic stability triggers activation of proto-oncogenes (e.g., KRAS) and inactivation of tumor suppression genes, namely TP53 and APC, which together drive the transition from adenoma to adenocarcinoma. On the one hand, p53 mutations confer resistance to classical chemotherapy but, on the other hand, they open the door for immunotherapy, as p53-mutated tumors are rich in neoantigens. Aberrant function of the TP53 gene product, p53, also affects stromal and non-stromal cells in the tumor microenvironment. Cancer-associated fibroblasts together with other immunosuppressive cells become valuable assets for the tumor by p53-mediated tumor signaling. In this review, we address the manifold implications of p53 mutations in CRC regarding therapy, treatment response and personalized medicine.
Collapse
Affiliation(s)
- Maurice Michel
- I. Department of Medicine, University Medical Center Mainz, 55131 Mainz, Germany; (M.M.); (L.K.); (A.M.); (P.R.G.)
| | - Leonard Kaps
- I. Department of Medicine, University Medical Center Mainz, 55131 Mainz, Germany; (M.M.); (L.K.); (A.M.); (P.R.G.)
- Institute of Translational Immunology and Research Center for Immune Therapy, University Medical Center Mainz, 55131 Mainz, Germany
| | - Annett Maderer
- I. Department of Medicine, University Medical Center Mainz, 55131 Mainz, Germany; (M.M.); (L.K.); (A.M.); (P.R.G.)
| | - Peter R. Galle
- I. Department of Medicine, University Medical Center Mainz, 55131 Mainz, Germany; (M.M.); (L.K.); (A.M.); (P.R.G.)
| | - Markus Moehler
- I. Department of Medicine, University Medical Center Mainz, 55131 Mainz, Germany; (M.M.); (L.K.); (A.M.); (P.R.G.)
| |
Collapse
|
|
32
|
Abstract
BACKGROUND The influence of microsatellite instability on prognosis in high-risk stage II colon cancer is unknown. OBJECTIVE This study aimed to investigate the relationship between microsatellite instability and overall survival in high-risk stage II colon cancer. DESIGN This is a retrospective review of the National Cancer Database from 2010 to 2016. SETTINGS This study included national cancer epidemiology data from the American College of Surgeons Commission on Cancer. PATIENTS Included were 16,788 patients with stage II colon adenocarcinoma and known microsatellite status (1709 microsatellite unstable). MAIN OUTCOME MEASURES The primary outcome measured was overall survival. RESULTS Microsatellite unstable cancers with high-risk features had significantly better overall survival than microsatellite stable cancers with high-risk features (5-year survival 80% vs 72%, p = 0.01), and had survival equivalent to microsatellite stable cancers with low-risk features (5-year survival, 80%). When stratified by specific high-risk features, patients with lymphovascular invasion, perineural invasion, or high-grade histology had overall survival similar to patients without these features, only in microsatellite unstable cancers. However, patients with high-risk features of T4 stage, positive margins, and <12 lymph nodes saw no survival benefit based on microsatellite status. This was confirmed on multivariable Cox regression modeling. A subgroup analysis of patients who did not receive chemotherapy similarly demonstrated that microsatellite unstable cancers with lymphovascular invasion, perineural invasion, or high-grade histology had overall survival similar to microsatellite unstable cancers without those features. LIMITATIONS The study is limited by the lack of specific clinical data and potential treatment bias. CONCLUSIONS In microsatellite unstable cancers, lymphovascular invasion, perineural invasion, and high-grade histology are not associated with worse overall survival, even when deferring adjuvant chemotherapy. These data support National Comprehensive Cancer Network recommendations to forego chemotherapy in stage II cancers with microsatellite instability and these features. In contrast, some high-risk features were associated with worse survival despite microsatellite unstable biology, and therapies to improve survival need to be explored. See Video Abstract at http://links.lww.com/DCR/B500. ¿EL ESTADO MICROSATÉLITE ESTÁ ASOCIADO CON EL PRONÓSTICO EN EL CÁNCER DE COLON EN ESTADIO II CON CARACTERÍSTICAS DE ALTO RIESGO: Se desconoce la influencia de la inestabilidad microsatélite en el pronóstico del cáncer de colon en estadio II de alto riesgo.Investigar la relación entre la inestabilidad microsatélite y la supervivencia general en el cáncer de colon en estadio II de alto riesgo.Revisión retrospectiva de la base de datos nacional del cáncer de 2010 a 2016.Este estudio incluyó datos nacionales de epidemiología del cáncer de la Comisión de Cáncer del Colegio Americano de Cirujanos.16,788 pacientes con adenocarcinoma de colon en estadio II y estado microsatélite conocido (1,709 microsatélite inestables).Supervivencia global.Los cánceres microsatélite inestables con características de alto riesgo tuvieron una supervivencia general significativamente mejor que los cánceres microsatélite estables con características de alto riesgo (supervivencia a 5 años 80% vs 72%, p = 0.01), y tuvieron una supervivencia equivalente a los cánceres microsatélite estables con características de bajo riesgo (supervivencia a 5 años 80%). Al estratificar por características específicas de alto riesgo, los pacientes con invasión linfovascular, invasión perineural o histología de alto grado tuvieron una supervivencia general similar a la de los pacientes sin estas características, solo en cánceres microsatélite inestables. Sin embargo, los pacientes con características de alto riesgo en estadio T4, márgenes positivos y <12 ganglios linfáticos no tuvieron ningún beneficio de supervivencia basado en el estado de microsatélites. Esto se confirmó en un modelo de regresión de Cox multivariable. Un análisis de subgrupos de pacientes que no recibieron quimioterapia demostró de manera similar que los cánceres microsatélite inestables con invasión linfovascular, invasión perineural o histología de alto grado tenían una supervivencia general similar a los cánceres microsatélite inestables sin esas características.El estudio está limitado por la falta de datos clínicos específicos y el posible sesgo de tratamiento.En los cánceres microsatélite inestables, la invasión linfovascular, la invasión perineural y la histología de alto grado no se asocian con una peor sobrevida general, incluso cuando se aplaza la quimioterapia adyuvante. Estos datos respaldan las recomendaciones de la National Comprehensive Cancer Network de omitir la quimioterapia en los cánceres en estadio II con inestabilidad microsatélite y estas características. Por el contrario, algunas características de alto riesgo se asociaron con una peor supervivencia a pesar de la biología microsatélite inestable, y es necesario considerar las terapias para mejorar la supervivencia.Consulte Video Resumen en http://links.lww.com/DCR/B500. (Traducción-Dr. Jorge Silva Velazco).
Collapse
|
|
33
|
Cheng Q, Wu Y, Xia H, Song X. RGL2 as an age-dependent factor regulates colon cancer progression. Comput Struct Biotechnol J 2021; 19:2190-2201. [PMID: 33995912 PMCID: PMC8102141 DOI: 10.1016/j.csbj.2021.04.006] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2020] [Revised: 04/02/2021] [Accepted: 04/03/2021] [Indexed: 12/13/2022] Open
Abstract
Colon cancer is the fourth leading cause of cancer-related death, and exhibited clinical differences among patients of different ages, including malignancy, metastasis, and mortality rate. Few studies, however, focus on the communications between aging and colon cancer. Here we identified age-dependent differentially expressed genes (DEGs) in colon cancer using TCGA transcriptome data. Through analyzing multi-omics high throughput data, including ATAC-Seq, DNaseI-Seq and ChIP-Seq, we obtained six age-dependent transcription factors in colon cancer, and their age-dependent targets, significantly affecting patients' overall survivals. Transcription factor ETS1 potentially functioned in both aging process and colon cancer progression through regulating its targets, RGL2 and SLC2A3. In addition, comparing with its relative lower expression levels in elderly patients, higher levels of RGL2 were detected in young patients, and significantly associated with larger tumor size, higher metastasis, and invasions of colon cancer, consistent with the clinical traits that young patients' colon cancer exhibited late stages with more aggressiveness. Thus, these elements may serve as keys linking aging and colon cancer, and providing new insights and basis for mechanism researches, as well as diagnosis and therapies of colon cancer, especially in young patients.
