Radiation to stromal fibroblasts increases invasiveness of pancreatic cancer cells through tumor-stromal interactions
Radiation to stromal fibroblasts increases invasiveness of pancreatic cancer cells through tumor-stromal interactions
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DOI：
10.1158/0008-5472.can-03-2464
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发表时间：
2004-05-01
期刊：
影响因子：
11.2
通讯作者：
Tanaka, M
中科院分区：
文献类型：
--
作者：
Ohuchida, K;Mizumoto, K;Tanaka, M
放射治疗是胰腺癌患者的主要治疗选择，但最近的证据表明，放射可以促进癌细胞的侵袭和转移。癌细胞和周围间质细胞之间的相互作用可能在肿瘤侵袭性进展中发挥重要作用。在本研究中，我们研究了胰腺癌细胞与辐射后的成纤维细胞共培养时的侵袭性表型。在体外侵袭实验中，我们发现与未经辐射的成纤维细胞共培养显著增加了胰腺癌细胞的侵袭能力，令人惊讶的是，当它们与经辐射的成纤维细胞共培养时，其侵袭力的增加进一步加速。照射后成纤维细胞分泌的肝细胞生长因子(HGF)没有变化，而胰腺癌细胞暴露于照射后的成纤维细胞培养上清液中，c-Met(HGF受体)的磷酸化和丝裂原活化蛋白激酶活性增加，这可能或部分是通过增加c-Met的表达实现的。我们还证明了辐射后的成纤维细胞的上清液加速了胰腺癌细胞的分散。HGF的特异性拮抗剂NK4可完全阻断照射后的成纤维细胞与胰腺癌细胞共培养后侵袭力的增强。这些数据表明，某些胰腺癌细胞的侵袭能力可能是通过上调胰腺癌细胞c-Met的表达/磷酸化和丝裂原激活的蛋白激酶活性而被辐射后的成纤维细胞释放的可溶性介质(S)增强的。我们目前的发现进一步支持了NK4在胰腺癌患者放射治疗中的潜在应用。
Radiotherapy represents a major treatment option for patients with pancreatic cancer, but recent evidence suggests that radiation can promote invasion and metastasis of cancer cells. Interactions between cancer cells and surrounding stromal cells may play an important role in aggressive tumor progression. In the present study, we investigated the invasive phenotype of pancreatic cancer cells in response to coculture with irradiated fibroblasts. Using in vitro invasion assay, we demonstrated that coculture with nonirradiated fibroblasts significantly increased the invasive ability of pancreatic cancer cells and, surprisingly, the increased invasiveness was further accelerated when they were cocultured with irradiated fibroblasts. The hepatocyte growth factor (HGF) secretion front fibroblasts remained unchanged after irradiation, whereas exposure of pancreatic cancer cells to supernatant from irradiated fibroblasts resulted in increased phosphorylation of c-Met (HGF receptor) and mitogen-activated protein kinase activity, possibly or partially via increased expression of c-Met. We also demonstrated that scattering of pancreatic cancer cells was accelerated by the supernatant from irradiated fibroblasts. The enhanced invasiveness of pancreatic cancer cells induced by coculture with irradiated fibroblasts was completely blocked by NK4, a specific antagonist of HGF. These data suggest that invasive potential of certain pancreatic cancer cells is enhanced by soluble mediator(s) released from irradiated fibroblasts possibly through up-regulation of c-Met expression/phosphorylation and mitogen-activated protein kinase activity in pancreatic cancer cells. Our present findings further support the potential use of NK4 during radiotherapy for patients with pancreatic cancer.