Immunoprofiling of Colitis-associated and Sporadic Colorectal Cancer and its Clinical Significance.
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ABSTRACT:
SUBMITTER: Soh JS
PROVIDER: S-EPMC6497720 | biostudies-literature | 2019 May
REPOSITORIES: biostudies-literature
Publications
Immunoprofiling of Colitis-associated and Sporadic Colorectal Cancer and its Clinical Significance.
Soh Jae Seung JS Jo Su In SI Lee Hyejin H Do Eun-Ju EJ Hwang Sung Wook SW Park Sang Hyoung SH Ye Byong Duk BD Byeon Jeong-Sik JS Yang Suk-Kyun SK Kim Ji Hun JH Yang Dong-Hoon DH Kim Sang-Yeob SY Myung Seung-Jae SJ
Scientific reports 20190502 1
Immunoprofiling is useful for predicting prognosis in various malignancies and provides targets for immunotherapy. Quantitative multispectral imaging system, which allows simultaneous detection of multiple immune markers, is a novel method for examining the tumor immune environment. We compared the expression levels of various surface markers in immune cells between colitis-associated cancer (CAC) and sporadic colorectal cancer (CRC) and evaluated the clinical usefulness of immunoprofiling in CR ...[more]
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Project description:BackgroundChronic inflammation is a significant factor in colorectal cancer (CRC) development, especially in colitis-associated CRC (CAC). T-cell exhaustion is known to influence inflammatory bowel disease (IBD) progression and antitumor immunity in IBD patients. This study aimed to identify unique immune infiltration characteristics in CAC patients.MethodsWe studied 20 CAC and 20 sporadic CRC (sCRC) patients, who were matched by tumor stage, grade, and location. Immunohistochemical staining targeted various T-cell markers (CD3, CD4, CD8, and FOXP3), T-cell exhaustion markers (TOX and TIGIT), a B-cell marker (CD20), and a neutrophil marker (CD66b) in tumor and tumor-free mucosa from both groups. The quantification of the tumor immune stroma algorithm assessed immune-infiltrating cells.ResultsCAC patients had significantly lower TOX+ cell infiltration than sCRC in tumors (p = 0.02) and paracancerous tissues (p < 0.01). Right-sided CAC showed increased infiltration of TOX+ cells (p = 0.01), FOXP3+ regulatory T-cells (p < 0.01), and CD20+ B-cells (p < 0.01) compared to left-sided CAC. In sCRC, higher tumor stages (III and IV) had significantly lower TIGIT+ infiltrate than stages I and II. In CAC, high CD3+ (p < 0.01) and CD20+ (p < 0.01) infiltrates correlated with improved overall survival. In sCRC, better survival was associated with decreased TIGIT+ cells (p < 0.038) and reduced CD8+ infiltrates (p = 0.02).ConclusionIn CAC, high CD3+ and CD20+ infiltrates relate to improved survival, while this association is absent in sCRC. The study revealed marked differences in TIGIT and TOX expression, emphasizing distinctions between CAC and sCRC. T-cell exhaustion appears to have a different role in CAC development.
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Project description:BACKGROUND:The development of colorectal cancer (CRC) is a complicated multistep process that involves an accumulation of mutations in tumor suppressor genes and oncogenes. In the process of DNA replication, base mismatch often occurs due to various factors leading to abnormal expression of mismatch repair genes (MMR), among which MLH1 and MSH2 are the most important. Recently, numerous studies indicated that MLH1/MSH2 phenotype is associated with CRC. We wanted to elucidate the role of MLH1/MSH2 in the prediction and prognosis of CRC through long-term clinical observation. AIM:To evaluate the prognostic and predictive significance of MLH1/MSH2 in patients with stage II-III CRC using immunohistochemical analysis and GeneScan. METHODS:Specimens from 681 patients with CRC (395 stage II and 286 stage III, 387 males and 294 females) who underwent curative surgical resection from 2013 to 2016 were tested. Immunohistochemistry was used to analyze MMR status and the microsatellite status of 133 patients was determined by GeneScan analysis. RESULTS:Five hundred and fifty (80.76%) patients were MLH1/MSH2 positive and 131 (19.24%) were negative by immunohistochemistry. MLH1/MSH2-positive tumors were significantly more frequent in the colon than in the rectum, and had poor differentiation and less mucin production (P < 0.05). Patients of different groups did not differ in terms of age, gender, tumor size, tumor stage, lymphocytic infiltration, or circumscribed margin. MLH1/MSH2-negative patients had a more favorable OS than MLH1/MSH2-positive patients (P < 0.001). Univariate and multivariate analyses demonstrated MLH1/MSH2 expression as an independent prognostic and predictive factor for stage II/III CRC. MLH1/MSH2 expression was a strong prognostic factor in all patients [P < 0.001, hazard ratio (HR) = 4.064, 95%CI: 2.241-7.369]. Adjuvant chemotherapy had a greater correlation with survival advantage in MLH1/MSH2-negative patients with stage III disease (P < 0.001, HR = 7.660, 95%CI: 2.974-15.883). However, patients with stage II disease or MLH1/MSH2-positive patients with stage III disease did not benefit from adjuvant chemotherapy. GeneScan analysis demonstrated that among 133 patients, 105 (78.95%) were microsatellite stable, and 28 (21.05%) had microsatellite instability (MSI), including 18 (13.53%) with high MSI and 10 (7.52%) with low MSI. This is consistent with the immunohistochemical results. CONCLUSION:MLH1/MSH2 phenotype constitutes a pathologically and clinically distinct subtype of sporadic CRC. MLH1/MSH2 is an independent prognostic and predictive factor for outcome of stage II-III CRC.