Collapse
Affiliation(s)
- Qingyu Cheng
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230001, China
| | - Yupeng Wu
- Department of Biochemistry and Molecular Biology, School of Laboratory Medicine, Bengbu Medical College, 2600 Donghai Avenue, Bengbu, Anhui, 233030, China
| | - Honghai Xia
- Department of Emergency Medicine, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230001, China
| | - Xiaoyuan Song
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230001, China
- MOE Key Laboratory for Membraneless Organelles and Cellular Dynamics, Hefei National Laboratory for Physical Sciences at the Microscale, CAS Key Laboratory of Brain Function and Disease, School of Life Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230026, China
| |
Collapse
|
|
34
|
Wang G, Han J, Wang G, Wu X, Huang Y, Wu M, Chen Y. ERO1α mediates endoplasmic reticulum stress-induced apoptosis via microRNA-101/EZH2 axis in colon cancer RKO and HT-29 cells. Hum Cell 2021; 34:932-944. [PMID: 33559868 DOI: 10.1007/s13577-021-00494-3] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2020] [Accepted: 01/18/2021] [Indexed: 01/15/2023]
Abstract
Although colon cancer is a leading and typical gastrointestinal tumor, there is little published data on the underlying molecular mechanisms of endoplasmic reticulum (ER) stress. Here, we investigated the role of ERO1α and its impact on microRNA (miR)-101 expression and ER stress in colon cancer cells. Cell ER stress was established by treating RKO or HT-29 cells with 1 μM thapsigargin (THG). Cell biological behaviors were detected using CCK-8, bromodeoxyuridine assay, flow cytometry and western blot. We also investigated the expression of ERO1α and miR-101 after THG treatment using RT-qPCR. Moreover, effects of ERO1α and miR-101 on ER stress of colon cancer cells were detected. Additionally, miR-101 impact on EZH2 expression and relevance of this regulation was confirmed by RT-qPCR and luciferase reporter. The regulation of miR-101/EZH2 axis and Wnt/β-catenin pathway in ER stress were investigated. Our results demonstrated that THG induced ER stress in colon cancer cells. Silencing ERO1α further promoted ER stress-induced cell apoptosis. ERO1α knockdown up-regulated miR-101 expression and promoted colon cancer cell apoptosis via regulating miR-101. Surprisingly, miR-101 negatively regulated EZH2 expression via miRNA-mRNA targeting. Moreover, ER stress promoted colon cancer cell apoptosis via regulating miR-101/EZH2 axis. Wnt/β-catenin pathway was also involved in the regulation of ERO1α/miR-101/EZH2 in ER stress of colon cancer cells. These findings illustrated that silencing ERO1α regulated ER stress-induced apoptosis via miR-101/EZH2 axis in RKO and HT-29 cells.
Collapse
Affiliation(s)
- Guoqin Wang
- Cancer Biotherapy Center, The Third Affiliated Hospital of Kunming Medical University, Yunnan Cancer Hospital, Kunming, 650118, Yunnan, China
| | - Jiangqiong Han
- Integrated Traditional Chinese and Western Medicine Department, The Third Affiliated Hospital of Kunming Medical University, Yunnan Cancer Hospital, Kunming, 650118, Yunnan, China
| | - Gaowei Wang
- Cancer Biotherapy Center, The Third Affiliated Hospital of Kunming Medical University, Yunnan Cancer Hospital, Kunming, 650118, Yunnan, China
| | - Xuesong Wu
- Department Gastrointestinal Surgery, The Third Affiliated Hospital of Kunming Medical University, Kunming, 650101, Yunnan, China
| | - Youguang Huang
- Tumor Institute of Yunnan Province, The Third Affiliated Hospital of Kunming Medical University, Kunming, 650101, Yunnan, China
| | - Min Wu
- Tumor Institute of Yunnan Province, The Third Affiliated Hospital of Kunming Medical University, Kunming, 650101, Yunnan, China
| | - Yunlan Chen
- Cadre Medical Department, The Third Affiliated Hospital of Kunming Medical University, Yunnan Cancer Hospital, No. 517 Kunzhou Road, Xishan District, Kunming, 650118, Yunnan, China.
| |
Collapse
|
|
35
|
Patel MR, Falchook GS, Hamada K, Makris L, Bendell JC. A phase 2 trial of trifluridine/tipiracil plus nivolumab in patients with heavily pretreated microsatellite-stable metastatic colorectal cancer. Cancer Med 2021; 10:1183-1190. [PMID: 33544407 PMCID: PMC7926002 DOI: 10.1002/cam4.3630] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2020] [Revised: 11/11/2020] [Accepted: 11/12/2020] [Indexed: 12/29/2022] Open
Abstract
Background Microsatellite‐stable (MSS) colorectal cancer (CRC) tends to be poorly immunogenic, with limited treatment options. In MSS CRC xenograft models, trifluridine/tipiracil (FTD/TPI) plus programed death 1 inhibitors resulted in synergistic antitumor activity and increased tumor immunogenicity. This phase 2 study evaluated FTD/TPI plus nivolumab in patients with MSS metastatic CRC. Methods This single‐arm, safety lead‐in study used a Simon's two‐stage design (enrolling 6 patients in the safety lead‐in, proceeding to stage 2 if ≥2 of the first 15 patients achieved a partial or complete response per immune‐related response criteria [irRC] within 6 months). Patients with histologically proven MSS mCRC, and disease progression after ≥2 prior chemotherapy regimens received FTD/TPI (35 mg/m2 twice daily; days 1–5 and 8–12 every 28 days) plus nivolumab (3 mg/kg every 2 weeks). Results Between August 2016 and January 2017, 18 patients (50% men; median age 56.5 years) were enrolled; 72% had colon cancer and 56% had KRAS mutations. All patients received treatment (median, 2.5 cycles [range, 1–8]). No dose‐limiting toxicities were observed in the study. The most frequent adverse events (AEs) of any cause and grade were nausea (67%), diarrhea (61%), and neutropenia (50%); 13 patients (72%) experienced grade ≥3 AEs. No patients discontinued treatment because of AEs. No patient achieved a tumor response (either per Response Evaluation Criteria in Solid Tumors [RECIST] or irRC), and the study did not progress to the second stage. Stable disease was achieved in 8 patients per irRC and in 10 patients per RECIST. Median progression‐free survival was 2.2 months (95% CI, 1.8–6.0 months) per irRC and 2.8 months (95% CI, 1.8–5.1 months) per RECIST. Conclusion Patients with refractory MSS metastatic CRC failed to experience clinical benefit with FTD/TPI plus nivolumab, although safety data in this population indicated tolerability and feasibility of this combination. Trial registration number NCT02860546.
