Tumor-Infiltrating FOXP3+ T Regulatory Cells Show Strong Prognostic Significance in Colorectal Cancer

Purpose To determine the prognostic significance of FOXP3+ lymphocyte (Treg) density in colorectal cancer compared with conventional histopathologic features and with CD8+ and CD45RO+ lymphocyte densities. Patients and Methods Tissue microarrays and immunohistochemistry were used to assess the densities of CD8+, CD45RO+, and FOXP3+ lymphocytes in tumor tissue and normal colonic mucosa from 967 stage II and stage III colorectal cancers. These were evaluated for associations with histopathologic features and patient survival. Results FOXP3+ Treg density was higher in tumor tissue compared with normal colonic mucosa, whereas CD8+ and CD45RO+ cell densities were lower. FOXP3+ Tregs were not associated with any histopathologic features, with the exception of tumor stage. Multivariate analysis showed that stage, vascular invasion, and FOXP3+ Treg density in normal and tumor tissue were independent prognostic indicators, but not CD8+ and CD45RO+. High FOXP3+ Treg density in normal mucosa was associated with worse prognosis (hazard ratio [HR] = 1.51; 95% CI, 1.07 to 2.13; P = .019). In contrast, a high density of FOXP3+ Tregs in tumor tissue was associated with improved survival (HR = 0.54; 95% CI, 0.38 to 0.77; P = .001). Conclusion FOXP3+ Treg density in normal and tumor tissue had stronger prognostic significance in colorectal cancer compared with CD8+ and CD45RO+ lymphocytes. The finding of improved survival associated with a high density of tumor-infiltrating FOXP3+ Tregs in colorectal cancer contrasts with several other solid cancer types. The inclusion of FOXP3+ Treg density may help to improve the prognostication of early-stage colorectal cancer.

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Assessment of vitamin D and VDR gene expression in colorectal cancer patients

Diagnostyka Laboratoryjna ◽

10.5604/01.3001.0008.2252 ◽

2015 ◽

Vol 51 (3) ◽

pp. 193-198

Author(s):

Joanna Berska ◽

Jolanta Bugajska ◽

Diana Hodorowicz-Zaniewska ◽

Krystyna Sztefko

Keyword(s):

Colorectal Cancer ◽

Vitamin D ◽

Serum Concentration ◽

Cancer Patients ◽

Colonic Mucosa ◽

Tumor Tissue ◽

Disease Stage ◽

Control Group ◽

Normal Colonic Mucosa ◽

Colorectal Cancer Patients

Background: Vitamin D insufficiency may increase risk and/or progression of cancer. Vitamin D acts through a nuclear receptor (VDR) which binding to vitamin D response elements causes changes in many genes expression. The aim: to assess the serum concentration of 25-hydroxycholecalciferol (25(OH)D3) and tissue VDR expression in colorectal cancer patients in relation to disease stage, tumor localization and disease progression. Material & Methods: The study group consisted of 39 patients with colorectal cancer (mean age 65,5±6,8 yrs, 23/16 male/female) and a control group consisted of 25 patients (mean age 51,0±6,9 yrs; 8/17 male/female) without gastrointestinal disease and without neoplasm. Serum level of 25(OH)D3 was measured by HPLC/UV. RNA was isolated from homogenized normal colonic mucosa and tumor tissue then RT-PCR was performed. Results: The mean serum concentration of 25(OH)D3 was lower in the colorectal cancer patients as compared to the control group. The difference was significantly lower only for the patients with the early stages of the disease (p<0.02) and for the patients with tumor present in rectum (p<0.03). Higher VDR expression in tumor tissue than in normal colonic mucosa was observed. For the patients with the early stages of the disease (stage A, B1, B2) higher expression of VDR as compared to the patients with advanced stages (stage C1, C2, D) was noticed. Moreover, VDR expression was higher in tumor tissue obtained from disease-free patients as compared to the patients with disease progression noted one-year-follow-up (p<0.04). Conclusion: Antitumor effect of vitamin D depends on VDR expression in tumor tissue.

