Shin Kunyoo, Lim Agnes, Zhao Chen, Sahoo Debashis, Pan Ying, Spiekerkoetter Edda, Liao Joseph C, Beachy Philip A
Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA; Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA 94305, USA.
Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Developmental Biology, Stanford University School of Medicine, Stanford, CA 94305, USA; Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA 94305, USA.
Cancer Cell. 2014 Oct 13;26(4):521-33. doi: 10.1016/j.ccell.2014.09.001.
Hedgehog (Hh) pathway inhibitors are clinically effective in treatment of basal cell carcinoma and medulloblastoma, but fail therapeutically or accelerate progression in treatment of endodermally derived colon and pancreatic cancers. In bladder, another organ of endodermal origin, we find that despite its initial presence in the cancer cell of origin Sonic hedgehog (Shh) expression is invariably lost during progression to invasive urothelial carcinoma. Genetic blockade of stromal response to Shh furthermore dramatically accelerates progression and decreases survival time. This cancer-restraining effect of Hh pathway activity is associated with stromal expression of BMP signals, which stimulate urothelial differentiation. Progression is dramatically reduced by pharmacological activation of BMP pathway activity with low-dose FK506, suggesting an approach to management of human bladder cancer.
刺猬（Hh）信号通路抑制剂在治疗基底细胞癌和髓母细胞瘤方面具有临床疗效，但在治疗内胚层来源的结肠癌和胰腺癌时治疗失败或加速疾病进展。在膀胱这个同样起源于内胚层的器官中，我们发现，尽管 Sonic hedgehog（Shh）最初存在于起源癌细胞中，但在进展为浸润性尿路上皮癌的过程中其表达总是会丢失。此外，对Shh的基质反应进行基因阻断会显著加速疾病进展并缩短生存时间。Hh信号通路活性的这种癌症抑制作用与骨形态发生蛋白（BMP）信号的基质表达有关，后者可刺激尿路上皮分化。低剂量FK506对BMP信号通路活性的药理激活可显著降低疾病进展，这提示了一种治疗人类膀胱癌的方法。
