Promotion of Epithelial to Mesenchymal Transformation by Hyaluronan
Annual summary 1 Jul 2003-30 Jun 2004
TUFTS UNIV BOSTON MA
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During carcinoma progression, tumor cells often undergo changes similar but not identical to epithelial-mesenchymal transitions in embryonic development. In this study I have demonstrated that experimental stimulation of hyaluronan synthesis in normal epithelial cells is sufficient to induce mesenchymal and transformed characteristics. Using recombinant adenoviral expression of hyaluronan synthase 2, 1 showed that increased hyaluronan production promotes anchorage- independent growth and invasiveness, induces gelatinase production, and stimulates phosphoinositide-3-kinaseAkt pathway activity in phenotypically normal MDCK canine kidney and MCF-lOA human mammary epithelial cells. Cells infected with hyaluronan synthase 2 adenovirus also acquire mesenchymal characteristics, including up-regulation of vimentin, dispersion of cytokeratin, and loss of organized adhesion proteins at intercellular boundaries. Furthermore, I showed that transforming effects of two well-described agents, hepatocyte growth factor and P-catenin, are dependent on byaluronan-cell interactions. Thus increased expression of hyaluronan is sufficient to induce epithelial to mesenchymal transition and acquisition of transformed properties in phenotypically normal epithelial cells. In addition I have shown that the extracellular matrix metalloproteinase inducer emmprin, promotes anchorage-independent growth and stimulates ErbB2, phosphoinositide 3-kinase Akt, MAP kinase and focal adhesion kinase cell survival signaling pathways in a hyaluronan-dependent manner.
- Medicine and Medical Research