Urology, University of Wisconsin - Madison

Identification of Sonic Hedgehog-Induced Stromal Factors That Stimulate Prostate Tumor Growth

Funding:

Department of Defense

Principal Investigator:

Aubie Shaw, MS (Wade Bushman, MD, PhD, Mentor)

Lab Website:

Dr. Bushman's Lab

Project Summary:

The goals of this proposal are to: (1) determine the mechanism by which Shh signaling accelerates tumor growth, (2) identify Shh targets in prostate tumor stroma, and (3) test the effect of individual target genes on tumor growth. Prostate cancer is the most common soft tissue malignancy in men and a leading cause of cancer death. The Sonic Hedgehog pathway is a developmental pathway that becomes reactivated in prostate cancer and accelerates growth of prostate tumors. During embryonic prostate development, Shh expressed by epithelial cells activates Shh target gene expression in adjacent stromal cells. Such cell-cell crosstalk facilitates epithelial growth and branching. In prostate cancer, Shh expressed by tumor epithelial cells activates Shh signaling and gene expression in tumor stromal cells. Cell-cell crosstalk in this case results in accelerated tumor growth. Recent studies have shown that chemical perturbation of hedgehog signaling in prostate tumors inhibits tumor growth. This suggests that the Shh pathway may present a reasonable target for anti-tumor therapies. We will use a newly developed bi-clonal xenograft model to - for the first time - identify gene products induced by Shh in prostate tumor stroma and characterize the mechanism of their effects on tumor growth. These studies will provide a set of clinically relevant mechanisms for tumor growth that have not been previously explored. These mechanisms may provide useful targets for interventions to prevent or slow prostate cancer progression.

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