Cadherins and cancer: how does cadherin dysfunction promote tumor progression?

Abstract

It has long been recognized that the cell-cell adhesion receptor, E-cadherin, is an important determinant of tumor progression, serving as a suppressor of invasion and metastasis in many contexts. Yet how the loss of E-cadherin function promotes tumor progression is poorly understood. In this review, we focus on three potential underlying mechanisms: the capacity of E-cadherin to regulate beta-catenin signaling in the canonical Wnt pathway; its potential to inhibit mitogenic signaling through growth factor receptors and the possible links between cadherins and the molecular determinants of epithelial polarity. Each of these potential mechanisms provides insights into the complexity that is likely responsible for the tumor-suppressive action of E-cadherin.

Figure 1

Overview of β-catenin signaling and its regulation. Free cytosolic β-catenin is regulated by the combination of a destruction complex (adenomatosis polyposis coli (APC), Axin, GSK3β and CK1) and binding to the cytoplasmic domain of classical cadherin adhesion receptors. Both mechanisms limit the pool of free cytosolic β-catenin and hence tend to inhibit signaling through the canonical Wnt pathway. For further details, see text and http://stanford.edu/Brnusse?wntwindow.html.