Urological Survey UROLOGICAL ONCOLOGY: PROSTATE CANCER Hedgehog Signalling in Prostate Regeneration, Neoplasia and Metastasis
Urological Survey UROLOGICAL ONCOLOGY: PROSTATE CANCER Hedgehog Signalling in Prostate Regeneration, Neoplasia and Metastasis
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发表时间：
2005
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影响因子：
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通讯作者：
S. S. Karhadkar-S.;P. Beachy
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文献类型：
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作者：
S. S. Karhadkar-S.;P. Beachy
编辑评论：在过去的30年里，我还没有读到过比这更重要的具有重大临床意义的基础科学观察。到目前为止，我们一直依靠激素疗法对前列腺癌进行全身治疗。这项研究为控制晚期前列腺癌提供了另一种重要机制。刺猬信号通路通常与包括肺、胰腺和前列腺在内的许多器官的胚胎发育有关。最近，它也被证明是很大比例的小细胞肺癌、胃癌、食道癌、胰腺癌和胆道癌生长的必要条件。本研究的重点是Hh在前列腺癌中的作用。虽然该通路在正常和恶性前列腺组织中均有表达，但在正常前列腺细胞和大多数低中度恶性肿瘤中不表达。然而，它在转移性肿瘤中含量很高。这些作者还在12例根治性前列腺切除术标本中的3例中证实了前列腺癌细胞的通路活性。Hh蛋白似乎负责前列腺上皮细胞和间质之间的正常稳态。我们从根治性前列腺切除术标本的评估中得知，当前列腺癌穿透前列腺包膜时，它很少从表面延伸超过几毫米，这表明这些细胞需要前列腺的环境。很可能它们真正需要的是Hh通路，当这些细胞能够制造Hh通路时，它们可以在不需要前列腺环境的情况下在远处存活。如果你愿意，他们可以把午餐打包带走。作者研究了Hh通路在人前列腺癌异种移植和高度转移的Dunning肿瘤模型中的作用。在这两种系统中，他们都能够证明，当他们使用环巴胺（一种阻断Hh活性的特异性药物）阻断Hh通路时，肿瘤迅速消退。这项研究为治疗晚期前列腺癌提供了一种新的系统性方法，而不是激素治疗提供了很大的希望，例如格列卫（伊马替尼，诺华制药公司，新泽西州东汉诺威）治疗前列腺癌。此外，如果Hh活性可以用来预测肿瘤是否会转移，这可以为个体患者的疾病自然史提供重要的见解。在这篇论文发表的时候，另外两篇手稿也支持了这些观点。1、2
Editorial Comment: In the last 30 years I have not read a more important basic science observation that had major clinical implications. Up to this time we have relied upon hormonal therapy for the systemic treatment of prostate cancer. This study provides insight to another major mechanism that offers tremendous promise for controlling advanced prostate cancer. The hedgehog signaling pathway is normally responsible for embryonic development of a number of organs including the lungs, pancreas and prostate. More recently, it has also been shown to be a requirement for the growth of a significant proportion of small cell lung cancers and carcinomas of the stomach, esophagus, pancreas and biliary tract. This study focuses on the role of Hh in prostate cancer. Although the pathway can be demonstrated in normal and malignant prostatic tissue, it is not expressed by normal prostate cells and by most low to moderate grade malignancies. However, it is present in high levels in metastatic tumors. These authors also demonstrated pathway activity in prostate cancer cells in 3 of 12 radical prostatectomy specimens. It appears that the Hh protein is responsible for the normal homeostasis that exists between the epithelial cells in the prostate and the stroma. We know from the evaluation of radical prostatectomy specimens that when prostate cancer penetrates through the prostatic capsule it rarely extends more than a few millimeters from the surface, suggesting that these cells require the environment of the prostate. It is likely that what they actually require is the Hh pathway and when these cells can manufacture the Hh pathway they can survive at distant sites without the need for the prostatic environment. If you like, they can pack their lunch and take it with them. The authors investigated the role of the Hh pathway in vivo in a human prostate cancer xenograft and in a highly metastatic Dunning tumor model. In both systems they were able to demonstrate that when they blocked the Hh pathway using cyclopamine, a specific agent that blocks Hh activity, the tumors rapidly regressed. This study provides great promise that a new systemic approach to the management of advanced prostate cancer, other than hormonal therapy, may be available in the future, eg a Gleevec (imatinib, Novartis Pharmaceuticals Corp., East Hanover, New Jersey) for prostate cancer. Furthermore, if Hh activity can be used to predict whether a tumor will metastasize, this could provide important insight into the natural history of the disease in the individual patient. Around the time this paper was published, 2 other manuscripts appeared that support these concepts. 1, 2