Collapse
Affiliation(s)
- Manish R Patel
- Florida Cancer Specialists and Sarah Cannon Research Institute, Sarasota, Florida, USA
| | | | | | | | - Johanna C Bendell
- Sarah Cannon Research Institute and Tennessee Oncology, Nashville, Tennessee, USA
| |
Collapse
|
|
36
|
Chen X, Sun J, Wang X, Yuan Y, Cai L, Xie Y, Fan Z, Liu K, Jiao X. A Meta-Analysis of Proteomic Blood Markers of Colorectal Cancer. Curr Med Chem 2021; 28:1176-1196. [PMID: 32338203 DOI: 10.2174/0929867327666200427094054] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2019] [Revised: 02/23/2020] [Accepted: 03/24/2020] [Indexed: 02/05/2023]
Abstract
BACKGROUND Early diagnosis will significantly improve the survival rate of colorectal cancer (CRC); however, the existing methods for CRC screening were either invasive or inefficient. There is an emergency need for novel markers in CRC's early diagnosis. Serum proteomics has gained great potential in discovering novel markers, providing markers that reflect the early stage of cancer and prognosis prediction of CRC. In this paper, the results of proteomics of CRC studies were summarized through a meta-analysis in order to obtain the diagnostic efficiency of novel markers. METHODS A systematic search on bibliographic databases was performed to collect the studies that explore blood-based markers for CRC applying proteomics. The detection and validation methods, as well as the specificity and sensitivity of the biomarkers in these studies, were evaluated. Newcastle- Ottawa Scale (NOS) case-control studies version was used for quality assessment of included studies. RESULTS Thirty-four studies were selected from 751 studies, in which markers detected by proteomics were summarized. In total, fifty-nine proteins were classified according to their biological function. The sensitivity, specificity, or AUC varied among these markers. Among them, Mammalian STE20-like protein kinase 1/ Serine threonine kinase 4 (MST1/STK4), S100 calcium-binding protein A9 (S100A9), and Tissue inhibitor of metalloproteinases 1 (TIMP1) were suitable for effect sizes merging, and their diagnostic efficiencies were recalculated after merging. MST1/STK4 obtained a sensitivity of 68% and a specificity of 78%. S100A9 achieved a sensitivity of 72%, a specificity of 83%, and an AUC of 0.88. TIMP1 obtained a sensitivity of 42%, a specificity of 88%, and an AUC of 0.71. CONCLUSION MST1/STK4, S100A9, and TIMP1 showed excellent performance for CRC detection. Several other markers also presented optimized diagnostic efficacy for CRC early detection, but further verification is still needed before they are suitable for clinical use. The discovering of more efficient markers will benefit CRC treatment.
Collapse
Affiliation(s)
- Xiang Chen
- The First Affiliated Hospital of Shantou University Medical College, Shantou, Guangdong 515041, China
| | - Jiayu Sun
- Department of Cell Biology and Genetics, Shantou University Medical College, Shantou, Guangdong 515041, China
| | - Xue Wang
- Shantou University Medical College, Shantou, Guangdong 515041, China
| | - Yumeng Yuan
- Department of Cell Biology and Genetics, Shantou University Medical College, Shantou, Guangdong 515041, China
| | - Leshan Cai
- The First Affiliated Hospital of Shantou University Medical College, Shantou, Guangdong 515041, China
| | - Yanxuan Xie
- The First Affiliated Hospital of Shantou University Medical College, Shantou, Guangdong 515041, China
| | - Zhiqiang Fan
- Department of Cell Biology and Genetics, Shantou University Medical College, Shantou, Guangdong 515041, China
| | - Kaixi Liu
- Shantou Central Hospital, Shantou, Guangdong 515041, China
| | - Xiaoyang Jiao
- Department of Cell Biology and Genetics, Shantou University Medical College, Shantou, Guangdong 515041, China
| |
Collapse
|
|
37
|
Chiavarina B, Costanza B, Ronca R, Blomme A, Rezzola S, Chiodelli P, Giguelay A, Belthier G, Doumont G, Van Simaeys G, Lacroix S, Yokobori T, Erkhem-Ochir B, Balaguer P, Cavailles V, Fabbrizio E, Di Valentin E, Gofflot S, Detry O, Jerusalem G, Goldman S, Delvenne P, Bellahcène A, Pannequin J, Castronovo V, Turtoi A. Metastatic colorectal cancer cells maintain the TGFβ program and use TGFBI to fuel angiogenesis. Theranostics 2021; 11:1626-1640. [PMID: 33408771 PMCID: PMC7778592 DOI: 10.7150/thno.51507] [Citation(s) in RCA: 50] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2020] [Accepted: 11/04/2020] [Indexed: 12/22/2022] Open
Abstract
Colorectal cancer (CRC) cells are traditionally considered unresponsive to TGFβ due to mutations in the receptors and/or downstream signaling molecules. TGFβ influences CRC cells only indirectly via stromal cells, such as cancer-associated fibroblasts. However, CRC cell ability to directly respond to TGFβ currently remains unexplored. This represents a missed opportunity for diagnostic and therapeutic interventions. Methods: We examined whether cancer cells from primary CRC and liver metastases respond to TGFβ by inducing TGFβ-induced protein ig-h3 (TGFBI) expression, and the contribution of canonical and non-canonical TGFβ signaling pathways to this effect. We then investigated in vitro and in vivo TGFBI impact on metastasis formation and angiogenesis. Using patient serum samples and an orthotopic mouse model of CRC liver metastases we assessed the diagnostic/tumor targeting value of novel antibodies against TGFBI. Results: Metastatic CRC cells, such as circulating tumor cells, directly respond to TGFβ. These cells were characterized by the absence of TGFβ receptor mutations and the frequent presence of p53 mutations. The pro-tumorigenic program orchestrated by TGFβ in CRC cells was mediated through TGFBI, the expression of which was positively regulated by non-canonical TGFβ signaling cascades. TGFBI inhibition was sufficient to significantly reduce liver metastasis formation in vivo. Moreover, TGFBI pro-tumorigenic function was linked to its ability to stimulate angiogenesis. TGFBI levels were higher in serum samples from untreated patients with CRC than in patients who were receiving chemotherapy. A radiolabeled anti-TGFBI antibody selectively targeted metastatic lesions in vivo, underscoring its diagnostic and therapeutic potential. Conclusions: TGFβ signaling in CRC cells directly contributes to their metastatic potential and stromal cell-independence. Proteins downstream of activated TGFβ, such as TGFBI, represent novel diagnostic and therapeutic targets for more specific anti-metastatic therapies.
