The carcinoma-associated antigen EpCAM upregulates c-myc and induces cell proliferation

Abstract

Epithelial cell adhesion molecule (EpCAM) is a membrane glycoprotein expressed on adenomatous and simple epithelia, where it is involved in homophilic adhesion at the basolateral membrane. Carcinomas strongly overexpress EpCAM through an, as yet, unknown mechanism. Interestingly, otherwise EpCAM-negative squamous epithelia are seen to express EpCAM concomitant with their transformation and de-differentiation. The amount of EpCAM and the number of expressing cells both increase with the grade of dysplasia. Despite an important amount of data correlating the expression of EpCAM with cellular proliferation and de-differentiation, such as the coexpression with Ki-67, a marker for proliferation, it is unknown whether EpCAM may directly contribute to carcinogenesis. Here, we show that EpCAM has a direct impact on cell cycle and proliferation, and the ability to rapidly upregulate the proto-oncogene c-myc and cyclin A/E. Human epithelial 293 cells as well as murine NIH3T3 fibroblasts expressing EpCAM had a decreased requirement for growth factors, enhanced metabolic activity and colony formation capacity. Importantly, the inhibition of EpCAM expression with antisense mRNA led to a strong decrease in proliferation and metabolism in human carcinoma cells. Moreover, domain swapping experiments demonstrated that the intracellular part of EpCAM is necessary and sufficient to transduce the effects described. Thus, the data presented here highlight the role of EpCAM, demonstrating for the first time a direct link to cell cycle and proliferation.

EpCAM (CD326) finding its role in cancer

“…In 2004, first evidence for a direct role of EpCAM in growth-promoting nuclear signalling was reported (Munz et al, 2004). These data and results published by the group of Gillanders (Osta et al, 2004) revived research on the biological function of EpCAM, which is now delivering breakthrough results.…”

“…This name is proposed to be EpCAM (without a dash) as an abbreviation for the ability of the protein to act as an epithelial-specific cell adhesion molecule (Litvinov et al, 1994) and activating molecule (Munz et al, 2004;Osta et al, 2004). It is also suggested to add in brackets on the first occurrence of the EpCAM name in a text the recently introduced cellular differentiation (CD) marker nomenclature for EpCAM, namely CD326.…”

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

“…Munz et al (2004) reported that Ep-CAM upregulated c-myc and induced cell proliferation, and Osta et al (2004) reported that specific ablation of Ep-CAM expression using RNA interference resulted in a dramatic decrease in the invasive potential of breast cancer cell lines. Furthermore, Sankpal et al (2009) reported that transcriptional repression of Ep-CAM expression activated breast cancer invasion controlled by p53 protein.…”

Lysis of cancer cells by autologous T cells in breast cancer pleural effusates treated with anti-EpCAM BiTE antibody MT110

“…Thirdly, EpCAM is expressed on socalled cancer stem cells in breast cancer and only those stem cells expressing EpCAM are highly tumorigenic in immunodeficient mice [52]. Fourthly, knockdown of Ep-CAM expression by a specific small inhibitory RNA in breast cancer cell lines inhibited proliferation, migration and invasiveness of cancer cells [53], and overexpression of EpCAM in quiescent cells increased these oncogenic parameters [54]. Based on the present data and the emerging biology of EpCAM in breast cancer, MT110 appears as an attractive therapeutic option for treatment of metastatic and therapeutic resistant stages of the disease.…”