Contribution of cell-cell adhesion to the progression of carcinoma: Implications for the diagnosis and treatment of cancer.

摘要

Cancer still remains a major health problem in the world. Recent advancements in therapy, while promising, have demonstrated the need for continued research. While cancer arises from all tissues, carcinomas, which arise from epithelial cells, are the predominant subtype. One of the basic characteristics of epithelial cells is cell-cell adhesion, which is ultimately lost during the development of the metastatic disease. However, evidence suggests that alterations to cell-cell adhesion occur throughout cancer progression and may contribute to advancement of the disease.; In epithelial cells, E-cadherin, and the catenins (alpha,beta) function in unison to form the adherens junction, a protein complex critical for cell-cell adhesion. However, the adherens junction also interacts with several well-known signaling pathways (Wnt, PI3 kinase-AKT, ERK1/2, EGFR). While a wealth of knowledge is available about how beta-catenin and the Wnt pathway regulate cell proliferation, little is understood about how E-cadherin and alpha-catenin are involved in these pathways.; alpha-catenin is commonly lost in cancer and its expression has been observed to suppress cell proliferation. By re-expressing alpha-catenin in alpha-catenin null prostate cancer cells, this work demonstrates that alpha-catenin decreases cell proliferation by protecting beta-catenin from activation/phosphorylation by the tyrosine kinase, Src. This regulatory function of alpha-catenin confers increased sensitivity to Src inhibition and provides tangible evidence for the use of alpha-catenin and Src inhibitors for prostate cancer therapy.; Recent evidence has demonstrated the presence of soluble E-cadherin (SECAD) in cancer patient serum. The correlation between cancer grade and SECAD serum levels suggests a possible function in cancer progression. Our studies indicate that SECAD ligation to E-cadherin activates Epidermal Growth Factor Receptor (EGFR). Activation of E-cadherin-EGFR signaling by SECAD inhibits apoptosis, demonstrating a positive pathological function for SECAD and E-cadherin in cancer.; The beta-subunit of Na, K-ATPase (NaK-beta1) has a well-documented function in cell-cell adhesion and loss of NaK-beta1 occurs during cancer progression. Exogenous expression of NaK-beta1 within a tumorigenic cell line, suppresses its tumorigenicity in both in-vivo and in-vitro. Further, suppression of tumorigenicity correlates to the cell-cell adhesion function of NaK-beta1, thus revealing a tumor suppressor function for the beta-subunit of the Na, K-ATPase.