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Chen G, Sun H, Chen Y, Wang L, Song O, Zhang J, Li D, Liu X, Feng L. Perineural Invasion in Cervical Cancer: A Hidden Trail for Metastasis. Diagnostics (Basel) 2024; 14:1517. [PMID: 39061654 PMCID: PMC11275432 DOI: 10.3390/diagnostics14141517] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2024] [Revised: 06/20/2024] [Accepted: 06/21/2024] [Indexed: 07/28/2024] Open
Abstract
Perineural invasion (PNI), the neoplastic invasion of nerves, is an often overlooked pathological phenomenon in cervical cancer that is associated with poor clinical outcomes. The occurrence of PNI in cervical cancer patients has limited the promotion of Type C1 surgery. Preoperative prediction of the PNI can help identify suitable patients for Type C1 surgery. However, there is a lack of appropriate preoperative diagnostic methods for PNI, and its pathogenesis remains largely unknown. Here, we dissect the neural innervation of the cervix, analyze the molecular mechanisms underlying the occurrence of PNI, and explore suitable preoperative diagnostic methods for PNI to advance the identification and treatment of this ominous cancer phenotype.
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Affiliation(s)
- Guoqiang Chen
- Department of Obstetrics and Gynecology, Second Affiliated Hospital of Naval Medical University, Shanghai 200003, China
- Department of Gynecology, The People’s Hospital of Baoan Shenzhen, The Second Affiliated Hospital of Shenzhen University, Shenzhen 518101, China
| | - Hao Sun
- Department of Obstetrics and Gynecology, Second Affiliated Hospital of Naval Medical University, Shanghai 200003, China
| | - Yunxia Chen
- Department of Gynecology, The People’s Hospital of Baoan Shenzhen, The Second Affiliated Hospital of Shenzhen University, Shenzhen 518101, China
| | - Li Wang
- Department of Gynecology, The People’s Hospital of Baoan Shenzhen, The Second Affiliated Hospital of Shenzhen University, Shenzhen 518101, China
| | - Ouyi Song
- Department of Gynecology, The People’s Hospital of Baoan Shenzhen, The Second Affiliated Hospital of Shenzhen University, Shenzhen 518101, China
| | - Jili Zhang
- Department of Gynecology, The People’s Hospital of Baoan Shenzhen, The Second Affiliated Hospital of Shenzhen University, Shenzhen 518101, China
| | - Dazhi Li
- Department of Gynecology, The People’s Hospital of Baoan Shenzhen, The Second Affiliated Hospital of Shenzhen University, Shenzhen 518101, China
| | - Xiaojun Liu
- Department of Obstetrics and Gynecology, Second Affiliated Hospital of Naval Medical University, Shanghai 200003, China
| | - Lixia Feng
- Department of Gynecology, The People’s Hospital of Baoan Shenzhen, The Second Affiliated Hospital of Shenzhen University, Shenzhen 518101, China
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Djikic Rom A, Dragicevic S, Jankovic R, Radojevic Skodric S, Sabljak P, Markovic V, Stojkovic JR, Barisic G, Nikolic A. Markers of Epithelial-Mesenchymal Transition and Mucinous Histology Are Significant Predictors of Disease Severity and Tumor Characteristics in Early-Onset Colorectal Cancer. Diagnostics (Basel) 2024; 14:1512. [PMID: 39061649 PMCID: PMC11275501 DOI: 10.3390/diagnostics14141512] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2024] [Revised: 07/08/2024] [Accepted: 07/11/2024] [Indexed: 07/28/2024] Open
Abstract
Approximately 20% of patients with colorectal cancer (CRC) are diagnosed with a mucinous subtype of this tumor, have a worse prognosis, and often show resistance to available therapies. Molecules from the mucin family are involved in the regulation of epithelial-mesenchymal transition (EMT), which significantly determines the cancer aggressiveness. This study aimed to examine the diagnostic and prognostic significance of mucinous histology and EMT markers in patients with early-onset CRC and their association with disease severity and tumor characteristics. This study included tumor tissue samples from 106 patients diagnosed with CRC before the age of 45, 53 with mucinous and 53 with non-mucinous tumors. The EMT status was determined by immunohistochemical analysis of E-cadherin and Vimentin in tissue sections. Mucinous tumors had significantly higher Mucin-1 (p < 0.001) and cytoplasmic E-cadherin (p = 0.043) scores; they were significantly less differentiated (p = 0.007), more advanced (p = 0.027), and predominately affected right the colon (p = 0.039) compared to non-mucinous tumors. Epithelial tumors were significantly better differentiated (p = 0.034) and with less prominent tumor budding (p < 0.001) than mesenchymal tumors. Mucin-1 and Vimentin were independent predictors of tumor differentiation (p = 0.006) and budding (p = 0.001), respectively. Mucinous histology and EMT markers are significant predictors of disease severity and tumor characteristics in early-onset colorectal cancer.
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Affiliation(s)
- Aleksandra Djikic Rom
- Department of Pathology, Pathohistology and Medical Cytology, University Clinical Center of Serbia, Pasterova 2, 11000 Belgrade, Serbia
| | - Sandra Dragicevic
- Gene Regulation in Cancer Group, Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, 11000 Belgrade, Serbia; (S.D.); (A.N.)
| | - Radmila Jankovic
- Institute of Pathology, Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia; (R.J.); (S.R.S.)
| | - Sanja Radojevic Skodric
- Institute of Pathology, Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia; (R.J.); (S.R.S.)
| | - Predrag Sabljak
- Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia; (P.S.); (V.M.); (J.R.S.); (G.B.)
- Clinic for Digestive Surgery—First Surgical Clinic, University Clinical Center of Serbia, 11000 Belgrade, Serbia
| | - Velimir Markovic
- Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia; (P.S.); (V.M.); (J.R.S.); (G.B.)
- Clinic for Digestive Surgery—First Surgical Clinic, University Clinical Center of Serbia, 11000 Belgrade, Serbia
| | - Jovana Rosic Stojkovic
- Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia; (P.S.); (V.M.); (J.R.S.); (G.B.)
| | - Goran Barisic
- Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia; (P.S.); (V.M.); (J.R.S.); (G.B.)
- Clinic for Digestive Surgery—First Surgical Clinic, University Clinical Center of Serbia, 11000 Belgrade, Serbia
| | - Aleksandra Nikolic
- Gene Regulation in Cancer Group, Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, 11000 Belgrade, Serbia; (S.D.); (A.N.)
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Son IT, Kang JH, Kim BC, Park JH, Kim JW. A Retrospective Multicenter Study of the Clinicopathological Characteristics and Prognosis of Young Adult Patients with Colorectal Cancer: Effects of Chemotherapy on Prognosis. J Clin Med 2023; 12:jcm12113634. [PMID: 37297829 DOI: 10.3390/jcm12113634] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2023] [Revised: 05/16/2023] [Accepted: 05/22/2023] [Indexed: 06/12/2023] Open
Abstract
BACKGROUND The objective of this study was to evaluate clinicopathologic features of young patients with colorectal cancer (CRC) and to compare their prognosis with those of older patients Methods: We retrospectively reviewed the medical records of patients who underwent surgery for stage 0-III CRC at four university-affiliated hospitals between January 2011 and December 2020. The patients were divided into two groups, the young adult group (≤45 years) and the older group (>45 years). RESULTS Of 1992 patients, 93 (4.6%) were young adults and 1899 (95.3%) were older patients. Young patients showed more symptoms (p = 0.014) and more poorly or undifferentiated adenocarcinoma (p = 0.047) than older patients. The young adult patients were more likely to receive adjuvant chemotherapy (p < 0.001) and multidrug agents (p = 0.029), and less likely to cease chemotherapy (p = 0.037). The five-year RFS (recurrence-free survival) rate was better in the young adults than in the older patients (p = 0.009). In the multivariable analysis, young age was a significant prognostic factor for better RFS (p = 0.015). CONCLUSIONS Young patients with CRC had more symptoms, aggressive histological features than older patients. They received more multidrug agents and discontinued chemotherapy less often, resulting in better prognosis.
