The Sonic Hedgehog Pathway Stimulates Prostate Tumor Growth by Paracrine Signaling and Recaptures Embryonic Gene Expression in Tumor Myofibroblasts

The Hedgehog (Hh) pathway contributes to prostate cancer growth and progression. The presence of robust Shh expression in both normal prostate and localized cancer challenged us to explain the unique growth promoting effect in cancer. We show here that paracrine Hh signaling exerts a non-cell autonomous effect on xenograft tumor growth and that Hh pathway activation in myofibroblasts alone is sufficient to stimulate tumor growth. Nine genes regulated by Hh in the mesenchyme of the developing prostate were found to be regulated in the stroma of Hh over-expressing xenograft tumors. Correlation analysis of gene expression in matched specimens of benign and malignant human prostate tissue revealed a partial 5 gene fingerprint of Hh-regulated expression in stroma of all cancers and the complete 9 gene fingerprint in the subset of tumors exhibiting a reactive stroma. No expression fingerprint was observed in benign tissues. We conclude that changes in the prostate stroma due to association with cancer result in an altered transcriptional response to Hh that mimics the growth promoting actions of the fetal mesenchyme. Patients with an abundance of myofibroblasts in biopsy tissue may comprise a sub-group that will exhibit a particularly good response to anti-Hedgehog therapy.