Department of Urology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia, USA.
Prostate. 2011 Dec;71(16):1711-22. doi: 10.1002/pros.21388. Epub 2011 Apr 25.
Sonic hedgehog (Shh) signaling plays a pivotal role in stromal-epithelial interaction during normal development but its role in tumor-stromal interaction during carcinogenic progression is less well defined. Since hormone refractory prostate cancer with bone metastasis is difficult to treat, it is crucial to investigate how androgen independent (AI) human prostate cancer cells communicate with their associated stroma.
Shh and its target transcription factor, Gli1 mRNA, were assessed by RT-PCR and/or quantitative RT-PCR in co-cultured cell recombinants comprised of AI C4-2 either with NPF (prostate fibroblasts from normal/benign prostate gland) or CPF (cancer-associated stromal fibroblasts) under Shh/cyclopamine (a hedgehog signaling inhibitor) treatment. Human bone marrow stromal (HS27A) cells were used as controls. In vivo investigation was performed by checking serum PSA and immunohistochemical staining for the apoptosis-associated M30 gene in mice bearing chimeric C4-2/NPF tumors.
We found that (1) Shh has minimal growth-stimulating effects on prostate cancer cells, but it stimulated the growth of NPF but not CPF; (2) active Shh signaling was found between AI C4-2 cells and NPF but not CPF; and (3) osteonectin (ON) is a Gli1 target gene in NPF and not in CPF, and ON up-regulation in NPF can be blocked by cyclopamine
Based on co-culture and chimeric tumor models, active Shh-mediated signaling was demonstrated between AI prostate cancer and NPF in a paracrine- and tumor progression-dependent manner. Our study suggests that drugs like cyclopamine that interfere with Shh signaling could be beneficial in preventing AI progression in prostate cancer cells.
sonic hedgehog（Shh）信号在正常发育过程中的基质-上皮相互作用中发挥关键作用，但在致癌进展过程中的肿瘤-基质相互作用中的作用尚不清楚。由于激素难治性前列腺癌伴骨转移难以治疗，因此研究雄激素非依赖性（AI）人前列腺癌细胞如何与其相关基质相互作用至关重要。
在共培养细胞重组体中评估 Shh 和其靶转录因子 Gli1 mRNA，该重组体由 AI C4-2 与 NPF（来自正常/良性前列腺的前列腺成纤维细胞）或 CPF（癌相关基质成纤维细胞）组成，在 Shh/环巴胺（ hedgehog 信号抑制剂）处理下。人骨髓基质（HS27A）细胞用作对照。通过检查携带嵌合 C4-2/NPF 肿瘤的小鼠的血清 PSA 和凋亡相关 M30 基因的免疫组织化学染色进行体内研究。
我们发现：（1）Shh 对前列腺癌细胞的生长刺激作用很小，但它刺激了 NPF 的生长，但不刺激 CPF 的生长；（2）在 AI C4-2 细胞与 NPF 之间发现了活跃的 Shh 信号，但在 CPF 之间没有发现；（3）骨粘连蛋白（ON）是 NPF 中 Gli1 的靶基因，而不是 CPF 中的靶基因，并且环巴胺可以阻断 NPF 中 ON 的上调。
基于共培养和嵌合肿瘤模型，证明了 AI 前列腺癌与 NPF 之间存在活跃的 Shh 介导的信号，这种信号是旁分泌和肿瘤进展依赖性的。我们的研究表明，像环巴胺这样干扰 Shh 信号的药物可能有助于预防前列腺癌细胞中的 AI 进展。