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Affiliation(s)
- Il Tae Son
- Department of Surgery, Hallym Sacred Heart Hospital, Hallym University College of Medicine, Anyang-si 445-907, Republic of Korea
| | - Jae Hyun Kang
- Department of Surgery, Dongtan Sacred Heart Hospital, Hallym University College of Medicine, 40, Sukwoo-Dong, Hwaseong-si 445-170, Republic of Korea
| | - Byung Chun Kim
- Department of Surgery, Kangnam Sacred Heart Hospital, Hallym University College of Medicine, 948-1, 1, Shingil-ro, Yeongdeungpo-gu, Seoul 150-950, Republic of Korea
| | - Jun Ho Park
- Department of Surgery, Kangdong Sacred Heart Hospital, Hallym University College of Medicine, 445 Gil-1-dong, Gangdong-gu, Seoul 134-701, Republic of Korea
| | - Jong Wan Kim
- Department of Surgery, Dongtan Sacred Heart Hospital, Hallym University College of Medicine, 40, Sukwoo-Dong, Hwaseong-si 445-170, Republic of Korea
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Xu K, Zheng S, Li B, Shao Y, Yin X. Molecular characterization of colorectal mucinous adenocarcinoma and adenocarcinoma, not otherwise specified, identified by multiomic data analysis. Front Mol Biosci 2023; 10:1150362. [PMID: 37091868 PMCID: PMC10114614 DOI: 10.3389/fmolb.2023.1150362] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2023] [Accepted: 02/27/2023] [Indexed: 04/08/2023] Open
Abstract
Adenocarcinoma not otherwise specified (AC) and mucinous adenocarcinoma (MC) have different biological behaviors and clinical features. We utilized our previous proteomic data and public transcriptome, single-cell transcriptome, and spatial transcriptome databases to profile the molecular atlas of the tumor microenvironments of MC, AC, and normal colon tissues. By exploring the general and specific molecular features of AC and MC, we found that AC was immune-active but exposed to a hypoxic microenvironment. MC cells could protect against DNA damage, and the microenvironment was unfavorable to leukocyte transendothelial migration. We identified several potential molecular and cellular targets of AC and MC for future research. We also highlighted that the major difference between AC and MC was not the variety of cell types and functions but possibly cell interactions. Stromal and epithelial cell interactions play important roles in both MC and AC, but different regulatory pathways were involved.
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Affiliation(s)
- Kailun Xu
- Department of Breast Surgery and Oncology (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, Key Laboratory of Molecular Biology in Medical Sciences, Zhejiang Province, China), Cancer Institute, The Second Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang Provincial Clinical Research Center for Cancer, Cancer Center of Zhejiang University, Hangzhou, Zhejiang, China
| | - Shu Zheng
- Department of Breast Surgery and Oncology (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, Key Laboratory of Molecular Biology in Medical Sciences, Zhejiang Province, China), Cancer Institute, The Second Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang Provincial Clinical Research Center for Cancer, Cancer Center of Zhejiang University, Hangzhou, Zhejiang, China
| | - Baosheng Li
- Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China
| | - Yingkuan Shao
- Department of Breast Surgery and Oncology (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, Key Laboratory of Molecular Biology in Medical Sciences, Zhejiang Province, China), Cancer Institute, The Second Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang Provincial Clinical Research Center for Cancer, Cancer Center of Zhejiang University, Hangzhou, Zhejiang, China
- *Correspondence: Yingkuan Shao, ; Xiaoyang Yin,
| | - Xiaoyang Yin
- Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China
- *Correspondence: Yingkuan Shao, ; Xiaoyang Yin,
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Gundamaraju R, Chong WC. Consequence of distinctive expression of MUC2 in colorectal cancers: How much is actually bad? Biochim Biophys Acta Rev Cancer 2021; 1876:188579. [PMID: 34139275 DOI: 10.1016/j.bbcan.2021.188579] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2021] [Revised: 06/08/2021] [Accepted: 06/10/2021] [Indexed: 12/18/2022]
Abstract
Colorectal cancer (CRC) exhibits complex pathogenesis via compromised intestinal mucosal barrier. It is accepted that goblet cells secrete mucin which line the intestinal mucosal barrier and offer wide range protection and maintain the gut integrity. The principal mucin in the small and large intestine which is Mucin2 (MUC2) is predominantly expressed in the goblet cells which play a pivotal role in intestinal homeostasis. Its disruption is associated with diverse diseases and carcinomas. MUC2 has lately been identified as a principal marker in various mechanisms and secretory cell lineage. While MUC2 expression is regulated by various modulators, alterations in its expression are associated with immunomodulation, differences in tumor immunity and also regulation of microbiota. In the light of current literature, the present review explicates the regulation, functional mechanisms and essential role of MUC2 in colorectal cancer and aids in providing deep understanding of pathogenesis of the disease and also specifies the importance of the MUC2 in gaining more insights about the subtypes of colorectal cancer and how it can succour in approximating the prognosis and survival of the patients.
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Affiliation(s)
- Rohit Gundamaraju
- ER Stress and Gut Mucosal Immunology Laboratory, School of Health Sciences, University of Tasmania, Launceston, Tasmania 7248, Australia.
| | - Wai Chin Chong
- Centre for Cancer Research, Hudson Institute of Medical Research, Clayton, Victoria 3168, Australia; Department of Molecular and Translational Science, School of Medicine, Nursing, and Health Science, Monash University, Clayton, Victoria 3168, Australia
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Vernmark K, Sun XF, Holmqvist A. Mucinous and Non-Mucinous Rectal Adenocarcinoma-Differences in Treatment Response to Preoperative Radiotherapy. J Pers Med 2020; 10:jpm10040226. [PMID: 33202796 PMCID: PMC7711895 DOI: 10.3390/jpm10040226] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2020] [Revised: 11/06/2020] [Accepted: 11/09/2020] [Indexed: 02/06/2023] Open
Abstract
There is a need to personalize the treatment for rectal cancer patients. The aim of this study was to analyze therapy response and prognosis after preoperative radiotherapy in rectal cancer patients with mucinous adenocarcinoma compared to those with non-mucinous adenocarcinoma. The study included retrospectively collected data from 433 patients, diagnosed with rectal cancer in the South East health care region in Sweden between 2004 and 2012. Patients with non-mucinous adenocarcinoma that received short-course radiotherapy before surgery had better overall survival, cancer specific survival, and disease-free survival, as well as distant- and local-recurrence-free survival (p = 0.003, p = 0.001, p = 0.002, p = 0.002, and p = 0.033, respectively) compared to the patients that received long-course radiotherapy with concomitant capecitabine. The results were still significant after adjusting for sex, age, stage, differentiation, and chemotherapy in the neoadjuvant and/or adjuvant setting, except for local-recurrence-free survival that was trending towards significance (p = 0.070). In patients with mucinous adenocarcinoma, no difference in survival was seen when comparing patients that had short-course radiotherapy and patients that had long-course radiotherapy. However, none of 18 patients with mucinous adenocarcinoma treated with long-course radiotherapy had local tumor progression, compared to 7% of 67 patients with non-mucinous adenocarcinoma. The results indicate that mucinous adenocarcinoma and non-mucinous adenocarcinoma may respond differently to radiotherapy.
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Affiliation(s)
- Karolina Vernmark
- Department of Biomedical and Clinical Sciences, Linköping University, 58183 Linköping, Sweden; (K.V.); (A.H.)
- Department of Oncology in Linköping, and Department of Surgery, Orthopaedics and Cancer care, Linköping University, 58183 Linköping, Sweden
| | - Xiao-Feng Sun
- Department of Biomedical and Clinical Sciences, Linköping University, 58183 Linköping, Sweden; (K.V.); (A.H.)
- Correspondence: ; Tel.: +46-10-1032066
| | - Annica Holmqvist
- Department of Biomedical and Clinical Sciences, Linköping University, 58183 Linköping, Sweden; (K.V.); (A.H.)
- Department of Oncology in Linköping, and Department of Surgery, Orthopaedics and Cancer care, Linköping University, 58183 Linköping, Sweden
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Li ZP, Liu XY, Kao XM, Chen YT, Han SQ, Huang MX, Liu C, Tang XY, Chen YY, Xiang D, Huang YD, Lei ZJ, Chu XY. Clinicopathological characteristics and prognosis of colorectal mucinous adenocarcinoma and nonmucinous adenocarcinoma: a surveillance, epidemiology, and end results (SEER) population-based study. ANNALS OF TRANSLATIONAL MEDICINE 2020; 8:205. [PMID: 32309352 PMCID: PMC7154470 DOI: 10.21037/atm.2020.01.52] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/10/2019] [Accepted: 12/27/2019] [Indexed: 02/05/2023]
Abstract
BACKGROUND Mucinous adenocarcinoma (MC) is a rare histological subtype of colorectal adenocarcinoma. Previous studies investigating the prognosis of MC have conflicting results and the proper treatment of MC remains unclear. METHODS This retrospective study presents the clinicopathological characteristics and prognosis of MC. This cohort study collected data from April 1 through August 01, 2018. This study used data on 107,735 patients with nonmucinous adenocarcinoma (NMC) and 9,494 with MC between 2009 and 2013 from the Surveillance, Epidemiology, and End Results program (SEER). Clinicopathological features were analyzed by chi-square test and survival curves by the Kaplan-Meier method. We used propensity score matching (PSM) to account for potential bias. Logistic regression and Cox proportional hazards models were used to compare and calculate adjusted risks of MC death. RESULTS MC was more frequent in patients with older age, large tumor size and moderate tumor grade compared with NMC (P<0.001). Five-year survival was lower for MC patients than NMC patients (P<0.001). Older age, later tumor node metastasis (TNM) stage and multiple tumors indicated a poorer prognosis while surgery gave better survival outcomes [hazard ratio (HR) =0.38; 95% confidence interval (CI), 0.33 to 0.44; P<0.001]. Younger age, left-side colon location and early disease stage were associated with better survival after surgery (P<0.001). CONCLUSIONS Age, TNM stage, tumor number and treatment were indicators of prognosis and surgery gave better survival for MC patients compared with those without surgery. Our study contributes to their clinical treatment.