Collapse
Affiliation(s)
- Barbara Chiavarina
- Cancer Research Institute of Montpellier, Tumor Microenvironment and Resistance to Treatment Laboratory, INSERM U1194, Montpellier, France
- Institut National de la Santé et de la Recherche Médicale, Montpellier, France
- Institut du Cancer de Montpellier, Montpellier, France
- Université de Montpellier, Montpellier, France
| | - Brunella Costanza
- Metastasis Research Laboratory, GIGA Cancer, University of Liège, Liège, Belgium
| | - Roberto Ronca
- University of Brescia, Department of Molecular and Translational Medicine, Brescia, Italy
| | - Arnaud Blomme
- Metastasis Research Laboratory, GIGA Cancer, University of Liège, Liège, Belgium
| | - Sara Rezzola
- University of Brescia, Department of Molecular and Translational Medicine, Brescia, Italy
| | - Paola Chiodelli
- University of Brescia, Department of Molecular and Translational Medicine, Brescia, Italy
| | - Ambre Giguelay
- Cancer Research Institute of Montpellier, Tumor Microenvironment and Resistance to Treatment Laboratory, INSERM U1194, Montpellier, France
- Institut National de la Santé et de la Recherche Médicale, Montpellier, France
- Institut du Cancer de Montpellier, Montpellier, France
- Université de Montpellier, Montpellier, France
- Cancer Research Institute of Montpellier, Cancer Bioinformatics and Systems Biology Team, INSERM U1194, Montpellier, France
| | - Guillame Belthier
- Institut National de la Santé et de la Recherche Médicale, Montpellier, France
- Université de Montpellier, Montpellier, France
- Institut de Génomique Fonctionnelle, Montpellier, France
- Centre National de la Recherche Scientifique, Montpellier, France
| | - Gilles Doumont
- Center for Microscopy and Molecular Imaging (CMMI), Université libre de Bruxelles (ULB), rue Adrienne Bolland 8, B-6041 Charleroi (Gosselies), Belgium
| | - Gaetan Van Simaeys
- Center for Microscopy and Molecular Imaging (CMMI), Université libre de Bruxelles (ULB), rue Adrienne Bolland 8, B-6041 Charleroi (Gosselies), Belgium
- Nuclear Medicine department, ULB Hôpital Érasme, route de Lennik 808, B-1070 Brussels, Belgium
| | - Simon Lacroix
- Center for Microscopy and Molecular Imaging (CMMI), Université libre de Bruxelles (ULB), rue Adrienne Bolland 8, B-6041 Charleroi (Gosselies), Belgium
- Nuclear Medicine department, ULB Hôpital Érasme, route de Lennik 808, B-1070 Brussels, Belgium
| | - Takehiko Yokobori
- Gunma University Initiative for Advanced Research, International Open Laboratory, Universities of Liege and Montpellier Laboratory, Gunma University, Gunma, Japan
| | - Bilguun Erkhem-Ochir
- Gunma University Initiative for Advanced Research, International Open Laboratory, Universities of Liege and Montpellier Laboratory, Gunma University, Gunma, Japan
| | - Patrick Balaguer
- Institut National de la Santé et de la Recherche Médicale, Montpellier, France
- Institut du Cancer de Montpellier, Montpellier, France
- Université de Montpellier, Montpellier, France
- Cancer Research Institute of Montpellier, Hormone Signaling and Cancer Laboratory, Montpellier, France
| | - Vincent Cavailles
- Institut National de la Santé et de la Recherche Médicale, Montpellier, France
- Institut du Cancer de Montpellier, Montpellier, France
- Université de Montpellier, Montpellier, France
- Cancer Research Institute of Montpellier, Hormone Signaling and Cancer Laboratory, Montpellier, France
| | - Eric Fabbrizio
- Institut National de la Santé et de la Recherche Médicale, Montpellier, France
- Institut du Cancer de Montpellier, Montpellier, France
- Université de Montpellier, Montpellier, France
- Cancer Research Institute of Montpellier, Oncogenic Pathways in Cancer Laboratory, INSERM U1194, Montpellier, France
| | | | | | - Olivier Detry
- Department of Abdominal Surgery, University Hospital, University of Liège, Liège, Belgium
| | - Guy Jerusalem
- Department of Medical Oncology, University Hospital, University of Liège, Liège, Belgium
| | - Serge Goldman
- Center for Microscopy and Molecular Imaging (CMMI), Université libre de Bruxelles (ULB), rue Adrienne Bolland 8, B-6041 Charleroi (Gosselies), Belgium
- Nuclear Medicine department, ULB Hôpital Érasme, route de Lennik 808, B-1070 Brussels, Belgium
| | - Philippe Delvenne
- Department of Pathology, University Hospital, University of Liège, Liège, Belgium
| | - Akeila Bellahcène
- Metastasis Research Laboratory, GIGA Cancer, University of Liège, Liège, Belgium
| | - Julie Pannequin
- Institut National de la Santé et de la Recherche Médicale, Montpellier, France
- Université de Montpellier, Montpellier, France
- Institut de Génomique Fonctionnelle, Montpellier, France
- Centre National de la Recherche Scientifique, Montpellier, France
| | - Vincent Castronovo
- Metastasis Research Laboratory, GIGA Cancer, University of Liège, Liège, Belgium
| | - Andrei Turtoi
- Cancer Research Institute of Montpellier, Tumor Microenvironment and Resistance to Treatment Laboratory, INSERM U1194, Montpellier, France
- Institut National de la Santé et de la Recherche Médicale, Montpellier, France
- Institut du Cancer de Montpellier, Montpellier, France
- Université de Montpellier, Montpellier, France
- Gunma University Initiative for Advanced Research, International Open Laboratory, Universities of Liege and Montpellier Laboratory, Gunma University, Gunma, Japan
| |
Collapse
|
|
38
|
Identification of 5-Gene Signature Improves Lung Adenocarcinoma Prognostic Stratification Based on Differential Expression Invasion Genes of Molecular Subtypes. BIOMED RESEARCH INTERNATIONAL 2020; 2020:8832739. [PMID: 33490259 PMCID: PMC7790577 DOI: 10.1155/2020/8832739] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/05/2020] [Revised: 11/25/2020] [Accepted: 12/13/2020] [Indexed: 12/11/2022]
Abstract
Background The acquisition of invasive tumor cell behavior is considered to be the cornerstone of the metastasis cascade. Thus, genetic markers associated with invasiveness can be stratified according to patient prognosis. In this study, we aimed to identify an invasive genetic trait and study its biological relevance in lung adenocarcinoma. Methods 250 TCGA patients with lung adenocarcinoma were used as the training set, and the remaining 250 TCGA patients, 500 ALL TCGA patients, 226 patients with GSE31210, 83 patients with GSE30219, and 127 patients with GSE50081 were used as the verification data sets. Subtype classification of all TCGA lung adenocarcinoma samples was based on invasion-associated genes using the R package ConsensusClusterPlus. Kaplan-Meier curves, LASSO (least absolute contraction and selection operator) method, and univariate and multivariate Cox analysis were used to develop a molecular model for predicting survival. Results As a consequence, two molecular subtypes for LUAD were first identified from all TCGA all data sets which were significant on survival time. C1 subtype with poor prognosis has higher clinical characteristics of malignancy, higher mutation frequency of KRAS and TP53, and a lower expression of immune regulatory molecules. 2463 differentially expressed invasion genes between C1 and C2 subtypes were obtained, including 580 upregulation genes and 1883 downregulation genes. Functional enrichment analysis found that upregulated genes were associated with the development of tumor pathways, while downregulated genes were more associated with immunity. Furthermore, 5-invasion gene signature was constructed based on 2463 genes, which was validated in four data sets. This signature divided patients into high-risk and low-risk groups, and the LUDA survival rate of the high-risk group is significantly lower than that of the low-risk group. Multivariate Cox analysis revealed that this gene signature was an independent prognostic factor for LUDA. Compared with other existing models, our model has a higher AUC. Conclusion In this study, two subtypes were identified. In addition, we developed a 5-gene signature prognostic risk model, which has a good AUC in the training set and independent validation set and is a model with independent clinical characteristics. Therefore, we recommend using this classifier as a molecular diagnostic test to assess the prognostic risk of patients with LUDA.