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The different immune profiles of normal colonic mucosa in cancer-free Lynch syndrome carriers and Lynch syndrome colorectal cancer patients

Gastroenterology ◽

10.1053/j.gastro.2021.11.029 ◽

2021 ◽

Author(s):

Lena Bohaumilitzky ◽

Klaus Kluck ◽

Robert Hüneburg ◽

Richard Gallon ◽

Jacob Nattermann ◽

...

Keyword(s):

Colorectal Cancer ◽

Lynch Syndrome ◽

Cancer Patients ◽

Colonic Mucosa ◽

Normal Colonic Mucosa ◽

Colorectal Cancer Patients

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Antioxidant Agents and Colorectal Carcinogenesis: Role of β-Carotene, Vitamin E and Vitamin C

Tumori Journal ◽

10.1177/030089169608200102 ◽

1996 ◽

Vol 82 (1) ◽

pp. 6-11 ◽

Cited By ~ 7

Author(s):

Giuseppe Pappalardo ◽

Antonio Guadalaxara ◽

Giuseppe Maiani ◽

Giovanni Illomei ◽

Mauro Trifero ◽

...

Keyword(s):

Colorectal Cancer ◽

Vitamin E ◽

Vitamin C ◽

Colonic Mucosa ◽

Genetic Alterations ◽

Colorectal Carcinogenesis ◽

Normal Colonic Mucosa ◽

Antioxidant Agents ◽

Β Carotene

In consideration of findings reported in the literature and of our study, we examined the correlation between antioxidants (β-carotene, vitamin C, vitamin E) and colorectal carcinogenesis. Although diagnostic progress has been made in the last decades, no significant improvements in death rates have been achieved in the western world. Exogenous factors might be responsible for a complex alteration process of normal colonic mucosa into adenoma and carcinoma. Free radicals and reactive oxygen metabolites, due to increased production or to reduced inactivation, following a decrease in the antioxidant burden in the mucosa, might cause damage to DNA, thereby resulting in genetic alterations. This might represent the cause of the transformation process: normal mucosa→ adenoma→ carcinoma. In a prospective study, we observed a reduction of β-carotene levels in normal colonic mucosa in patients with polyps and colorectal cancer. We also showed that β-carotene supplementation raises levels of this micronutrient in the colonic mucosa of these patients. Findings from the literature and our trials show a significant decrease in the antioxidant capacity of colorectal mucosa in patients affected by colorectal cancer, although there is a significant interindividual variability. Such results suggest a possible chemopreventive role of antioxidant agents in colorectal cancer.

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Prognostic significance of tumor stromal and epithelial claudin 2 in metastatic colorectal cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.15_suppl.3597 ◽

2013 ◽

Vol 31 (15_suppl) ◽

pp. 3597-3597

Author(s):

Artur Mezheyeuski ◽

Tormod Kyrre Guren ◽

Bengt Glimelius ◽

Per Pfeiffer ◽

Elin Kure ◽

...

Keyword(s):