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Affiliation(s)
- Zhi-Ping Li
- Department of Medical Oncology, Jinling Hospital, The First School of Clinical Medicine, Southern Medical University, Nanjing 210002, China
| | - Xin-Yi Liu
- Department of Radiology, Shenzhen Children's Hospital, Shantou University Medical College, Shenzhen 518000, China
| | - Xiao-Ming Kao
- Department of General Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing 210002, China
| | - Yi-Tian Chen
- Department of Medical Oncology, Jinling Hospital, Medical School of Nanjing University, Nanjing 210002, China
| | - Si-Qi Han
- Department of Medical Oncology, Jinling Hospital, Medical School of Nanjing University, Nanjing 210002, China
| | - Meng-Xi Huang
- Department of Medical Oncology, Jinling Hospital, Medical School of Nanjing University, Nanjing 210002, China
| | - Chao Liu
- Department of Medical Oncology, Jinling Hospital, Nanjing Clinical School of Nanjing Medical University, Nanjing 210002, China
| | - Xin-Yi Tang
- Department of Medical Oncology, Jinling Hospital, Medical School of Nanjing University, Nanjing 210002, China
| | - Yan-Yan Chen
- Department of Medical Oncology, Jinling Hospital, Medical School of Nanjing University, Nanjing 210002, China
| | - Dan Xiang
- Department of Medical Oncology, Jinling Hospital, Medical School of Nanjing University, Nanjing 210002, China
| | - Ya-Di Huang
- Department of Medical Oncology, Jinling Hospital, The First School of Clinical Medicine, Southern Medical University, Nanjing 210002, China
| | - Zeng-Jie Lei
- Department of Medical Oncology, Jinling Hospital, The First School of Clinical Medicine, Southern Medical University, Nanjing 210002, China
- Department of Medical Oncology, Jinling Hospital, Medical School of Nanjing University, Nanjing 210002, China
| | - Xiao-Yuan Chu
- Department of Medical Oncology, Jinling Hospital, The First School of Clinical Medicine, Southern Medical University, Nanjing 210002, China
- Department of Medical Oncology, Jinling Hospital, Medical School of Nanjing University, Nanjing 210002, China
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A Purified Aspartic Protease from Akkermansia Muciniphila Plays an Important Role in Degrading Muc2. Int J Mol Sci 2019; 21:ijms21010072. [PMID: 31861919 PMCID: PMC6982040 DOI: 10.3390/ijms21010072] [Citation(s) in RCA: 34] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2019] [Revised: 12/16/2019] [Accepted: 12/17/2019] [Indexed: 12/16/2022] Open
Abstract
Akkermansia muciniphila can produce various mucin-degrading proteins. However, the functional characteristics of these proteins and their role in mucin degradation are unclear. Of the predicted protein-coding genes, Amuc_1434, which encodes for a hypothetical protein, is the focus in this study. A recombinant enzyme Amuc_1434 containing the 6× His-tag produced in Escherichia coli (hereinafter termed Amuc_1434*) was isolated to homogeneity and biochemically characterised. Results showed that the enzyme can hydrolyse hemoglobin with an activity of 17.21 U/μg. The optimal pH and temperature for hemoglobin hydrolysis of Amuc_1434* were found to be around 8.0 and 40 °C, respectively. Amuc_1434* is identified as a member of the aspartic protease family through the action of inhibitor pepstatin A. Amuc_1434* promotes the adhesion of colon cancer cell line LS174T, which can highly express Muc2. Significantly Amuc_1434* can degrade Muc2 of colon cancer cells. Amuc_1434 is mainly located in the colon of BALB/c mice. These results suggest that the presence of Amuc_1434 from Akkermansia muciniphila may be correlated with the restoration of gut barrier function by decreasing mucus layer thickness.
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Wang ZX, Yang LP, Wu HX, Yang DD, Ding PR, Xie D, Chen G, Li YH, Wang F, Xu RH. Appraisal of Prognostic Interaction between Sidedness and Mucinous Histology in Colon Cancer: A Population-Based Study Using Inverse Probability Propensity Score Weighting. J Cancer 2019; 10:388-396. [PMID: 30719132 PMCID: PMC6360297 DOI: 10.7150/jca.28014] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2018] [Accepted: 10/03/2018] [Indexed: 12/13/2022] Open
Abstract
Introduction: Colon cancer with different sidedness (right vs. left) and histology (mucinous vs. non-mucinous) may represent different disease entities. We investigated whether the prognostic values of sidedness and histology differed according to each other. Materials and Methods: We analyzed 81342 patients with stage II-IV colon cancer from the Surveillance, Epidemiology, and End Results database between 2004 and 2012. Patients were divided into four subgroups on the basis of sidedness and histology: non-mucinous right-sided, non-mucinous left-sided, mucinous right-sided, and mucinous left-sided subgroups. Among each tumor stage, median overall survival (mOS) was compared between these subgroups after inverse probability propensity score weighting to handle confounding factors. Results: In the stage IV subgroup, the prognosis for non-mucinous left-sided tumors (weighted mOS, 24.5 months) was significantly better than that for non-mucinous right-sided tumors (weighted mOS, 16.5 months; P<0.001) and that for mucinous left-sided tumors (weighted mOS, 16.5 months; P<0.001), whereas the survival was similar between left-sided and right-sided tumors with the mucinous subtype (weighted mOS, 16.5 months for both; P=0.570; test for interaction between sidedness and histology, Pinteraction <0.001), and between mucinous and non-mucinous tumors in the right-sided colon (weighted mOS, 16.5 months for both; P=0.207). Similar findings were detected in the stage III subgroup (Pinteraction <0.001). In the stage II subgroup, the survival was comparable among the four sidedness-histology subgroups (P=0.159 and Pinteraction =0.466). Conclusions: In stage III/IV colon cancer, the prognostic value of sidedness differed according to histology, and vice versa. By contrast, neither should be considered in risk stratification for stage II colon cancer.
