Thymosin β-4 in colorectal cancer is localized predominantly at the invasion front in tumor cells undergoing epithelial mesenchymal transition

摘要

Objective: Thymosin β-4 (Tβ 4) is a ubiquitous peptide that plays pivotal roles in the cytoskeletal system and in cell differentiation during embryogenesis. Recently, a role for Tβ 4 has been proposed in experimental and human carcinogenesis. This study was aimed at evaluating the correlation between Tβ 4 immunoractivity and colorectal cancer, with particular attemption to tumor cells undergoing epithelial-mesenchymal transition. Methods and Results: 86 intestinal biopsies were retrospectively analyzed including 76 colorectal adenocarcinomas with evident features of epithelial-mesenchymal transition, and 10 samples of normal colorectal mucosa. Paraffin sections were immunostained for Tβ 4 and for E-cadherin. Total RNA was isolated from frozen specimens obtained, at surgery, from the normal colon mucosa, the deeper regions and the superficial tumor regions in four cases of colon cancer. Tβ 4 immunoreactivity was detected in the vast majority (59/76) of colon carcinomas, showing a patchy distribution, with well differentiated areas significantly more reactive than the less differentiated tumor zones. We also noted a zonal pattern in the majority of tumors, characterized by a progressive increase in immunostaining for Tβ 4 from the superficial toward the deepest tumor regions. The strongest expression for Tβ 4 was frequently detected in invading tumor cells with features of epithelial-mesenchymal transition. The increase in reactivity for Tβ 4 matched with a progressive decrease in E-cadherin expression in invading cancer cells. At mRNA level, the differences in Tβ 4 expression between the surrounding colon mucosa and the tumors samples were not significant. Conclusions: Our data show that Tβ 4 is expressed in the majority of colon cancers, with preferential immunoreactivity in deep tumor regions. The preferential expression of the peptide and the increase in intensity of the immunostaining at the invasion front suggests a possible link between the peptide and the process of epithelial mesenchymal transition, suggesting a role for Tβ 4 in colorectal cancer invasion and metastasis.