Hypoxia triggers hedgehog-mediated tumor-stromal interactions in pancreatic cancer.
Hypoxia triggers hedgehog-mediated tumor-stromal interactions in pancreatic cancer.
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DOI：
10.1158/0008-5472.can-11-1433
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发表时间：
2013-06-01
期刊：
影响因子：
11.2
通讯作者：
Powis G
中科院分区：
文献类型：
--
作者：
Spivak-Kroizman TR;Hostetter G;Posner R;Aziz M;Hu C;Demeure MJ;Von Hoff D;Hingorani SR;Palculict TB;Izzo J;Kiriakova GM;Abdelmelek M;Bartholomeusz G;James BP;Powis G
胰腺癌的特点是促结缔组织增生反应，形成致密的纤维炎症微环境，促进缺氧，并由于血液灌注量减少而限制癌症药物的输送。在这里，我们描述了一种新的肿瘤-间质相互作用，这可能有助于解释结缔组织增生在这种癌症中的流行。具体地说，我们发现，肿瘤缺氧激活低氧诱导因子-1α强烈地激活了癌细胞分泌Sonic Hedgehog配体SHH，进而导致基质成纤维细胞增加纤维组织沉积。为了支持这一发现，胰腺肿瘤中HIF-1α和SHH水平的升高被确定为患者存活率下降的标志。反复的缺氧和促结缔组织增生在前馈循环中相互放大，使肿瘤更具侵袭性，对治疗更具抵抗力。这一环路可被抑制HIF-1的α所阻断，这足以阻断SHH的产生和HH信号。综上所述，我们的研究结果表明，低氧肿瘤产生的HIF-1α增加触发了胰腺癌的结缔组织反应，该反应随后被涉及血流减少和缺氧增加的循环的前馈循环放大。我们的发现加强了测试HIF抑制剂的理由，因此可能代表着胰腺癌的一种新的治疗选择。
Pancreatic cancer is characterized by a desmoplastic reaction that creates a dense fibroinflammatory microenvironment, promoting hypoxia and limiting cancer drug delivery due to decreased blood perfusion. Here we describe a novel tumor-stroma interaction that may help explain the prevalence of desmoplasia in this cancer. Specifically, we found that activation of HIF-1α by tumor hypoxia strongly activates secretion of the sonic hedgehog ligand SHH by cancer cells which in turn causes stromal fibroblasts to increase fibrous tissue deposition. In support of this finding, elevated levels of HIF-1α and SHH in pancreatic tumors were determined to be markers of decreased patient survival. Repeated cycles of hypoxia and desmoplasia amplified each other in a feed forward loop that made tumors more aggressive and resistant to therapy. This loop could be blocked by HIF-1α inhibition, which was sufficient to block SHH production and HH signaling. Taken together, our findings suggest that increased HIF-1α produced by hypoxic tumors triggers the desmoplasic reaction in pancreatic cancer, which is then amplified by a feed forward loop involving cycles of decreased blood flow and increased hypoxia. our findings strengthen the rationale for testing HIF inhibitors may therefore represent a novel therapeutic option for pancreatic cancer.