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Affiliation(s)
- Zi-Xian Wang
- Department of Medical Oncology, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, 510060, China
| | - Lu-Ping Yang
- Department of Medical Oncology, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, 510060, China.,Faculty of Medical Sciences, Sun Yat-Sen University, Guangzhou, 510080, China
| | - Hao-Xiang Wu
- Department of Medical Oncology, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, 510060, China.,Faculty of Medical Sciences, Sun Yat-Sen University, Guangzhou, 510080, China
| | - Dong-Dong Yang
- Department of Medical Oncology, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, 510060, China
| | - Pei-Rong Ding
- Department of Colorectal Surgery, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, 510060, China
| | - Dan Xie
- Department of Pathology, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, 510060, China
| | - Gong Chen
- Department of Colorectal Surgery, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, 510060, China
| | - Yu-Hong Li
- Department of Medical Oncology, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, 510060, China
| | - Feng Wang
- Department of Medical Oncology, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, 510060, China
| | - Rui-Hua Xu
- Department of Medical Oncology, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, 510060, China
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Kasprzak A, Siodła E, Andrzejewska M, Szmeja J, Seraszek-Jaros A, Cofta S, Szaflarski W. Differential expression of mucin 1 and mucin 2 in colorectal cancer. World J Gastroenterol 2018; 24:4164-4177. [PMID: 30271081 PMCID: PMC6158483 DOI: 10.3748/wjg.v24.i36.4164] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/16/2018] [Revised: 08/15/2018] [Accepted: 08/24/2018] [Indexed: 02/06/2023] Open
Abstract
AIM To determine tissue expression (mRNA, protein) of two types of mucins [mucin 1 (MUC1) and mucin 2 (MUC2)] in patients with colorectal cancer (CRC). METHODS Expression of membrane-bound mucin (MUC1) and secretory mucin (MUC2) in CRC (mRNA, protein) were analyzed in tissue material including fragments of tumors obtained from CRC patients (n = 34), and fragments of normal colorectal tissue from the same patients (control). The analysis was conducted using real-time quantitative polymerase chain reaction (RT-qPCR) (transcripts), immunohistochemistry (IHC) (apomucins), and the modern approach for morphometric analysis of IHC reaction (HSV filter software). Results on tissue expression of both mucins (mRNA, protein) were compared to histological alterations in colorectal cancer samples and correlated with selected clinical data in the patients. The statistical analysis was conducted using Statistica PL v. 12.0 software. RESULTS Significantly higher expression of the MUC1 mRNA in the CRC, compared with the control and the borderline correlation of mRNA expression with MUC1 protein levels in colorectal samples was observed. The expression of apomucins concerned cell membranes (MUC1) and cytoplasm (MUC2) and occurred both in control tissues and in most cancerous samples. There were no significant relationships between MUC1 (mRNA, protein) and the clinicopathological data of patients. MUC2 protein expression was significantly lower as compared to the control, while MUC2 mRNA expression was comparable in both groups. The MUC1/MUC2 ratio was significantly higher in CRC tissues than in the control. The higher expression of MUC2 was a feature of mucinous CRC subtypes, and characterized higher histological stage of tumors. Negative correlations have been obtained between MUC2 and the Ki-67 antigen, as well as between MUC2 and p53 protein expressions in CRC. CONCLUSION A combination of tissue overexpression of MUC1, reduced MUC2 expression, and high ratio of MUC1/MUC2 is a factor of poor prognosis in CRC patients. MUC2 tissue expression allows to differentiate mucinous and nonmucinous CRC subtypes.
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Affiliation(s)
- Aldona Kasprzak
- Department of Histology and Embryology, Poznan University of Medical Sciences, Poznan 60-781, Poland
| | - Elżbieta Siodła
- Department of Histology and Embryology, Poznan University of Medical Sciences, Poznan 60-781, Poland
| | - Małgorzata Andrzejewska
- Department of Histology and Embryology, Poznan University of Medical Sciences, Poznan 60-781, Poland
| | - Jacek Szmeja
- Chair and Department of General Surgery, Endocrinological and Gastroenterological Oncology, Poznan University of Medical Sciences, Poznan 60-355, Poland
| | - Agnieszka Seraszek-Jaros
- Department of Bioinformatics and Computational Biology, Chair of Clinical Pathomorphology, Poznan University of Medical Sciences, Poznan 60-529, Poland
| | - Szczepan Cofta
- Department of Pulmonology, Allergology and Respiratory Oncology, Poznan University of Medical Science, Poznan 60-569, Poland
| | - Witold Szaflarski
- Department of Histology and Embryology, Poznan University of Medical Sciences, Poznan 60-781, Poland
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Sarioglu S, Akturk G, Sokmen S, Ellidokuz H, Canda AE, Unlu M, Sirin AH, Sagol O, Terzi C, Fuzun M. The Prognostic Implications of FIX and FLO Patterns in Mucinous Colon Carcinomas. J Gastrointest Cancer 2018; 50:254-259. [PMID: 29376207 DOI: 10.1007/s12029-018-0059-6] [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: 11/25/2022]
Abstract
PURPOSE Colon mucinous carcinomas (MUCs) have two morphological patterns: (i) glands lined by mucinous epithelium with direct contact to the stroma (FIX) and (ii) carcinoma cells floating in mucin (FLO). In this study, we evaluated the prognostic value of these patterns. METHODS Digital images were captured from the 38 MUC's tissue sections. A grid with 140 points was laid over the computer screen. Totally, 100 points, falling on tumor cells floating in mucin (FLO patterned cells) or on cells contacting stroma (FIX patterned cells), were counted. Tumors were grouped according to the median value of the FIX patterned cells. Cases with more than this value were grouped as FIX and less were grouped as FLO cases. The prognostic value of FIX and FLO pattern was evaluated. RESULTS The median for FIX patterned cells was 66%, and the cases with lower values than this were grouped as FLO (N = 18; 47.37%), while the rest were grouped as FIX cases. There was no significant difference between FIX and FLO cases for overall survival cases (p = 0.167). For FIX cases, 62.7 and 51.3% of the patients were alive at second and third years, while this was 78.9 and 72.4% for the FLO group, respectively. CONCLUSIONS This is the first study using a quantitative methodology depending on count pointing to evaluate FIX/FLO feature of MUCs to the best of our knowledge, although we could not observed any prognostic and clinicopathologic relationship statistically. This distinctive feature should be studied in larger cohorts with prognostic information, with a quantitative method, like the one that was applied in this study, in order to achieve strict conclusions.
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Affiliation(s)
- Sulen Sarioglu
- Faculty of Medicine, Department of Pathology, Dokuz Eylul University, Inciralti, Izmir, Turkey.
| | - Guray Akturk
- Faculty of Medicine, Department of Pathology, Dokuz Eylul University, Inciralti, Izmir, Turkey.,Memorial Sloan Kettering Cancer Center, Department of Pathology, Precision Pathology Biobanking Center, New York, USA
| | - Selman Sokmen
- Faculty of Medicine, Department of General Surgery, Dokuz Eylul University, Izmir, Turkey
| | - Hulya Ellidokuz
- Faculty of Medicine, Institute of Oncology, Dokuz Eylul University, Izmir, Turkey
| | - Aras Emre Canda
- Faculty of Medicine, Department of General Surgery, Dokuz Eylul University, Izmir, Turkey
| | - Mehtat Unlu
- Faculty of Medicine, Department of Pathology, Dokuz Eylul University, Inciralti, Izmir, Turkey
| | - Abdullah Haluk Sirin
- Faculty of Medicine, Department of General Surgery, Dokuz Eylul University, Izmir, Turkey
| | - Ozgul Sagol
- Faculty of Medicine, Department of Pathology, Dokuz Eylul University, Inciralti, Izmir, Turkey
| | - Cem Terzi
- Faculty of Medicine, Department of General Surgery, Dokuz Eylul University, Izmir, Turkey
| | - Mehmet Fuzun
- Faculty of Medicine, Department of General Surgery, Dokuz Eylul University, Izmir, Turkey
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12
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Yu D, Gao P, Song Y, Yang Y, Chen X, Sun Y, Li A, Wang Z. The differences on efficacy of oxaliplatin in locally advanced colon cancer between mucinous and nonmucinous adenocarcinoma. Cancer Med 2018; 7:600-615. [PMID: 29380562 PMCID: PMC5852364 DOI: 10.1002/cam4.1333] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2017] [Revised: 12/14/2017] [Accepted: 12/18/2017] [Indexed: 12/28/2022] Open
Abstract
Until now, it remains unclear how to best use the histological subtype in clinical practice. This study aimed to compare differences in the efficacy of postoperative chemotherapy among different histological subtypes of colon adenocarcinomas. Using the Surveillance, Epidemiology, and End Results‐Medicare database, 51,200 patients with stage II or III primary colon carcinomas who underwent resection for curative intent between 1992 and 2008 were included. The survival benefit was evaluated using a Cox proportional hazards model, interaction analyses, and propensity score‐matched techniques. There was no significant difference in survival for low‐risk stage II mucinous adenocarcinoma (MA) or nonmucinous adenocarcinoma (NMA) between 5‐FU and oxaliplatin‐treated groups (P = 0.387 for MA, P = 0.629 for NMA). Patients with high‐risk stage II NMA who received the oxaliplatin chemotherapy regimen had significantly improved cancer‐specific survival (CSS) compared with the 5‐FU group (P = 0.004), while those with MA saw no improvement (P = 0.690). For stage III tumors, patients with NMA who received the oxaliplatin chemotherapy regimen had significantly improved CSS compared with the 5‐FU group (P < 0.001), while those with MA saw no improvement (P = 0.300). There were significant interactions between chemotherapy regimen and histological subtype. For patients with resected colon cancer who received 5‐FU‐based postoperative chemotherapy, oxaliplatin chemotherapy prolongs CSS for stage III and high‐risk stage II NMA. Conversely, there was no similar improvement with addition of oxaliplatin for patients with stage III or stage II MA.
