Growth and metastasis of human prostate cancer require angiogenesis. Interleukin (IL)-8 is a proangiogenic factor overexpressed in advanced human prostate cancer. How IL-8 expression is regulated in prostate cancer is unclear. Transforming growth factor (TGF)-beta 1, also overexpressed in advanced prostate cancer, promotes angiogenesis by unknown mechanisms. Dr. Dong's previous studies show that interferon-beta gene therapy down regulates TGF-beta1 and IL-8 expression, inhibits angiogenesis, and suppresses growth of orthotopic tumors of human prostate cancer cells in mice. His preliminary studies show that prostate cancer cells constitutively express TGF-beta1 and IL-8, and TGF-beta 1 enhances IL-8 expression. He hypothesizes that TGF-beta1 is the primary factor in tumor environment that stimulates IL-8 expression in human prostate cancer. He will test this hypothesis and investigate mechanisms by which TGF-beta1 stimulates IL-8 expression in human prostate cancer cells, in orthotopic models of prostate cancer in nude mice, and in surgical specimens of human prostate cancers.
In specific aim 1, he will further characterize the role of TGF-beta1 in stimulating IL-8 expression in prostate cancer cells. Effects of downregulation of endogenous TGF-beta1, interruption of TGF-beta1 and its receptor interaction, and restoration of TGF-beta receptor on IL-8 expression will be determined.
In specific aim 2, he will study the role of TGF-beta1 and TGF-beta signaling pathways in regulating IL-8 expression in orthotopic tumors of human prostate cancer cells in nude mice. Expression of IL-8 and TGF-beta1 in tumors formed by cells with different metastatic potentials or by those stablely transfected with dominant negative mutants of three key molecules in TGF-beta signaling pathways will be determined.
Specific aim 3 will determine the correlation of TGF-beta1 overexpression with IL-8 expression, angiogenesis, and metastasis in surgical specimens of human prostate cancers.
In specific aim 4, he will investigate molecular pathways that regulate IL-8 expression by TGF-beta1. TGF-beta1-stimulated IL-8 expression and IL-8 gene promoter activation in cells lacking the three TGF-beta signaling pathways as well as transcription factors involved will be determined.