Collapse
|
|
39
|
Tian X, Zhu X, Meng W, Bai S, Shi M, Xiang S, Zhao C, Wang Y. A 12-immune cell signature to predict relapse and guide chemotherapy for stage II colorectal cancer. Aging (Albany NY) 2020; 12:18363-18383. [PMID: 32855365 PMCID: PMC7585080 DOI: 10.18632/aging.103707] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2020] [Accepted: 07/06/2020] [Indexed: 01/24/2023]
Abstract
The management of stage II colorectal cancer is still difficult. We aimed to construct a new immune cell-associated signature for prognostic evaluation and guiding chemotherapy in stage II colorectal cancer. We used the "Cell Type Identification by Estimating Relative Subsets of RNA Transcripts" (CIBERSORT) method to estimate the fraction of 22 immune cells by analyzing bulk tumor transcriptomes and a LASSO Cox regression model to select the prognostic immune cells. A 12-immune cell prognostic classifier, ISCRC, was built, which could successfully discriminate the high-risk patients in the training cohort (GSE39582: HR = 3.16, 95% CI: 1.85-5.40, P < 0.0001) and another independent cohorts (GSE14333: HR = 3.47, 95% CI: 1.18-10.15, P =0.0167). The receiver operating characteristic analysis revealed that the AUC of the ISCRC model was significantly greater than that of oncotypeDX model (0.7111 versus 0.5647, p=0.0152). We introduced the propensity score matching analysis to eliminate the selection bias; survival analysis showed relatively poor prognosis after chemotherapy in stage II CRC patients. Furthermore, a nomogram was built for clinicians and did well in the calibration plots. In conclusion, this immune cell-based signature could improve prognostic prediction and may help guide chemotherapy in stage II colorectal cancer patients.
Collapse
Affiliation(s)
- Xianglong Tian
- Department of Gastroenterology, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xiaoqiang Zhu
- School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pok Fu Lam, Hong Kong SAR, China
| | - Wenying Meng
- Department of Gastroenterology, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Shiguang Bai
- Department of Internal Medicine, People's Hospital of Jinping County, Yunnan Province, China
| | - Min Shi
- Department of Gastroenterology, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Shihao Xiang
- Department of Gastroenterology, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Chen Zhao
- Department of Gastroenterology, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yugang Wang
- Department of Gastroenterology, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| |
Collapse
|
|
40
|
Mukherji R, Marshall JL, Seeber A. Genomic Alterations and Their Implications on Survival in Nonmetastatic Colorectal Cancer: Status Quo and Future Perspectives. Cancers (Basel) 2020; 12:E2001. [PMID: 32707813 PMCID: PMC7465976 DOI: 10.3390/cancers12082001] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2020] [Revised: 07/17/2020] [Accepted: 07/18/2020] [Indexed: 02/08/2023] Open
Abstract
The selection of treatment according to genomic alterations is a standard approach in metastatic colorectal cancer but is only starting to have an impact in the earlier stages of the disease. The status if genes like KRAS, BRAF, and MMR has substantial survival implications, and concerted research efforts have revolutionized treatment towards precision oncology. In contrast, a genomic-based approach has not changed the adjuvant setting after curative tumor-resection in the daily routine so far. This review focuses on the current knowledge regarding prognostic and predictive genomic biomarkers in patients with locally advanced nonmetastasized colorectal cancer. Furthermore, we provide an outlook on future challenges for a personalized adjuvant treatment approach in patients with colorectal cancer.
Collapse
Affiliation(s)
- Reetu Mukherji
- Ruesch Center for The Cure of Gastrointestinal Cancers, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC 20057, USA;
| | - John L. Marshall
- Ruesch Center for The Cure of Gastrointestinal Cancers, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC 20057, USA;
| | - Andreas Seeber
- Department of Hematology and Oncology, Comprehensive Cancer Center Innsbruck, Medical University of Innsbruck, Innsbruck A-6020, Austria;
| |
Collapse
|
|
41
|
Discovery of a novel selective water-soluble SMAD3 inhibitor as an antitumor agent. Bioorg Med Chem Lett 2020; 30:127396. [PMID: 32738967 DOI: 10.1016/j.bmcl.2020.127396] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2020] [Revised: 07/02/2020] [Accepted: 07/06/2020] [Indexed: 12/18/2022]
Abstract
Targeting the SMAD3 protein is an attractive therapeutic strategy for treating cancer, as it avoids the potential toxicities due to targeting the TGF-β signaling pathway upstream. Compound SIS3 was the first selective SMAD3 inhibitor developed that had acceptable activity, but its poor water solubility limited its development. Here, a series of SIS3 analogs was created to investigate the structure-activity relationship for inhibiting the activation of SMAD3. On the basis of this SAR, further optimization generated a water-soluble compound, 16d, which was capable of effectively blocking SMAD3 activation in vitro and had similar NK cell-mediated anticancer effects in vivo to its parent SIS3. This study not only provided a preferable lead compound, 16d, for further drug discovery or a potential tool to study SMAD3 biology, but also proved the effectiveness of our strategy for water-solubility driven optimization.
Collapse
|
|
42
|
Erbs E, Rafaelsen SR, Lindebjerg J, Jensen LH, Hansen TF. The impact of mismatch repair status to the preoperative staging of colon cancer: implications for clinical management. COLORECTAL CANCER 2020. [DOI: 10.2217/crc-2020-0001] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
Aims: We sought to investigate if mismatch repair (MMR) status influences the preoperative staging of local colon cancer. Methods: Data from 590 patients in the Danish Colorectal Cancer Group national clinical database who were operated on for stage I-III colon cancer in 2010-15 were included. MMR status was determined by immunohistochemistry. Results: 22.9% had deficient(d) MMR tumors. Correlation of the clinical and pathological T-category was significant for both groups. The correlation of pre- and postoperative N-category was inferior (p >0.05) in dMMR cancers compared to a significant (p <0.01) correlation in proficient MMR cancers. 64.8% of dMMR tumors assessed node-positive demonstrated no sign of metastatic involvement at the postoperative assessment. Conclusion: MMR status seems to impact the accuracy of preoperative lymph node staging.
Collapse
Affiliation(s)
- Emilie Erbs
- Danish Colorectal Cancer Center South, Vejle Hospital, Institute of Regional Health Research, University of Southern Denmark, Vejle 7100, Denmark
| | - Søren Rafael Rafaelsen
- Danish Colorectal Cancer Center South, Vejle Hospital, Institute of Regional Health Research, University of Southern Denmark, Vejle 7100, Denmark
| | - Jan Lindebjerg
- Danish Colorectal Cancer Center South, Vejle Hospital, Institute of Regional Health Research, University of Southern Denmark, Vejle 7100, Denmark
| | - Lars Henrik Jensen
- Danish Colorectal Cancer Center South, Vejle Hospital, Institute of Regional Health Research, University of Southern Denmark, Vejle 7100, Denmark
| | - Torben Frøstrup Hansen
- Danish Colorectal Cancer Center South, Vejle Hospital, Institute of Regional Health Research, University of Southern Denmark, Vejle 7100, Denmark
| |
Collapse
|
|
43
|
Circulating Tumor DNA as a Novel Biomarker Optimizing Chemotherapy for Colorectal Cancer. Cancers (Basel) 2020; 12:cancers12061566. [PMID: 32545750 PMCID: PMC7352651 DOI: 10.3390/cancers12061566] [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: 05/20/2020] [Revised: 06/10/2020] [Accepted: 06/12/2020] [Indexed: 12/22/2022] Open
Abstract
Liquid biopsy is a minimally invasive method for detecting soluble factors, including circulating tumor DNA (ctDNA), in body fluids. ctDNA carrying tumor-specific genetic or epigenetic alterations is released into circulation from tumor cells. ctDNA in the plasma contains somatic mutations that have occurred in the tumor, and reflects tumor progression and therapeutic effects promptly and accurately. Furthermore, ctDNA is useful for early detection of recurrence and estimation of prognosis and may be utilized for diagnosis and personalized medicine for treatment selection. Thus, in the near future, it will be possible to select the most appropriate treatment based on real-time genetic information using ctDNA.