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Affiliation(s)
- Dehao Yu
- Department of Surgical Oncology and General Surgery, The First Hospital of China Medical University, 155 North Nanjing Street, Heping District, Shenyang City, 110001, China
| | - Peng Gao
- Department of Surgical Oncology and General Surgery, The First Hospital of China Medical University, 155 North Nanjing Street, Heping District, Shenyang City, 110001, China
| | - Yongxi Song
- Department of Surgical Oncology and General Surgery, The First Hospital of China Medical University, 155 North Nanjing Street, Heping District, Shenyang City, 110001, China
| | - Yuchong Yang
- Department of Surgical Oncology and General Surgery, The First Hospital of China Medical University, 155 North Nanjing Street, Heping District, Shenyang City, 110001, China
| | - Xiaowan Chen
- Department of Surgical Oncology and General Surgery, The First Hospital of China Medical University, 155 North Nanjing Street, Heping District, Shenyang City, 110001, China
| | - Yu Sun
- Department of Surgical Oncology and General Surgery, The First Hospital of China Medical University, 155 North Nanjing Street, Heping District, Shenyang City, 110001, China
| | - Ailin Li
- Department of Radiation Oncology, The First Hospital of China Medical University, 155 North Nanjing Street, Heping District, Shenyang City, 110001, China
| | - Zhenning Wang
- Department of Surgical Oncology and General Surgery, The First Hospital of China Medical University, 155 North Nanjing Street, Heping District, Shenyang City, 110001, China
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13
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Zhao L, Bao F, Yan J, Liu H, Li T, Chen H, Li G. Poor prognosis of young patients with colorectal cancer: a retrospective study. Int J Colorectal Dis 2017; 32:1147-1156. [PMID: 28389779 DOI: 10.1007/s00384-017-2809-5] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 03/30/2017] [Indexed: 02/04/2023]
Abstract
PURPOSE The present study aimed to explore the survival outcomes of patients with colorectal cancer (CRC) aged 35 years and younger. METHODS This retrospective cohort study included a total of 995 patients with CRC treated between January 2003 and September 2011. The patients were assorted into the young (aged 18-35 years) and older (aged 36-75 years) groups. The clinical characteristics and survival outcomes of the patients in the young group were compared with those of the patients in the older group for evaluation. RESULTS Compared with the older group, a significantly higher number of patients in the young group had right-sided colon cancer (30.9 vs. 19.6%, P = 0.026), high histologic grade tumor (14.7 vs. 6.4%, P = 0.021), and stage III disease (50.0 vs. 35.5%, P = 0.016). In stage III disease, compared with the older group, the patients in the young group had worse survival outcome in terms of 5-year overall survival (OS, P = 0.007), cancer-specific survival (CSS, P = 0.010), and disease-free survival (DFS, P = 0.039). Multivariate analysis revealed that age ≤35 years was an independent risk factor in terms of 5-year OS (hazard ratio [HR] = 1.68; 95% confidence interval [CI]: 1.12-2.54; P = 0.012), CSS (HR = 1.74; 95% CI: 1.15-2.65; P = 0.009), and DFS (HR = 1.58; 95% CI: 1.06-2.35; P = 0.024). CONCLUSIONS The young patients with CRC aged 35 years and younger had worse prognosis compared with older patients, especially for stage III disease.
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Affiliation(s)
- Liying Zhao
- Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, People's Republic of China
| | - Feng Bao
- Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, People's Republic of China
- Department of General Surgery, Mianyang Central Hospital, Mianyang, People's Republic of China
| | - Jun Yan
- Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, People's Republic of China
| | - Hao Liu
- Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, People's Republic of China
| | - Tingting Li
- Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, People's Republic of China
| | - Hao Chen
- Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, People's Republic of China
| | - Guoxin Li
- Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, People's Republic of China.
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Kaneko K, Kawai K, Kazama S, Murono K, Sasaki K, Yasuda K, Ohtani K, Nishikawa T, Tanaka T, Kiyomatsu T, Hata K, Nozawa H, Ishihara S, Morikawa T, Fukayama M, Watanabe T. Clinical significance of mucinous components in rectal cancer after preoperative chemoradiotherapy. Surg Today 2016; 47:697-704. [DOI: 10.1007/s00595-016-1419-0] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2016] [Accepted: 09/01/2016] [Indexed: 12/20/2022]
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15
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Mismatch repair deficiency as a prognostic factor in mucinous colorectal cancer. Mod Pathol 2016; 29:266-74. [PMID: 26769140 DOI: 10.1038/modpathol.2015.159] [Citation(s) in RCA: 40] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2015] [Revised: 12/01/2015] [Accepted: 12/02/2015] [Indexed: 12/14/2022]
Abstract
There is some uncertainty about pathological grading of mucinous colorectal adenocarcinoma, defined as colorectal cancer demonstrating at least 50% mucinous differentiation. Under the WHO 2000 classification mucinous colorectal cancer was considered high grade. However under the current WHO 2010 classification microsatellite unstable/mismatch repair-deficient (MSI/MMRd) mucinous colorectal cancer is considered low grade, whereas microsatellite stable/mismatch repair proficient (MSS/MMRp) tumours are high grade. However there is little empirical evidence for this approach. We therefore compared the long term survival of patients with MSI/MMRd vs MSS/MMRp mucinous colorectal cancer in a large unselected cohort of patients undergoing surgery at our institution from 1998 to 2011. There were 2608 patients in the cohort, of which 264 (10.1%) were mucinous. 95 (36%) of the mucinous tumours were microsatellite unstable. The all-cause 5-year survival of mucinous MSI/MMRd colorectal cancer was similar to that of non-mucinous low-grade colorectal cancer (73 vs 67%, P=0.368), and significantly better than that of both non-mucinous high-grade (73 vs 53%, P<0.001) and mucinous MSS/MMRp colorectal cancer (73 vs 57%, P=0.023). The 5-year survival of mucinous MSS/MMRp colorectal cancer was slightly better than that of non-mucinous high-grade patients (57 vs 53%, P=0.027), but significantly worse than that of non-mucinous low-grade colorectal cancer (57 vs 67%, P=0.018). In multivariate Cox regression analysis, conventional histological grade based on glandular differentiation maintained prognostic significance (P=0.003) whereas MSI/MMRd status just failed to be statistically significant (P=0.062). Our findings support the WHO 2010 approach that as a group mucinous MSS/MMRp colorectal cancers are biologically aggressive. However, grading based exclusively on MSI/MMR status may be overly simplistic as conventional grading based on the degree of glandular differentiation still holds greater prognostic significance in multivariate analysis.
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16
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Wang MJ, Ping J, Li Y, Holmqvist A, Adell G, Arbman G, Zhang H, Zhou ZG, Sun XF. Prognostic Significance and Molecular Features of Colorectal Mucinous Adenocarcinomas: A Strobe-Compliant Study. Medicine (Baltimore) 2015; 94:e2350. [PMID: 26705231 PMCID: PMC4697997 DOI: 10.1097/md.0000000000002350] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/20/2015] [Revised: 12/01/2015] [Accepted: 12/02/2015] [Indexed: 02/05/2023] Open
Abstract
Mucinous adenocarcinoma (MC) is a special histology subtype of colorectal adenocarcinoma. The survival of MC is controversial and the prognostic biomarkers of MC remain unclear. To analyze prognostic significance and molecular features of colorectal MC. This study included 755,682 and 1001 colorectal cancer (CRC) patients from Surveillance, Epidemiology, and End Results program (SEER, 1973-2011), and Linköping Cancer (LC, 1972-2009) databases. We investigated independently the clinicopathological characteristics, survival, and variety of molecular features from these 2 databases. MC was found in 9.3% and 9.8% patients in SEER and LC, respectively. MC was more frequently localized in the right colon compared with nonmucinous adenocarcinoma (NMC) in both SEER (57.7% vs 37.2%, P < 0.001) and LC (46.9% vs 27.7%, P < 0.001). Colorectal MC patients had significantly worse cancer-specific survival (CSS) than NMC patients (SEER, P < 0.001; LC, P = 0.026), prominently in stage III (SEER, P < 0.001; LC, P = 0.023). The multivariate survival analysis showed that MC was independently related to poor prognosis in rectal cancer patients (SEER, hazard ratios [HR], 1.076; 95% confidence intervals [CI], 1.057-1.096; P < 0.001). In LC, the integrated analysis of genetic and epigenetic features showed that that strong expression of PINCH (HR, 3.954; 95% CI, 1.493-10.47; P = 0.013) and weak expression of RAD50 (HR 0.348, 95% CI, 0.106-1.192; P = 0.026) were significantly associated with poor CSS of colorectal MC patients. In conclusion, the colorectal MC patients had significantly worse CSS than NMC patients, prominently in stage III. MC was an independent prognostic factor associated with worse survival in rectal cancer patients. The PINCH and RAD50 were prognostic biomarkers for colorectal MC patients.
