The Cadherin Interaction as a Rate Limiting Step in Breast Cancer Metastasis to the Liver
Annual summary rept. 1 Mar 2006-28 Feb 2009
PITTSBURGH UNIV PA
Pagination or Media Count:
Our overall objective is to identify molecular elements that enable breast cancer cells to establish metastases. Finding targeted approaches to inhibit rate-limiting events of metastatic growth is preferable to using therapeutics that are cytotoxic on a systemic level. Cadherins make up a family of adhesion molecules that mediate Ca2-dependent cell-cell adhesion at points of cell-cell adhesion Goodwin and Yap, 2004. Epithelial-cadherin E-cadherin, the prototype classical cadherin present on the surface of most epithelial cells, has a cytoplasmic domain that anchors the cell adhesion molecule to the actin cytoskeleton via catenin-based complexes. It is generally considered that E-cadherin directs homotypic binding, organizing cells of the same lineage into a functional tissue during morphogenesis Pla et al., 2001. Thus, E-cadherin is central to epithelial cell differentiation and suppression of proliferation and migration. Finding E-cadherin downregulated or even lost in invasive and metastatic carcinomas buttressed this role of E-cadherin in modulating the epithelial phenotype Hirohashi, 1998. It has been hypothesized that loss of Ecadherin allows individual tumor cells to break from the primary tumor mass at the same time as enabling autocrine pro-proliferative and -migratory signaling to ensue from receptors and ligands physiologically separated by cell polarity and the E-cadherin-based tight junctions. This was supported experimentally when poorly differentiated and invasive carcinoma cells could be made less so by transfection with E-cadherin cDNA, with well-differentiated carcinomas becoming more aggressive when antibodies blocked.
- Medicine and Medical Research
- Adhesives, Seals and Binders