Hyaluronan, a component of pericellular and extracellular matrices, influences migration, growth, and adhesion of cells through its interaction with cell surface hyaluronan receptors. These interactions have been implicated in the cascade of events leading to growth and metastasis of several tumors. Recent studies have shown that perturbation of interactions between hyaluronan and CD44, a major cell surface receptor for hyaluronan, inhibits growth of murine melanomas in vivo and melanoma cells in culture. In particular, hyaluronan oligomers have a strong inhibitory effect. Since hyaluronan has been used extensively in human surgical procedures and is thus known to be non-toxic, hyaluronan oligomers may be an effective anti-cancer agent.
Specific Aim 1 of this application proposes to consolidate this possibility by: a) optimizing the conditions for inhibition of tumor in vivo by the hyaluronan oligomers, b) determining whether the inhibitory effect extend to a variety of tumor types, c) investigating the efficacy of treatment at different stages of tumor progression, and d) studying the effect of perturbing hyaluronan-CD44 interaction on tumor invasion and metastasis. The second specific aim will investigate the mechanism whereby perturbation of hyaluronan-CD44 interactions, especially by hyaluronan oligomers, influences tumor cell growth. This work will focus on three possibilities: a) that these oligomers disrupt a transmembrane complex of """"""""nascent"""""""" hyaluronan, CD44, and an intracellular, hyaluronan-binding, cell cycle regulatory factor, termed Cdc37; b) that hyaluronan oligomers antagonize interaction of hyaluronan polymer with CD44 by competing for binding but failing to induce intracellular signals; c) that hyaluronan oligomers induce apoptosis. It is anticipated that the results of this study will lead to new approaches to treatment of human cancers.
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