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J. Biol. Chem., Vol. 278, Issue 46, 45801-45810, November 14, 2003
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Elevated Hyaluronan Production Induces Mesenchymal and Transformed Properties in Epithelial Cells*
From the Department of Anatomy and Cellular Biology, Tufts University School of Medicine, Boston, Massachusetts 02111
During carcinoma progression, tumor cells often undergo changes similar (but not identical) to epithelialmesenchymal transitions in embryonic development. In this study, we demonstrate 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, we show that increased hyaluronan production promotes anchorage-independent growth and invasiveness, induces gelatinase production, and stimulates phosphoinositide 3-kinase/Akt pathway activity in phenotypically normal Madin-Darby canine kidney and MCF-10A human mammary epithelial cells. Cells infected with hyaluronan synthase-2 adenovirus also acquired mesenchymal characteristics, including up-regulation of vimentin, dispersion of cytokeratin, and loss of organized adhesion proteins at intercellular boundaries. Furthermore, we show that the transforming effects of two well described agents, hepatocyte growth factor (HGF) and 
-catenin, are dependent on hyaluronan-cell interactions. Perturbation of endogenous hyaluronan polymer interactions by treatment with hyaluronan oligomers is shown here to reverse the transforming effects of HGF and -catenin in Madin-Darby canine kidney and MCF-10A human mammary epithelial cells. Also, HGF and -catenin induced assembly of hyaluronan-dependent pericellular matrices similar to those surrounding mesenchymal cells. Thus, increased expression of hyaluronan is sufficient to induce epithelial-mesenchymal transition and acquisition of transformed properties in phenotypically normal epithelial cells.
Received for publication, July 26, 2003
* This work was supported by National Institutes of Health Grants CA73839 and CA82867 (to B. P. T.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Present address: Dept. of Cell Biology and Anatomy, Medical University of South Carolina, Charleston, SC 29425.
To whom correspondence and reprint requests should be addressed: Dept. of Cell Biology and Anatomy, Medical University of South Carolina, 173 Ashley Ave., Charleston, SC 29425. Tel.: 843-792-7004; Fax: 843-792-0664; E-mail: toolebp{at}musc.edu.
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