The Hedgehog (Hh) pathway contributes to prostate cancer growth and progression. The presence of robust Sonic Hedgehog (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 overexpressing xenograft tumors. Correlation analysis of gene expression in matched specimens of benign and malignant human prostate tissue revealed a partial five-gene fingerprint of Hh-regulated expression in stroma of all cancers and the complete nine-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 subgroup that will exhibit a particularly good response to anti-Hh therapy.
Bibliographical noteFunding Information:
We thank Alejandro Muñoz, PhD, and Glen Leverson, PhD, for assistance with statistical analysis. The Gli2-mutB expression construct was generously provided by Maximilian Muenke at NIH (Bethesda, MD, USA). This work was supported by the Department of Defense Prostate Cancer Program Graduate Training Award W81XWH-06-1-0060 (AS), Department of Defense Award W81XWH-04-1-0263 (WB), the NIDDK Award DK056238-06 (WB) and the Robert and Delores Schnoes Chair in Urologic Research.
Dr Bushman’s work has been funded by the NIH, DOD and the Prostate Cancer Foundation. He has collaborated with both Curis Inc. and Astra Zeneca on studies of Hh signaling
- Prostate cancer
- Reactive stroma
- Tumor microenvironment