title: Stromal hyaluronan interaction with epithelial CD44 variants promotes prostate cancer invasiveness by augmenting expression and function of hepatocyte growth factor and androgen receptor.
abstract: The main aim of our study is to determine the significance of the stromal microenvironment in the malignant behavior of prostate cancer. The stroma-derived growth factors/cytokines and hyaluronan act in autocrine/paracrine ways with their receptors, including receptor-tyrosine kinases and CD44 variants (CD44v), to potentiate and support tumor epithelial cell survival. Overexpression of hyaluronan, CD44v9 variants, and stroma-derived growth factors/cytokines are specific features in many cancers, including prostate cancer. Androgen/androgen receptor interaction has a critical role in regulating prostate cancer growth. Our previous study showed that 1) that increased synthesis of hyaluronan in normal epithelial cells promotes expression of CD44 variants; 2) hyaluronan interaction with CD44v6-v9 promotes activation of receptor-tyrosine kinase, which stimulates phosphatidylinositol 3-kinase-induced cell survival pathways; and 3) CD44v6/short hairpin RNA reduces colon tumor growth in vivo (Misra, S., Hascall, V. C., De Giovanni, C., Markwald, R. R., and Ghatak, S. (2009) J. Biol. Chem. 284, 12432-12446). Our results now show that hepatocyte growth factor synthesized by myofibroblasts associated with prostate cancer cells induces activation of HGF-receptor/cMet and stimulates hyaluronan/CD44v9 signaling. This, in turn, stabilizes the androgen receptor functions in prostate cancer cells. The stroma-derived HGF induces a lipid raft-associated signaling complex that contains CD44v9, cMet/phosphatidylinositol 3-kinase, HSP90 and androgen receptor. CD44v9/short hairpin RNA reverses the assembly of these components in the complex and inhibits androgen receptor function. Our results provide new insight into the hyaluronan/CD44v9-regulated androgen receptor function and the consequent malignant activities in prostate cancer cells. The present study describes a physiologically relevant in vitro model for studying the molecular mechanisms by which stroma-derived HGF and hyaluronan influence androgen receptor and CD44 functions in the secretory epithelia during prostate carcinogenesis.
authors.affiliation: Department of Regenerative Medicine and Cell Biology and Division of Rheumatology and Immunology, Medical University of South Carolina, 171 Ashley Ave., Charleston, SC 29425, USA. ghatak@musc.edu
authors.forename: Shibnath
authors.initials: S
authors.lastname: Ghatak
authors.forename: Vincent C
authors.initials: VC
authors.lastname: Hascall
authors.forename: Roger R
authors.initials: RR
authors.lastname: Markwald
authors.forename: Suniti
authors.initials: S
authors.lastname: Misra
mesh_terms: D015153:Blotting, Western; D002460:Cell Line; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D002470:Cell Survival; D015972:Gene Expression Regulation, Neoplastic; D017228:Hepatocyte Growth Factor / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D018960:Hyaluronan Receptors / Q000235:genetics / Q000378:metabolism*; D006820:Hyaluronic Acid / Q000378:metabolism*; D008297:Male; D021962:Membrane Microdomains / Q000378:metabolism; D008954:Models, Biological; D009361:Neoplasm Invasiveness; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D011485:Protein Binding; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: C448906:CD44v9 antigen; D018960:Hyaluronan Receptors; D011944:Receptors, Androgen; D017228:Hepatocyte Growth Factor; D006820:Hyaluronic Acid; D019859:Proto-Oncogene Proteins c-met