Collapse
|
|
44
|
Koulis C, Yap R, Engel R, Jardé T, Wilkins S, Solon G, Shapiro JD, Abud H, McMurrick P. Personalized Medicine-Current and Emerging Predictive and Prognostic Biomarkers in Colorectal Cancer. Cancers (Basel) 2020; 12:cancers12040812. [PMID: 32231042 PMCID: PMC7225926 DOI: 10.3390/cancers12040812] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2020] [Revised: 03/24/2020] [Accepted: 03/24/2020] [Indexed: 12/12/2022] Open
Abstract
Colorectal cancer (CRC) is the third most common cancer diagnosed worldwide and is heterogeneous both morphologically and molecularly. In an era of personalized medicine, the greatest challenge is to predict individual response to therapy and distinguish patients likely to be cured with surgical resection of tumors and systemic therapy from those resistant or non-responsive to treatment. Patients would avoid futile treatments, including clinical trial regimes and ultimately this would prevent under- and over-treatment and reduce unnecessary adverse side effects. In this review, the potential of specific biomarkers will be explored to address two key questions—1) Can the prognosis of patients that will fare well or poorly be determined beyond currently recognized prognostic indicators? and 2) Can an individual patient’s response to therapy be predicted and those who will most likely benefit from treatment/s be identified? Identifying and validating key prognostic and predictive biomarkers and an understanding of the underlying mechanisms of drug resistance and toxicity in CRC are important steps in order to personalize treatment. This review addresses recent data on biological prognostic and predictive biomarkers in CRC. In addition, patient cohorts most likely to benefit from currently available systemic treatments and/or targeted therapies are discussed in this review.
Collapse
Affiliation(s)
- Christine Koulis
- Cabrini Monash University Department of Surgery, Cabrini Health, Malvern 3144, VIC, Australia; (R.Y.); (R.E.); (S.W.); (G.S.); (P.M.)
- Correspondence: ; Tel.: +61-03-9508-3547
| | - Raymond Yap
- Cabrini Monash University Department of Surgery, Cabrini Health, Malvern 3144, VIC, Australia; (R.Y.); (R.E.); (S.W.); (G.S.); (P.M.)
| | - Rebekah Engel
- Cabrini Monash University Department of Surgery, Cabrini Health, Malvern 3144, VIC, Australia; (R.Y.); (R.E.); (S.W.); (G.S.); (P.M.)
- Department of Anatomy and Developmental Biology, Monash University, Clayton 3800, VIC, Australia; (T.J.); (H.A.)
- Monash Biomedicine Discovery Institute, Stem Cells and Development Program, Monash University, Clayton 3800, VIC, Australia
| | - Thierry Jardé
- Department of Anatomy and Developmental Biology, Monash University, Clayton 3800, VIC, Australia; (T.J.); (H.A.)
- Monash Biomedicine Discovery Institute, Stem Cells and Development Program, Monash University, Clayton 3800, VIC, Australia
- Centre for Cancer Research, Hudson Institute of Medical Research, Clayton 3168, VIC, Australia
| | - Simon Wilkins
- Cabrini Monash University Department of Surgery, Cabrini Health, Malvern 3144, VIC, Australia; (R.Y.); (R.E.); (S.W.); (G.S.); (P.M.)
- Department of Epidemiology and Preventive Medicine, Monash University, Melbourne 3000, VIC, Australia
| | - Gemma Solon
- Cabrini Monash University Department of Surgery, Cabrini Health, Malvern 3144, VIC, Australia; (R.Y.); (R.E.); (S.W.); (G.S.); (P.M.)
| | - Jeremy D. Shapiro
- Cabrini Haematology and Oncology Centre, Cabrini Health, Malvern 3144, VIC, Australia;
| | - Helen Abud
- Department of Anatomy and Developmental Biology, Monash University, Clayton 3800, VIC, Australia; (T.J.); (H.A.)
- Monash Biomedicine Discovery Institute, Stem Cells and Development Program, Monash University, Clayton 3800, VIC, Australia
| | - Paul McMurrick
- Cabrini Monash University Department of Surgery, Cabrini Health, Malvern 3144, VIC, Australia; (R.Y.); (R.E.); (S.W.); (G.S.); (P.M.)
| |
Collapse
|
|
45
|
Whole genome analysis identifies the association of TP53 genomic deletions with lower survival in Stage III colorectal cancer. Sci Rep 2020; 10:5009. [PMID: 32193467 PMCID: PMC7081316 DOI: 10.1038/s41598-020-61643-6] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2019] [Accepted: 02/19/2020] [Indexed: 11/13/2022] Open
Abstract
DNA copy number aberrations (CNA) are frequently observed in colorectal cancers (CRC). There is an urgent need for CNA-based biomarkers in clinics,. n For Stage III CRC, if combined with imaging or pathologic evidence, these markers promise more precise care. We conducted this Stage III specific biomarker discovery with a cohort of 134 CRCs, and with a newly developed high-efficiency CNA profiling protocol. Specifically, we developed the profiling protocol for tumor-normal matched tissue samples based on low-coverage clinical whole-genome sequencing (WGS). We demonstrated the protocol’s accuracy and robustness by a systematic benchmark with microarray, high-coverage whole-exome and -genome approaches, where the low-coverage WGS-derived CNA segments were highly accordant (PCC >0.95) with those derived from microarray, and they were substantially less variable if compared to exome-derived segments. A lasso-based model and multivariate cox regression analysis identified a chromosome 17p loss, containing the TP53 tumor suppressor gene, that was significantly associated with reduced survival (P = 0.0139, HR = 1.688, 95% CI = [1.112–2.562]), which was validated by an independent cohort of 187 Stage III CRCs. In summary, this low-coverage WGS protocol has high sensitivity, high resolution and low cost and the identified 17p-loss is an effective poor prognosis marker for Stage III patients.
Collapse
|
|
46
|
Auslander N, Wolf YI, Koonin EV. Interplay between DNA damage repair and apoptosis shapes cancer evolution through aneuploidy and microsatellite instability. Nat Commun 2020; 11:1234. [PMID: 32144251 PMCID: PMC7060240 DOI: 10.1038/s41467-020-15094-2] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2019] [Accepted: 02/14/2020] [Indexed: 02/07/2023] Open
Abstract
Driver mutations and chromosomal aneuploidy are major determinants of tumorigenesis that exhibit complex relationships. Here, we identify associations between driver mutations and chromosomal aberrations that define two tumor clusters, with distinct regimes of tumor evolution underpinned by unique sets of mutations in different components of DNA damage response. Gastrointestinal and endometrial tumors comprise a separate cluster for which chromosomal-arm aneuploidy and driver mutations are mutually exclusive. The landscape of driver mutations in these tumors is dominated by mutations in DNA repair genes that are further linked to microsatellite instability. The rest of the cancer types show a positive association between driver mutations and aneuploidy, and a characteristic set of mutations that involves primarily genes for components of the apoptotic machinery. The distinct sets of mutated genes derived here show substantial prognostic power and suggest specific vulnerabilities of different cancers that might have therapeutic potential.
