Elevated hyaluronan production induces mesenchymal and transformed properties in epithelial cells.
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 beta-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 beta-catenin in Madin-Darby canine kidney and MCF-10A human mammary epithelial cells. Also, HGF and beta-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.
Zoltan-Jones
Alexandra
A
Department of Anatomy and Cellular Biology, Tufts University School of Medicine, Boston, Massachusetts 02111, USA.
Huang
Lei
L
Ghatak
Shibnath
S
Toole
Bryan P
BP
D000256:Adenoviridae / Q000235:genetics / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D002448:Cell Adhesion; D002460:Cell Line; D003094:Collagen; D003598:Cytoskeletal Proteins / Q000378:metabolism; D003599:Cytoskeleton; D004285:Dogs; D004338:Drug Combinations; D004847:Epithelial Cells / Q000378:metabolism*; D018093:Gelatinases / Q000096:biosynthesis; D014453:Glucuronosyltransferase / Q000096:biosynthesis / Q000378:metabolism; D006801:Humans; D000076002:Hyaluronan Synthases; D006820:Hyaluronic Acid / Q000096:biosynthesis* / Q000378:metabolism; D015151:Immunoblotting; D007633:Keratins / Q000378:metabolism; D007797:Laminin; D008648:Mesoderm / Q000378:metabolism*; D051379:Mice; D008856:Microscopy, Fluorescence; D009361:Neoplasm Invasiveness; D010641:Phenotype; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011233:Precipitin Tests; D011509:Proteoglycans; D013997:Time Factors; D015534:Trans-Activators / Q000378:metabolism; D014162:Transfection; D051176:beta Catenin
C495270:CTNNB1 protein, human; C495267:CTNNB1 protein, mouse; D003598:Cytoskeletal Proteins; D004338:Drug Combinations; D007797:Laminin; D011509:Proteoglycans; D015534:Trans-Activators; D051176:beta Catenin; C059485:matrigel; D007633:Keratins; D006820:Hyaluronic Acid; D003094:Collagen; D014453:Glucuronosyltransferase; C101754:HAS2 protein, human; C491099:Has2 protein, mouse; D000076002:Hyaluronan Synthases; D019869:Phosphatidylinositol 3-Kinases; D018093:Gelatinases