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Affiliation(s)
- Mo-Jin Wang
- From the Department of Gastrointestinal Surgery, Institute of Digestive Surgery and State key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China (M-JW, Z-GZ, X-FS); Department of Oncology, and Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden (M-JW, JP, AH, GA, X-FS); Department of Paediatric Surgery, Institute of Digestive Surgery and State key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China (YL); Department of Surgery, and Department of Clinical and Experimental Medicine, Linköping University, Norrköping (GA); and School of Medicine, Örebro University, Örebro, Sweden (HZ)
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17
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Foda AARM, El-Hawary AK, Aziz AA. Colorectal adenocarcinoma with mucinous component: relation of MMP-13, EGFR, and E-cadherin expressions to clinicopathological features and prognosis. APMIS 2015; 123:502-8. [PMID: 25907382 DOI: 10.1111/apm.12379] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2014] [Accepted: 02/01/2015] [Indexed: 01/15/2023]
Abstract
The aim of this study was to compare colorectal adenocarcinoma with mucinous component, ordinary adenocarcinoma (OA) and mucinous adenocarcinoma (MA) regarding clinicopathological parameters, survival, EGFR, MMP-13, and E-cadherin. We studied tumor tissue specimens from 28 patients with adenocarcinoma with mucinous component, 47 with OA, and 56 with MA, who underwent radical surgery from January 2007 to January 2012 at the Gastroenterology Centre, Mansoura University, Egypt. High density manual tissue microarrays were constructed and immunohistochemistry for EGFR, MMP-13, and E-cadherin was done. Colorectal adenocarcinoma with mucinous component (AWMC) was significantly associated with more perineural invasion, lower EGFR, and MMP-13 expressions than OA, with no difference in E-cadherin expression. Conversely, only microscopic abscess formation was significantly more with colorectal AWMC than MC with no difference in EGFR, MMP-13 and E-cadherin expression between both groups. Colorectal AWMC showed a better survival than MA with no difference with OA. In a univariate analysis, EGFR, MMP-13, and E-cadherin expressions did not show a significant impact on disease-free or overall survival in patients with colorectal AWMC. Colorectal AWMC remains a vague entity that resembles OA in some clinicopathological and molecular respects as well as MA.
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Affiliation(s)
| | | | - Azza Abdel Aziz
- Pathology Department, Faculty of Medicine, Mansoura University, Mansoura, Egypt
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18
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Akiyama S, Kikuchi D, Mitani T, Fujii T, Yamada A, Matsui A, Ogawa O, Iizuka T, Hoteya S, Kaise M. A case of mucinous adenocarcinoma in the setting of chronic colitis associated with intestinal spirochetosis and intestinal stricture. Medicine (Baltimore) 2015; 94:e493. [PMID: 25634199 PMCID: PMC4602947 DOI: 10.1097/md.0000000000000493] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/10/2014] [Revised: 12/27/2014] [Accepted: 12/30/2014] [Indexed: 01/16/2023] Open
Abstract
Mucinous adenocarcinoma (MC) is a unique pathological type of colorectal cancer (CRC). The development of MC is often associated with intestinal inflammation and/or microsatellite instability (MSI). Moreover, MC has clinicopathological characteristics that render making the correct diagnosis difficult such as extramural progression. Meanwhile, intestinal spirochetosis (IS) is a condition in which colonic epithelial cells are colonized and/or infected by spirochetes. Intestinal inflammation due to IS occurs by the destruction of colonic microvilli and induces chronic diarrhea. Recently, it was reported that the prevalence of IS tended to be high in patients with sessile serrated adenomas/polyps, the precursor of MSI-high CRC including MC. This study presents a case of MC in the setting of intestinal inflammation due to IS and tries to clarify the cause of MC development by performing immunohistochemical stain of resected specimen for DNA mismatch repair (MMR) proteins. This patient is a 63-year-old man with no symptoms who had a positive fecal occult blood test. Subsequent endoscopic findings and biopsy results revealed intestinal stricture of the transverse colon and chronic infective colitis associated with IS. Metronidazole therapy was initiated but was not effective. Although follow-up colonoscopy was performed repeatedly, intestinal perforation occurred 20 months later. Subtotal colectomy and ileostomy were performed. Pathological examination of resected specimens revealed MC with normal expression of MMR proteins, including MLH1, MSH2, MSH6, and PMS2. The histopathological classification was Union for International Cancer Control (UICC) IIIB and adjuvant chemotherapy was initiated. This is an interesting case of MC developing in the setting of chronic colitis associated with IS. It seemed that the cause of MC development was not MSI but intestinal inflammation. Besides, endoscopic diagnosis of MC in this case was difficult because of the extramural progression and lack of obvious atypical colonic glands in biopsy specimens. This report provides evidence for an association between neoplasm and IS-induced intestinal inflammation. Moreover, we suggest that making the diagnosis of MC could be difficult because of its unique clinicopathological characteristics.
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Affiliation(s)
- Shintaro Akiyama
- From the Department of Gastroenterology (SA, DK, TM, AY, AM, OO, TI, SH, MK); and Department of Pathology (TF), Toranomon Hospital, Tokyo, Japan
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Laskar RS, Ghosh SK, Talukdar FR. Rectal cancer profiling identifies distinct subtypes in India based on age at onset, genetic, epigenetic and clinicopathological characteristics. Mol Carcinog 2014; 54:1786-95. [PMID: 25418895 DOI: 10.1002/mc.22250] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2014] [Revised: 09/26/2014] [Accepted: 10/10/2014] [Indexed: 01/13/2023]
Abstract
Rectal cancer is a heterogeneous disease that develops through multiple pathways characterized by genetic and epigenetic alterations. India has a comparatively higher proportion of rectal cancers and early-onset cases. We analyzed genetic (KRAS, TP53 and BRAF mutations, and MSI), epigenetic alterations (CpG island methylation detection of 10 tumor-related genes/loci), the associated clinicopathological features and survival trend in 80 primary rectal cancer patients from India. MSI was detected using BAT 25 and BAT 26 mononucleotide markers and mutation of KRAS, TP53, and BRAF V600E was detected by direct sequencing. Methyl specific polymerase chain reaction was used to determine promoter methylation status of the classic CIMP panel markers (P16, hMLH1, MINT1, MINT2, and MINT31) as well as other tumor specific genes (DAPK, RASSF1, BRCA1, and GSTP1). MSI and BRAF mutations were uncommon but high frequencies of overall KRAS mutations (67.5%); low KRAS codon 12 and a novel KRAS G15S mutation with concomitant RASSF1 methylation in early onset cases were remarkable. Hierarchical clustering as well as principal component analysis identified three distinct subgroups of patients having discrete age at onset, clinicopathological, molecular and survival characteristics: (i) a KRAS associated CIMP-high subgroup; (ii) a significantly younger MSS, CIMP low, TP53 mutant group having differential KRAS mutation patterns, and (iii) a CIMP-negative, TP53 mutated group. The early onset subgroup exhibited the most unfavorable disease characteristics with advanced stage, poorly differentiated tumors and had the poorest survival compared to the other subgroups. Genetic and epigenetic profiling of rectal cancer patients identified distinct subtypes in Indian population.
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Hugen N, van Beek JJP, de Wilt JHW, Nagtegaal ID. Insight into mucinous colorectal carcinoma: clues from etiology. Ann Surg Oncol 2014; 21:2963-70. [PMID: 24728741 DOI: 10.1245/s10434-014-3706-6] [Citation(s) in RCA: 72] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2014] [Indexed: 12/17/2022]
Abstract
The prognostic impact of mucinous carcinoma (MC) in colorectal cancer (CRC) has been subject to debate ever since the introduction of the classification of tumors according to their histological differentiation. MC is a distinct clinical and pathological entity within the spectrum of CRC and accounts for approximately 10-15 % of cases. Factors involved in MC development have not been completely understood, but clinical observations may lead to a better insight into the etiology of MC. In this article, we provide an in-depth review of the literature regarding etiological aspects of MC. We show that there are worldwide differences in the prevalence of MC, with low rates in Asian countries and higher rates in the western world. Moreover, MC is more commonly diagnosed in patients suffering from inflammatory bowel diseases or Lynch syndrome and an increased rate of MC is observed in patients with radiotherapy-induced CRCs. These findings are suggestive of a different oncogenic development. Identification of conditions that are associated with MC generates insight into the etiological pathways leading to the development of this special subtype.
