Prostate cancer is the second leading cause of malignancy-related mortality in males in the United States. While carcinogenesis is a complex process that involves multiple stages of transformation, clinically significant tumor growth and metastasis are dependent upon angiogenesis. This neovascularization allows new blood vessels to form which supply the tumor with oxygen and nutrients necessary for growth. Evidence suggests that net tumor-derived angiogenesis is determined by an imbalance in the expression of angiogenic and angiostatic factors in the local milieu of the tumor. We hypothesize that in part, net tumor- derived angiogenesis is determined by an imbalance in the expression of angiogenic as compared to angiostatic CXC chemokines. Our preliminary data demonstrates that IL-8 is a common angiogenic CXC chemokine which is constitutively overexpressed by prostate cancer cell lines. Furthermore, the expression of IL-8 positively correlates with prostate cancer growth in a SCID mouse model. In addition, the expression of the angiostatic CXC chemokine IP-10 is inversely correlated with prostate cancer growth and metastasis. Using a variety of molecular and cellular techniques, experiments are designed to examine the effect of neutralizing the angiogenic IL-8 and/or overexpressing the angiostatic IP-10 CXC chemokines on growth of prostate cancer cell lines in SCID mice. Specifically we will abrogate angiogenic CXC expression by stable transfection of appropriate anti-sense IL-8 vectors. Conversely, we will enhance angiostatic or angiogenic CXC expression by stable transfection or adenoviral infection of appropriate IL-8 or IP-10 cDNA constructs. We can confirm the specificity of these changes using neutralizing Abs to CXC chemokines in bioassays for angiogenesis as well as in SCID mice. The genetic dysregulation of these chemokines will be examined and characterized in prostate cancer cell lines. We will identify what transcriptional and post-transcriptional mechanisms account for the dysregulated overexpression of angiogenic CXC chemokines. These studies should lead to new insights into the biology of prostate cancer growth and metastasis, and pave the way to adapt adjuvant therapies for the treatment of this widespread disease.
Showing the most recent 10 out of 11 publications