Collapse
Affiliation(s)
- Noam Auslander
- National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, MD, 20894, USA.
| | - Yuri I Wolf
- National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, MD, 20894, USA
| | - Eugene V Koonin
- National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, MD, 20894, USA.
| |
Collapse
|
|
47
|
Wong CK, Lambert AW, Ozturk S, Papageorgis P, Lopez D, Shen N, Sen Z, Abdolmaleky HM, Győrffy B, Feng H, Thiagalingam S. Targeting RICTOR Sensitizes SMAD4-Negative Colon Cancer to Irinotecan. Mol Cancer Res 2020; 18:414-423. [PMID: 31932471 DOI: 10.1158/1541-7786.mcr-19-0525] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2019] [Revised: 11/04/2019] [Accepted: 12/16/2019] [Indexed: 12/15/2022]
Abstract
Deciphering molecular targets to enhance sensitivity to chemotherapy is becoming a priority for effectively treating cancers. Loss of function mutations of SMAD4 in colon cancer are associated with metastatic progression and resistance to 5-fluorouracil (5-FU), the most extensively used drug of almost all chemotherapy combinations used in the treatment of metastatic colon cancer. Here, we report that SMAD4 deficiency also confers resistance to irinotecan, another common chemotherapeutic frequently used alone or in combination with 5-FU against colon cancer. Mechanistically, we find that SMAD4 interacts with and inhibits RICTOR, a component of the mTORC2 complex, resulting in suppression of downstream effector phosphorylation of AKT at Serine 473. In silico meta-analysis of publicly available gene expression datasets derived from tumors indicates that lower levels of SMAD4 or higher levels of RICTOR/AKT, irrespective of the SMAD4 status, correlate with poor survival, suggesting them as strong prognostic biomarkers and targets for therapeutic intervention. Moreover, we find that overexpression of SMAD4 or depletion of RICTOR suppresses AKT signaling and increases sensitivity to irinotecan in SMAD4-deficient colon cancer cells. Consistent with these observations, pharmacologic inhibition of AKT sensitizes SMAD4-negative colon cancer cells to irinotecan in vitro and in vivo. Overall, our study suggests that hyperactivation of the mTORC2 pathway is a therapeutic vulnerability that could be exploited to sensitize SMAD4-negative colon cancer to irinotecan. IMPLICATIONS: Hyperactivation of the mTORC2 pathway in SMAD4-negative colon cancer provides a mechanistic rationale for targeted inhibition of mTORC2 or AKT as a distinctive combinatorial therapeutic opportunity with chemotherapy for colon cancer.
Collapse
Affiliation(s)
- Chen Khuan Wong
- Graduate Program in Genetics and Genomics, Boston University School of Medicine, Boston, Massachusetts.,Biomedical Genetics Section, Department of Medicine, Boston University School of Medicine, Boston, Massachusetts
| | - Arthur W Lambert
- Graduate Program in Molecular and Translational Medicine, Boston University School of Medicine, Boston, Massachusetts
| | - Sait Ozturk
- Graduate Program in Molecular and Translational Medicine, Boston University School of Medicine, Boston, Massachusetts
| | - Panagiotis Papageorgis
- Department of Life Sciences, School of Sciences, European University Cyprus, Nicosia, Cyprus
| | - Delia Lopez
- Graduate Program in Molecular and Translational Medicine, Boston University School of Medicine, Boston, Massachusetts
| | - Ning Shen
- Department of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Boston, Massachusetts
| | - Zaina Sen
- Biomedical Genetics Section, Department of Medicine, Boston University School of Medicine, Boston, Massachusetts
| | - Hamid M Abdolmaleky
- Biomedical Genetics Section, Department of Medicine, Boston University School of Medicine, Boston, Massachusetts
| | - Balázs Győrffy
- MTA TTK Lendület Cancer Biomarker Research Group, Institute of Enzymology, Budapest, Hungary.,Semmelweis University 2nd Department of Pediatrics, Budapest, Hungary
| | - Hui Feng
- Department of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Boston, Massachusetts
| | - Sam Thiagalingam
- Graduate Program in Genetics and Genomics, Boston University School of Medicine, Boston, Massachusetts. .,Biomedical Genetics Section, Department of Medicine, Boston University School of Medicine, Boston, Massachusetts.,Graduate Program in Molecular and Translational Medicine, Boston University School of Medicine, Boston, Massachusetts.,Department of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Boston, Massachusetts.,Department of Pathology and Laboratory Medicine, Boston University School of Medicine, Boston, Massachusetts
| |
Collapse
|
|
48
|
Mo S, Cai X, Zhou Z, Li Y, Hu X, Ma X, Zhang L, Cai S, Peng J. Nomograms for predicting specific distant metastatic sites and overall survival of colorectal cancer patients: A large population-based real-world study. Clin Transl Med 2020; 10:169-181. [PMID: 32508027 PMCID: PMC7240852 DOI: 10.1002/ctm2.20] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2020] [Revised: 03/19/2020] [Accepted: 03/20/2020] [Indexed: 01/04/2023] Open
Abstract
BACKGROUND This study aims to develop functional nomograms to predict specific distant metastatic sites and overall survival (OS) of colorectal cancer (CRC) patients. METHODS CRC case data were retrospectively recruited from a large population-based public dataset. Nomograms were developed to predict the probabilities of specific distant metastatic sites and OS of CRC patients. The performance of nomogram was evaluated with the concordance index (C-index), calibration curves, area under the curve (AUC), and decision curve analysis (DCA). RESULTS A total of 142 343 cases were included in the current study. On the basis of univariate and multivariate analyses, clinicopathological features were correlated with specific distant metastatic sites and survival outcomes and were used to establish nomograms. The nomograms showed excellent accuracy in predicting specific distant metastatic sites. The C-indexes for the prediction of liver, lung, bone, and brain metastases were 0.82 (95% confidence interval (CI), 0.81-0.83), 0.80 (95% CI, 0.78-0.81), 0.83 (95% CI, 0.79-0.86), and 0.73 (95% CI, 0.72-0.84), respectively. Then, a prognostic nomogram integrating clinicopathological features and specific distant metastatic sites was established to predict 1-, 3-, and 5-year OS of CRC, with AUCs of 0.764 (95% CI, 0.741-0.783), 0.762 (95% CI, 0.745-0.781), and 0.745 (95% CI, 0.730-0.761), respectively. DCA showed that the prognostic nomogram had a better clinical application value than current TNM staging system. CONCLUSIONS Based on clinicopathological features, original nomograms were constructed for clinicians to predict specific distant metastatic sites and OS of CRC patients. These models could help to support the postoperative personalized assessment.
