Fig. 5. Receptor cross-talk in metastatic dissemination. In a “resting” cell, integrins are engaged, cadherin-mediated adhesion is intact and proteinase expression is low. Several key events occur in an “activated” cell (for example, ligand or mutational activation of EGFR signaling, or other mechanisms to stimulate cadherin or integrin-mediated signal transduction). Disruption of cadherin-based cell adhesion and/or integrin clustering initiate signaling cascades that lead to increased proteinase production and activation. Secreted and membrane-associated proteinases may then participate in continued disruption of cadherin function through cleavage protein domains and generation of the soluble E-cadherin ectodomain. The shed E-cadherin ectodomain may potentiate junction dissolution through protein:protein interactions with endogenous E-cadherin. Subsequent acquisition of the invasive phenotype accompanies dissemination of cells from the primary tumor, potentiating intraperitoneal metastasis. A more detailed understanding of these processes may lead to novel strategies for therapeutic intervention(s) that prevent the establishment of metastases.
