Role of alpha V Beta 6-Mediated Latent TGF-Beta Activation in Prostate Cancer

摘要

Abundant evidence suggests that overexpression of TGF-beta by prostate cancer cells enhances their ability to grow and metastasize. TGF-beta is secreted by cells in a latent form that results from a noncovalent interaction between TGF-beta and its propeptide (latency- associated peptide, LAP) . Mechanisms leading to active TGF-beta are poorly understood at present. Our lab discovered a mechanism of TGF-beta activation in which the integrin alpha V beta 6 binds to an ROD sequence near the C-terminus of LAP. alpha V beta 6 is only expressed in epithelial cells. We hypothesize that alpha V beta 6, by activating TGF-beta 1, is an important regulator of normal prostate epithelial proliferation, and that overexpression of alpha V beta 6 by prostate tumor cells acts in concert with overexpression of its ligand latent TGF-beta 1 to produce active TGF-beta 1 and promote growth of the tumor. In this work, we are testing whether the beta 6 integrin subunit is regulated by androgen, whether it is overexpressed in human prostate cancer, and whether it affects growth and metastasis of prostate cancer in an animal model. Our results to date indicate that beta 6 is expressed in prostate luminal epithelial cells, which activate TGF beta 1 in a beta 6-dependent manner, and that beta 6 expression is upregulated in the mouse in a delayed fashion after castration.