Division of Urology, Department of Surgery, University of Wisconsin, Madison, WI 53792, USA.
Oncogene. 2009 Dec 17;28(50):4480-90. doi: 10.1038/onc.2009.294. Epub 2009 Sep 28.
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.
刺猬（Hh）途径有助于前列腺癌的生长和进展。在正常前列腺和局限性癌症中均存在强大的 Sonic Hedgehog（Shh）表达，这使我们难以解释癌症中独特的促生长作用。我们在这里表明，旁分泌 Hh 信号对异种移植肿瘤生长具有非细胞自主效应，并且单独激活成纤维细胞中的 Hh 途径足以刺激肿瘤生长。在发育中的前列腺间质中受 Hh 调节的 9 个基因被发现受到 Hh 过表达异种移植肿瘤基质的调节。对良性和恶性人前列腺组织匹配标本中的基因表达进行相关性分析显示，所有癌症基质中存在 Hh 调节表达的部分五基因指纹，而在反应性基质子集中则存在完整的九基因指纹。在良性组织中未观察到表达指纹。我们得出的结论是，由于与癌症相关，前列腺基质的变化导致对 Hh 的转录反应发生改变，从而模拟了胎儿间质的促生长作用。在活检组织中存在大量成纤维细胞的患者可能构成一个亚组，他们将对抗 Hh 治疗表现出特别好的反应。