Colorectal Cancer ◽

Alkaline Phosphatase ◽

Cancer Cells ◽

Tumor Tissue ◽

Primary Cultures ◽

Prognostic Significance ◽

Tumor Stroma ◽

Phase Iii ◽

Rank Test ◽

Worse Prognosis

3597 Background: Tight junctions (TJ) are the most apical epithelial cell–cell adhesions. Claudin super-family trans-membrane proteins, including claudin 2 (cl2), are important components of TJs. Expression of cl2 has been reported to be elevated in colorectal cancer (CRC) and its up-regulation increases tumorigenicity of CRC cells in vitro. The aim of this study was to analyze the prognostic significance of cl2 in CRC. Methods: A tissue microarray (TMA) from the stage IV CRC patients of the phase III NORDIC-VII study was used. Cl2 IHC staining was evaluated in a semi-quantitative manner in cancer cells (cl2-C) and in the tumor stroma (cl2-S). Primary fibroblasts were established from human CRC tumor tissue and non-tumor colon tissue, and evaluated by immunoblotting. Results: Analyses of the TMA derived from the NORDIC-VII cohort revealed that cancer cell expression and tumor stroma expression of cl2 was associated with shorter OS in a Log-Rank test for trend (cl2-C, n=315, p=0.018; cl2-S, n=319, p=0.020). Expression of cl2-S, but not cl2-C was prognostic in multivariate analysis including WHO performance status, alkaline phosphatase level and BRAF mutation status (HR=1.30; 95% CI 1.08-1.56; p=0.006). When cl2-C and cl2-S expression was combined the prognostic significance was increased. The group with high cl2-C and high cl2-S (N=182), when compared with the rest of the cases (n=129), displayed a worse prognosis in terms of OS (19.1 mo vs 27.2 mo; p=0.003) in univariate analyses (HR=1.55, 95% CI 1.16-2.08, p=0.003) and in multivariate analyses (HR=1.52, 95% CI 1.13-2.05, p=0.006). Immunoblotting analysis of primary cultures of fibroblasts confirmed cl2 expression in fibroblasts from CRC tissue and from non-tumor tissue, with higher expression observed in the tumor fibroblasts. Conclusions: CRC display a previously un-reported stromal expression of cl2 of prognostic significance. High cl2-S is associated with worse prognosis in patients with metastatic CRC, in a manner independent of WHO status, alkaline phosphatase levels and BRAF status. Furthermore, high expression of cl2 in both cancer cells and the tumor stroma is also associated with poor prognosis.

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An Assessment of Database-Validated microRNA Target Genes in Normal Colonic Mucosa: Implications for Pathway Analysis

Cancer Informatics ◽

10.1177/1176935117716405 ◽

2017 ◽

Vol 16 ◽

pp. 117693511771640 ◽

Cited By ~ 7

Author(s):

Martha L Slattery ◽

Jennifer S Herrick ◽

John R Stevens ◽

Roger K Wolff ◽

Lila E Mullany

Keyword(s):

Colorectal Cancer ◽

Mrna Expression ◽

Messenger Rna ◽

Colonic Mucosa ◽

Target Gene ◽

Target Genes ◽

Multiple Comparisons ◽

Normal Colonic Mucosa ◽

Seed Region ◽

Discovery Phase

Background: Determination of functional pathways regulated by microRNAs (miRNAs), while an essential step in developing therapeutics, is challenging. Some miRNAs have been studied extensively; others have limited information. In this study, we focus on 254 miRNAs previously identified as being associated with colorectal cancer and their database-identified validated target genes. Methods: We use RNA-Seq data to evaluate messenger RNA (mRNA) expression for 157 subjects who also had miRNA expression data. In the replication phase of the study, we replicated associations between 254 miRNAs associated with colorectal cancer and mRNA expression of database-identified target genes in normal colonic mucosa. In the discovery phase of the study, we evaluated expression of 18 miRNAs (those with 20 or fewer database-identified target genes along with miR-21-5p, miR-215-5p, and miR-124-3p which have more than 500 database-identified target genes) with expression of 17 434 mRNAs to identify new targets in colon tissue. Seed region matches between miRNA and newly identified targeted mRNA were used to help determine direct miRNA-mRNA associations. Results: From the replication of the 121 miRNAs that had at least 1 database-identified target gene using mRNA expression methods, 97.9% were expressed in normal colonic mucosa. Of the 8622 target miRNA-mRNA associations identified in the database, 2658 (30.2%) were associated with gene expression in normal colonic mucosa after adjusting for multiple comparisons. Of the 133 miRNAs with database-identified target genes by non-mRNA expression methods, 97.2% were expressed in normal colonic mucosa. After adjustment for multiple comparisons, 2416 miRNA-mRNA associations remained significant (19.8%). Results from the discovery phase based on detailed examination of 18 miRNAs identified more than 80 000 miRNA-mRNA associations that had not previously linked to the miRNA. Of these miRNA-mRNA associations, 15.6% and 14.8% had seed matches for CRCh38 and CRCh37, respectively. Conclusions: Our data suggest that miRNA target gene databases are incomplete; pathways derived from these databases have similar deficiencies. Although we know a lot about several miRNAs, little is known about other miRNAs in terms of their targeted genes. We encourage others to use their data to continue to further identify and validate miRNA-targeted genes.

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