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Project description:BackgroundColorectal cancers develop through several pathways, including the adenoma-carcinoma sequence and colitis-associated carcinogenesis. An altered intestinal microflora has been reported to be associated with the development and progression of colorectal cancer via these pathways. We identified Lactobacillus casei-derived ferrichrome as a mediator of the bacterial anti-tumor effect of colorectal cancer cells through the upregulation of DDIT3. In this study, we investigated the anti-tumor effects of ferrichrome on precancerous conditions and cancer cells associated with sporadic as well as colitis-associated colorectal cancer.MethodsSRB and MTT assays were performed to assess growth inhibition in vitro. Eighteen organoids were prepared from biopsy specimens obtained by colonoscopy. An AOM-DSS carcinogenesis model and xenograft model of colorectal cancer cells were generated for the assessment of the tumor suppressive effect of ferrichrome in vivo.ResultsFerrichrome inhibited the cell growth of colorectal cancer cells in vitro and in in vivo xenograft models. Ferrichrome exerted a strong tumor-suppressive effect that was superior to that of currently available anti-tumor agents, including 5-FU and cisplatin, both in vitro and in vivo. The tumor-suppressive effect of the combination of ferrichrome and 5-FU was superior to that of single treatment with either drug. The tumor suppressive effects of ferrichrome were confirmed through the upregulation of DDIT3 in patient-derived organoids of adenoma and carcinoma. Ferrichrome inhibited the tumor progression in the AOM-DSS model while exhibiting no anti-inflammatory effect in the DSS-colitis model, suggesting that ferrichrome inhibited cancer cells, but not a precancerous condition, via the colitis-associated pathway.ConclusionsFerrichrome exerts a tumor suppressive effect on precancerous conditions and cancer cells associated with sporadic as well as colitis-associated colorectal cancer. The anti-tumor effect of ferrichrome was mediated by the upregulation of DDIT3, and was superior to that of 5-FU or cisplatin. These results suggest that Lactobacillus brevis-derived ferrichrome may be a candidate anti-tumor drug for the treatment of colorectal neoplasms.
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Project description:Purpose and Experimental Design: The purpose of this study is to find a methylation-related gene that could become a biomarker or therapeutic target in colorectal carcinoma (CRC). We screened candidate genes suspected to be silenced by DNA methylation using oligonucleotide microarray analysis. To investigate the clinical significance of one candidate gene (UNC5B), we analyzed the correlation between mRNA expression and clinicopathological features using clinical tissue samples. Finally, methylation specific PCR analysis was performed to reveal whether the promoter region was methylated in CRC cell lines. Results: We found 75 candidate genes that were potentially suppressed by DNA methylation in CRC. We focused on UNC5B, a possible tumor suppressor gene and regulator of apoptosis known to be inactivated in CRC. The mRNA expression analysis using tissue samples revealed that UNC5B mRNA was down-expressed in about 20% of CRC patients, and the patients with low-UNC5B-expression tumors showed a significantly higher recurrence rate after curative surgery. According to the univariate and multivariate analysis, low UNC5B expression was an independent risk factor for postoperative recurrence in stage I, II, and III CRC patients. Furthermore, patients with low expression of UNC5B in tumors had significantly poorer prognosis than those with high expression of UNC5B. Although UNC5B mRNA expression was restored by the demethylation treatment in CRC cell lines, the promoter region of UNC5B was not methylated. Conclusion: UNC5B is a potential biomarker for the selection of patients with high risk of postoperative recurrence and worse prognosis in CRC.
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2011-02-28 | GSE21510 | GEO
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2013-04-01 | E-GEOD-43338 | biostudies-arrayexpress
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