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Affiliation(s)
- Niek Hugen
- Department of Surgery, Radboud University Medical Center, HB, Nijmegen, The Netherlands,
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Ciarrocchi A, Amicucci G. Sporadic carcinoma of the colon-rectum in young patients: a distinct disease? A critical review. J Gastrointest Cancer 2014; 44:264-9. [PMID: 23712253 DOI: 10.1007/s12029-013-9507-5] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
INTRODUCTION Colon carcinoma is rare in patients under 40 years but incidence is increasing. Results regarding outcome of this age group have been controversial and difficult to interpret. Some authors have reported a worse prognosis related to advanced stage at diagnosis and cancer-aggressive behavior. We tried to assess whether sporadic colon carcinoma in young patients is a distinct disease with different etiology and how this reflects on outcome. METHODS Most relevant papers published and indexed on PubMed in the last 20 years were reviewed. Epidemiological data were retrieved from the Surveillance, Epidemiology and End Results database and discussed. DISCUSSION Stage-specific analyses adjusted for age have demonstrated that prognosis is related to tumor stage regardless of age. Advanced stage is partly due to tumor biology and to delayed diagnosis. Younger patients show a better performance status that allows aggressive multimodal treatment. CONCLUSION Colon carcinoma in young adults appears to be a distinct disease characterized by biological aggressiveness, but prognosis is not worse due to a better performance status at time of surgical intervention.
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Affiliation(s)
- Andrea Ciarrocchi
- General and Emergency Surgery, Department of Surgery, University of L'Aquila, 67100, L'Aquila, Italy.
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Hugen N, Verhoeven RHA, Radema SA, de Hingh IHJT, Pruijt JFM, Nagtegaal ID, Lemmens VEPP, de Wilt JHW. Prognosis and value of adjuvant chemotherapy in stage III mucinous colorectal carcinoma. Ann Oncol 2013; 24:2819-24. [PMID: 24057984 DOI: 10.1093/annonc/mdt378] [Citation(s) in RCA: 85] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
Abstract
BACKGROUND Colorectal mucinous adenocarcinoma (MC) has been associated with impaired prognosis compared with nonmucinous adenocarcinoma (NMC). Response to palliative chemotherapy is poor in metastatic disease, but the benefit of adjuvant chemotherapeutic treatment has never been assessed in large patient groups. This study analyses overall survival and efficacy of adjuvant chemotherapy in terms of survival in patients following radical resection for MC. PATIENTS AND METHODS This population-based study involved 27 251 unselected patients diagnosed with colorectal carcinoma between 1990 and 2010 and recorded in a prospective pathology-based registry. Kaplan-Meier analysis and log-rank testing were used to estimate survival. Cox proportional hazard model was used to calculate multivariate hazard ratios for death. RESULTS MC was found in 12.3% (N = 3052) of colorectal tumors with a different distribution compared with NMC, with 24.4% located in the rectum and 54.3% in the proximal colon (versus 38.0% and 30.6%), P < 0.0001. NMC was more often classified as stage I disease than MC (20.5% versus 10.9%), P < 0.0001. After adjustments for covariates, MC was associated with a higher risk of death only when located in the rectum [hazard ratio 1.22; 95% confidence interval (CI) 1.11-1.34]. Multivariate regression analysis showed a similar survival after adjuvant chemotherapy for stage III MC and NMC patients. CONCLUSIONS The poor prognosis for MC is only present in rectal cancer. In the adjuvant setting, there is no difference in the efficacy of chemotherapy between MC and NMC; therefore, current adjuvant treatment recommendations should not take histology into account.
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Affiliation(s)
- N Hugen
- Department of Surgery, Radboud University Nijmegen Medical Centre, Nijmegen
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23
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Chen JX, Tang XD, Xiang DB, Dong XL, Peng FY, Sun GY. TNM stages and prognostic features of colorectal mucinous adenocarcinomas: a meta analysis. Asian Pac J Cancer Prev 2013; 13:3427-30. [PMID: 22994772 DOI: 10.7314/apjcp.2012.13.7.3427] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
AIM The significance of the mucinous adenocarcinoma in TNM staging and prognosis for colorectal tumor patients is still controversial. The aim was to provide a meta-analysis for TNM staging and prognostic features of colorectal tumors. METHODS 30 individual case-control studies were finally included into this meta-analysis, involving a total of 444,489 cancer cases and 45,050 mucinous adenocarcinomas, of relations with TNM staging and prognostic features. RESULTS Compared to non-mucinous adenocarcinoma patients, the TNM IV stage accounted for a larger percentage of mucinous adenocarcinomas (OR=1.48, 95%CI 1.28-1.71, POR<0.001) and the prognosis was significantly poor (HR=1.06, 95%CI 1.04-1.08, P<0.001). After heterogeneity testing, the results was similar to the holistic approach outcome (HR=1.48, 95%CI 1.35-1.62, P<0.001). CONCLUSION Compared to patients with non-mucinous adenocarcinomas, mucinous adenocarcinoma patients with later TNM staging make up a big percentage, and mucinous adenocarcinoma is an independent risk factor for poor prognosis.
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Affiliation(s)
- Jing-Xiang Chen
- Department of Emergency, Jiangjin Central Hospital, Chongqing, China
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24
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Li L, Huang PL, Yu XJ, Bu XD. Clinicopathological Significance of Mucin 2 Immuno-histochemical Expression in Colorectal Cancer: A Meta-Analysis. Chin J Cancer Res 2012; 24:190-5. [PMID: 23358901 PMCID: PMC3555282 DOI: 10.1007/s11670-012-0190-z] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2011] [Accepted: 06/07/2011] [Indexed: 01/05/2023] Open
Abstract
OBJECTIVE To evaluate the association between mucin 2 (MUC2) expression and clinicopathological characters of colorectal cancer. METHODS A literature search was performed on December 31, 2010 according to defined selection criteria. We evaluated the correlation between MUC2 (detected by immunohistochemistry) and clinicopathological characters of colorectal cancer. According to the tumor histological type, differentiation, location and TNM staging of colorectal carcinoma, we divided the clinicopathological characteristics into different subgroups. Fixed and random effects models were applied for estimation of the summarized risk ratios (RRs) and 95% confidence intervals (CIs) in different subgroups. Finally, forest plots and funnel plots were created to allow for visual comparison of the results or the effect of publication bias. RESULTS According with the inclusive criteria, fourteen studies (n=1,558) were eligible for the meta-analysis. We observed a trend towards a correlation of MUC2 higher positivity in mucinous than non-mucinous carcinoma (RR, 2.10; 95% CI, 1.30-3.40; P=0.002) and less positivity in distal than proximal colon (RR, 0.74; 95% CI, 0.64-0.85; P=0.000). There was no statistically significance for the association between MUC2 expression and differentiation or TNM staging of colorectal cancer, but MUC2 overexpression tended to be associated with the presence of T stage tumor (RR, 1.17; P=0.052). CONCLUSION MUC2 overexpression was associated with the mucinous and proximal colorectal cancer.
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Affiliation(s)
- Li Li
- Department of Pathology, Affiliated First Hospital, Nanjing Medical University, Nanjing 210006, China
| | - Pei-lin Huang
- Department of Pathology, School of Medicine, Southeast University, Nanjing 210009, China
| | - Xiao-jin Yu
- Department of Epidemiology and Statistics, School of Public Health, Southeast University, Nanjing 210009, China
| | - Xiao-dong Bu
- Department of Pathology, School of Medicine, Southeast University, Nanjing 210009, China
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25
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The insulin receptor substrate 1 (IRS1) in intestinal epithelial differentiation and in colorectal cancer. PLoS One 2012; 7:e36190. [PMID: 22558377 PMCID: PMC3338610 DOI: 10.1371/journal.pone.0036190] [Citation(s) in RCA: 52] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2010] [Accepted: 04/01/2012] [Indexed: 12/13/2022] Open
Abstract
Colorectal cancer (CRC) is associated with lifestyle factors that affect insulin/IGF signaling, of which the insulin receptor substrate 1 (IRS1) is a key transducer. We investigated expression, localization and pathologic correlations of IRS1 in cancer-uninvolved colonic epithelium, primary CRCs with paired liver metastases and in vitro polarizing Caco2 and HT29 cells. IRS1 mRNA and protein resulted higher, relative to paired mucosa, in adenomas of familial adenomatous polyposis patients and in CRCs that overexpressed c-MYC, ß-catenin, InsRß, and IGF1R. Analysis of IRS1 immunostaining in 24 cases of primary CRC with paired colonic epithelium and hepatic metastasis showed that staining intensity was significantly higher in metastases relative to both primary CRC (P<0.01) and colonic epithelium (P<0.01). Primary and metastatic CRCs, compared to colonic epithelium, contained significantly higher numbers of IRS1-positive cells (P = 0.013 and P = 0.014, respectively). Pathologic correlations in 163 primary CRCs revealed that diffuse IRS1 staining was associated with tumors combining differentiated phenotype and aggressive markers (high Ki67, p53, and ß-catenin). In Caco 2 IRS1 and InsR were maximally expressed after polarization, while IGF1R was highest in pre-polarized cells. No nuclear IRS1 was detected, while, with polarization, phosphorylated IRS1 (pIRS1) shifted from the lateral to the apical plasma membrane and was expressed in surface cells only. In HT29, that carry mutations constitutively activating survival signaling, IRS1 and IGF1R decreased with polarization, while pIRS1 localized in nuclear spots throughout the course. Overall, these data provide evidence that IRS1 is modulated according to CRC differentiation, and support a role of IRS1 in CRC progression and liver metastatization.
