Loss of membranous Ep-CAM in budding colorectal carcinoma cells

Abstract

Tumor budding is a histological feature that reflects loss of adhesion of tumor cells and is associated with locoregional metastasis of colorectal carcinoma. Although nuclear localization of b-catenin is associated with tumor budding, the molecular mechanism remains largely elusive. In this study, we hypothesize that the epithelial cell adhesion molecule (Ep-CAM) is involved in tumor budding. In order to address this question, we performed immunohistochemistry on Ep-CAM using three different antibodies (monoclonal antibodies Ber-ep4 and 311-1K1 and a polyclonal antibody) and a double staining on b-catenin and Ep-CAM. In addition, Ep-CAM mRNA was monitored with mRNA in situ hybridization. Subsequently, we determined the effect of Ep-CAM staining patterns on tumor spread in rectal cancer. In contrast to the tumor mass, budding cells of colorectal carcinoma displayed lack of membranous but highly increased cytoplasmic Ep-CAM staining and nuclear translocation of b-catenin. mRNA in situ hybridization suggested no differences in Ep-CAM expression between the invasive front and the tumor mass. Importantly, reduced Ep-CAM staining at the invasive margin of rectal tumor specimens (n ¼ 133) correlated significantly with tumor budding, tumor grade and an increased risk of local recurrence (P ¼ 0.001, P ¼ 0.04 and P ¼ 0.03, respectively). These data demonstrate abnormal processing of Ep-CAM at the invasive margin of colorectal carcinomas. Our observations indicate that loss of membranous Ep-CAM is associated with nuclear b-catenin localization and suggest that this contributes to reduced cell-cell adhesions, increased migratory potential and tumor budding.

Reduction in Membranous Immunohistochemical Staining for the Intracellular Domain of Epithelial Cell Adhesion Molecule Correlates with Poor Patient Outcome in Primary Colorectal Adenocarcinoma

“…In the present study, loss of membranous epcam staining was associated w ith poorly differentiated tumours and poor survival. Those findings are similar to results from other studies 6 . Recent studies have proposed that the proteolytic cleavage of epcam-icd triggers a signalling cascade leading to the activation of the Wnt/ beta-catenin pathway 3 .…”

“…Expression of epcam has been observed in various epithelial neoplasms, including gastrointestinal, thyroid, kidney, prostate, breast, and lung carcinomas 6,7 , leading to its selection as a target for immunotherapy. The human anti-epcam antibody adecatumumab and the murine monoclonal antibody edrecolomab were developed in hope that they could be used in targeted cancer therapy.…”

“…The loss of membranous epcam has been observed in budding colorectal carcinoma cells, as has increased cytoplasmic staining for epcam and nuclear staining for beta-catenin 6 . In the same study, reduced epcam staining was also shown to correlate with tumour grade and increased risk of local recurrence.…”

“…Alterations in epcam expression have been identified in several epithelial neoplasms, including lung, breast, prostate, hepatocellular, and renal cell carcinoma 6,7 . In breast cancer cell lines, silencing of epcam by rna interference assays has been found to reduce cell proliferation and invasion 8 .…”

Ep-CAM is a significant prognostic factor in pancreatic cancer patients by suppressing cell activity

“…It has a role as an adhesion molecule that suppresses metastasis by holding cells in place (Basak et al, 1998), while induces dissociation of cadherin-mediated adhesion to promote invasion and metastasis (Gumbiner, 1996;Litvinov et al, 1997). For example, Gosens et al (2007) reported that Ep-CAM expression decreased in budding part of colorectal cancer and Rao et al (2005) reported that Ep-CAM expression was lower in circulating tumors cells compared with their corresponding primary tumors. The significance of Ep-CAM expression in pancreatic cancer H Akita et al…”