Collapse
Affiliation(s)
- Shaobo Mo
- Department of Colorectal SurgeryFudan University Shanghai Cancer CenterShanghaiChina
- Department of Oncology, Shanghai Medical CollegeFudan UniversityShanghaiChina
| | - Xin Cai
- Department of Radiation OncologyShanghai Proton and Heavy Ion CenterShanghaiChina
- Shanghai Engineering Research Center of Proton and Heavy Ion Radiation TherapyShanghaiChina
| | - Zheng Zhou
- Department of Colorectal SurgeryFudan University Shanghai Cancer CenterShanghaiChina
- Department of Oncology, Shanghai Medical CollegeFudan UniversityShanghaiChina
| | - Yaqi Li
- Department of Colorectal SurgeryFudan University Shanghai Cancer CenterShanghaiChina
- Department of Oncology, Shanghai Medical CollegeFudan UniversityShanghaiChina
| | - Xiang Hu
- Department of Colorectal SurgeryFudan University Shanghai Cancer CenterShanghaiChina
- Department of Oncology, Shanghai Medical CollegeFudan UniversityShanghaiChina
| | - Xiaoji Ma
- Department of Colorectal SurgeryFudan University Shanghai Cancer CenterShanghaiChina
- Department of Oncology, Shanghai Medical CollegeFudan UniversityShanghaiChina
| | - Long Zhang
- Department of Colorectal SurgeryFudan University Shanghai Cancer CenterShanghaiChina
- Department of Cancer InstituteFudan University Shanghai Cancer CenterFudan UniversityShanghaiChina
| | - Sanjun Cai
- Department of Colorectal SurgeryFudan University Shanghai Cancer CenterShanghaiChina
- Department of Oncology, Shanghai Medical CollegeFudan UniversityShanghaiChina
| | - Junjie Peng
- Department of Colorectal SurgeryFudan University Shanghai Cancer CenterShanghaiChina
- Department of Oncology, Shanghai Medical CollegeFudan UniversityShanghaiChina
| |
Collapse
|
|
49
|
Zhou Z, Mo S, Dai W, Xiang W, Han L, Li Q, Wang R, Liu L, Zhang L, Cai S, Cai G. Prognostic nomograms for predicting cause-specific survival and overall survival of stage I-III colon cancer patients: a large population-based study. Cancer Cell Int 2019; 19:355. [PMID: 31889907 PMCID: PMC6935115 DOI: 10.1186/s12935-019-1079-4] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2019] [Accepted: 12/17/2019] [Indexed: 02/07/2023] Open
Abstract
Background The purpose of this study was to build functional nomograms based on significant clinicopathological features to predict cause-specific survival (CSS) and overall survival (OS) in patients with stage I–III colon cancer. Methods Data on patients diagnosed with stage I–III colon cancer between 2010 and 2015 were downloaded from the Surveillance, Epidemiology, and End Results (SEER) database. Univariate and multivariate Cox analyses were used to identify independent prognostic factors, which were used to construct nomograms to predict the probabilities of CSS and OS. The performance of the nomogram was assessed by C-indexes, receiver operating characteristic (ROC) curves and calibration curves. Decision curve analysis (DCA) was used to compare clinical usage between the nomogram and the tumor–node–metastasis (TNM) staging system. Results Based on the univariate and multivariate analyses, features that correlated with survival outcomes were used to establish nomograms for CSS and OS prediction. The nomograms showed favorable sensitivity at predicting 1-, 3-, and 5-year CSS and OS, with a C-index of 0.78 (95% confidence interval (CI) 0.77–0.80) for CSS and 0.74 (95% CI 0.73–0.75) for OS. Calibration curves and ROC curves revealed excellent predictive accuracy. The clinically and statistically significant prognostic performance of the nomogram generated with the entire group of patients and risk scores was validated by a stratified analysis. DCA showed that the nomograms were more clinically useful than TNM stage. Conclusion Novel nomograms based on significant clinicopathological characteristics were developed and can be used as a tool for clinicians to predict CSS and OS in stage I–III colon cancer patients. These models could help facilitate a personalized postoperative evaluation.
Collapse
Affiliation(s)
- Zheng Zhou
- 1Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, 270 Dong'an Road, Shanghai, 200032 China.,2Department of Oncology, Shanghai Medical College, Fudan University, 270 Dong'an Road, Shanghai, 200032 China
| | - Shaobo Mo
- 1Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, 270 Dong'an Road, Shanghai, 200032 China.,2Department of Oncology, Shanghai Medical College, Fudan University, 270 Dong'an Road, Shanghai, 200032 China
| | - Weixing Dai
- 1Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, 270 Dong'an Road, Shanghai, 200032 China.,2Department of Oncology, Shanghai Medical College, Fudan University, 270 Dong'an Road, Shanghai, 200032 China
| | - Wenqiang Xiang
- 1Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, 270 Dong'an Road, Shanghai, 200032 China.,2Department of Oncology, Shanghai Medical College, Fudan University, 270 Dong'an Road, Shanghai, 200032 China
| | - Lingyu Han
- 1Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, 270 Dong'an Road, Shanghai, 200032 China.,2Department of Oncology, Shanghai Medical College, Fudan University, 270 Dong'an Road, Shanghai, 200032 China
| | - Qingguo Li
- 1Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, 270 Dong'an Road, Shanghai, 200032 China.,2Department of Oncology, Shanghai Medical College, Fudan University, 270 Dong'an Road, Shanghai, 200032 China
| | - Renjie Wang
- 1Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, 270 Dong'an Road, Shanghai, 200032 China.,2Department of Oncology, Shanghai Medical College, Fudan University, 270 Dong'an Road, Shanghai, 200032 China
| | - Lu Liu
- 4School of Foreign Languages and Cultures, Chongqing University, Chongqing, 401331 China
| | - Long Zhang
- 1Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, 270 Dong'an Road, Shanghai, 200032 China.,Department of Cancer Institute, Fudan University Shanghai Cancer Center, Fudan University, Shanghai, 200032 China
| | - Sanjun Cai
- 1Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, 270 Dong'an Road, Shanghai, 200032 China.,2Department of Oncology, Shanghai Medical College, Fudan University, 270 Dong'an Road, Shanghai, 200032 China
| | - Guoxiang Cai
- 1Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, 270 Dong'an Road, Shanghai, 200032 China.,2Department of Oncology, Shanghai Medical College, Fudan University, 270 Dong'an Road, Shanghai, 200032 China
| |
Collapse
|
|
50
|
Promising Colorectal Cancer Biomarkers for Precision Prevention and Therapy. Cancers (Basel) 2019; 11:cancers11121932. [PMID: 31817090 PMCID: PMC6966638 DOI: 10.3390/cancers11121932] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2019] [Accepted: 12/02/2019] [Indexed: 12/19/2022] Open
Abstract
Colorectal cancer (CRC) has been ranked as the third most prevalent cancer worldwide. Indeed, it represents 10.2% of all cancer cases. It is also the second most common cause of cancer mortality, and accounted for about 9.2% of all cancer deaths in 2018. Early detection together with a correct diagnosis and staging remains the most effective clinical strategy in terms of disease recovery. Thanks to advances in diagnostic techniques, and improvements of surgical adjuvant and palliative therapies, the mortality rate of CRC has decreased by more than 20% in the last decade. Cancer biomarkers for the early detection of CRC, its management, treatment and follow-up have contributed to the decrease in CRC mortality. Herein, we provide an overview of molecular biomarkers from tumor tissues and liquid biopsies that are approved for use in the CRC clinical setting for early detection, follow-up, and precision therapy, and of biomarkers that have not yet been officially validated and are, nowadays, under investigation.
Collapse
|