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Chung MY, Park YS, Ryu SR, Ahn SB, Kim SH, Jo YJ, Han JK, Joo JE. A case of colonic mucinous adenocarcinoma in 19-year-old male patient. Clin Endosc 2012; 45:103-7. [PMID: 22741141 PMCID: PMC3363130 DOI: 10.5946/ce.2012.45.1.103] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/23/2011] [Revised: 10/31/2011] [Accepted: 11/23/2011] [Indexed: 12/28/2022] Open
Abstract
Colorectal cancer is rare in teenagers, especially without known risk factors. Colon cancer in young age is more likely to be diagnosed at advanced-stage, to present unfavorable tumor histology such as mucinous carcinoma, and poor outcome. We report a case of sporadic mucinous adenocarcinoma of the colon in a 19-year-old male patient without any risk factors. He complained of severe left abdominal pain that developed 1 month ago. He had a distended abdomen with severe tenderness on the left lower quadrant. A distal descending colon mass causing mechanical obstruction was observed on abdominal computed tomography. Emergency colonoscopy showed a large, fungating mass obstructing the lumen at 40 cm from the anal verge. Biopsy of the colonic mass suggested a mucinous adenocarcinoma. After decompression by colonic stent, the patient was transferred to the general surgery department for left hemicolectomy. The lesion was confirmed to be a mucinous adenocarcinoma (7.0×4.5 cm). For hereditary nonpolyposis colorectal cancer evaluation, immunohistochemical staining for MLH1 and MSH2 was normal. Reverse transcription polymerase chain reaction analysis did not detect microinstability in any of the markers tested. The patient had no familial history of cancer. Mucinous adenocarcinoma has high frequencies of poor differentiation, advanced tumor stage, loss of mismatch repair gene expression, and increased MUC2 expression. A mucinous histology is considerably more frequent in children and adolescent than in adults. Adequate invasive study is also necessary for young age patients.
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Affiliation(s)
- Mi Yeon Chung
- Department of Internal Medicine, Eulji Medical Center, Eulji University School of Medicine, Seoul, Korea
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Langner C, Harbaum L, Pollheimer MJ, Kornprat P, Lindtner RA, Schlemmer A, Vieth M, Rehak P. Mucinous differentiation in colorectal cancer--indicator of poor prognosis? Histopathology 2012; 60:1060-72. [PMID: 22348346 DOI: 10.1111/j.1365-2559.2011.04155.x] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
AIMS To analyse the prognostic impact of mucinous differentiation in colorectal mucinous adenocarcinomas and adenocarcinomas with a mucinous component. METHODS AND RESULTS A total of 381 tumours were reviewed for mucinous differentiation by two independent pathologists. Mismatch repair status was assessed by immunohistochemistry. Prognostic significance was assessed by univariate and multivariate analyses. Eighty-one (21%) tumours were Union Internationale Contre le Cancer (UICC) Stage I, 120 (31%) Stage II, 126 (33%) Stage III and 54 (14%) Stage IV. Mucinous adenocarcinomas accounted for 12% and adenocarcinomas with a mucinous component for 19% of tumours. Mucinous differentiation was associated significantly with mismatch repair protein deficiency. The presence of extracellular mucin, regardless of extent, did not affect patients' outcome, while tumour grade, vascular and perineural invasion, tumour border configuration and budding were associated significantly with outcome. Cox analysis proved venous invasion to be an independent predictor of outcome in mucinous adenocarcinomas and both venous invasion and tumour budding as independent predictors of outcome in adenocarcinomas with any amount of mucin. CONCLUSIONS Mucinous adenocarcinomas and/or adenocarcinomas with mucinous component do not differ from conventional adenocarcinomas with respect to prognosis and histological predictors of outcome. Hence, recording of mucinous differentiation may be used as an indicator of mismatch repair deficiency, but not for prognostic stratification.
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Affiliation(s)
- Cord Langner
- Institute of Pathology, Medical University of Graz, Auenbruggerplatz 25, Graz, Austria.
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Suppression of mucin 2 enhances the proliferation and invasion of LS174T human colorectal cancer cells. Cell Biol Int 2012; 35:1121-9. [PMID: 21605079 DOI: 10.1042/cbi20100876] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Abstract
Altered expression of MUC2 (mucin 2) is related to tumour development in colorectal cancer. Colorectal mucinous carcinomas are positive for MUC2 expression, whereas MUC2 is down-regulated in non-mucinous adenocarcinomas. In the present study, we down-regulated MUC2 expression by RNAi (RNA interference) and investigated the in vitro and in vivo effects on the proliferation and invasion/migration potential of the LS174T human colorectal cancer cells. The LS174T cell line is a goblet-cell-like colorectal cancer cell line that continuously produces high levels of MUC2. Inhibition of MUC2 expression in vitro by transfection of LS174T cells with the recombinant plasmid pcDNA6.2-GW/EmGFP-miR-MUC2 led to the production of a stably transfected MUC2-RNAi LS174T cell line. The proliferation and invasion/migration of MUC2-RNAi cells in vitro were significantly higher than those in control cells, as assessed by MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide], colony formation and transwell assays. Subcutaneous injection of MUC2-RNAi LS174T cells into nude mice resulted in the development of subcutaneous tumours visible to the naked eye after 1 week. The growth rate of tumours derived from MUC2-RNAi LS174T cells was greater than that of tumours derived from control cells. Ki67 and matrix metalloproteinase-9 proteins were detected by immunohistochemistry in the xenografts. The expression levels of these proteins were higher in the MUC2-RNAi-derived xenografts than in xenografts derived from control cells. Although the role of MUC2 in colorectal tumorigenesis is not fully understood, these results strongly suggest a relationship between the proliferation and invasion of LS174T cells and the expression of MUC2.
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Mekenkamp LJM, Heesterbeek KJ, Koopman M, Tol J, Teerenstra S, Venderbosch S, Punt CJA, Nagtegaal ID. Mucinous adenocarcinomas: poor prognosis in metastatic colorectal cancer. Eur J Cancer 2012; 48:501-9. [PMID: 22226571 DOI: 10.1016/j.ejca.2011.12.004] [Citation(s) in RCA: 124] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2011] [Revised: 12/06/2011] [Accepted: 12/09/2011] [Indexed: 12/28/2022]
Abstract
PURPOSE Mucinous histology of metastatic colorectal cancer (CRC) has been associated with poor prognosis, however this has never been assessed in large well-defined study populations treated with the current used systemic agents. We investigated the prognostic value of mucinous histology in two large phase III studies in metastatic CRC. PATIENTS AND METHODS The study population included 1010 metastatic CRC patients who were treated with chemotherapy and targeted therapies in two phase III studies. Patients were classified according to the histology of the primary tumour in mucinous adenocarcinomas (MC) and non-mucinous adenocarcinomas (AC). RESULTS Patients with MC (n=99) were older, had more often a normal serum lactate dehydrogenase (LDH), extrahepatic localisation of metastases, larger primary tumour diameter and a higher T classification compared to patients with AC (n=911). A deficient mismatch repair system and BRAF mutations were observed in 17% and 22% of patients with MC, compared to 3% and 7% in patients with AC, respectively. Clinical outcome was investigated in both studies separately, showing a worse overall survival (OS), progression free survival and overall response rate in patients with MC compared to patients with AC. Patients with MC received less cycles of treatment compared to AC, but did not suffer from a higher incidence of grade 3/4 toxicity. In multivariate analysis, mucinous histology was as an independent negative prognostic factor for OS, resulting in a combined hazard ratio of 1.78 (95%confidence interval (CI) 1.35-2.35). CONCLUSIONS Patients with metastatic mucinous CRC have distinct clinicopathological features and poor response to chemotherapy and targeted agents. The strong negative prognostic value of MC warrants the use of this pathological feature as a stratification factor for clinical trials in metastatic CRC.
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Affiliation(s)
- Leonie J M Mekenkamp
- Department of Pathology, Radboud University Nijmegen Medical Centre, The Netherlands
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