Tumor-stromal cell interaction under hypoxia increases the invasiveness of pancreatic cancer cells through the hepatocyte growth factor/c-Met pathway
Tumor-stromal cell interaction under hypoxia increases the invasiveness of pancreatic cancer cells through the hepatocyte growth factor/c-Met pathway
复制标题
DOI：
10.1002/ijc.22178
复制
发表时间：
2006-12-15
影响因子：
6.4
通讯作者：
Miyazaki, Kohji
中科院分区：
文献类型：
--
作者：
Ide, Takao;Kitajima, Yoshihiko;Miyazaki, Kohji
据报道，肿瘤中的缺氧环境在胰腺癌进展中发挥重要作用。基质细胞和癌细胞之间的相互作用也导致胰腺癌的恶性行为。在本研究中，我们研究了缺氧刺激是否影响基质癌细胞和胰腺癌细胞。我们的研究结果表明，缺氧显着升高了胰腺癌 (PK8) 和成纤维细胞 (MRC5) 中的 HIF-1 α 表达。低氧刺激加速了PK8细胞的侵袭活性，因此当用低氧MRC5细胞制备的条件培养基（低氧条件培养基）培养低氧PK8细胞时，侵袭性进一步加速。缺氧条件下PK8细胞中MMP-2、MMP-7、MT1-MMP和c-Met表达增加。缺氧刺激还增加了 MRC5 细胞的肝细胞生长因子 (HGF) 分泌，从而导致 PK8 细胞中 c-Met 磷酸化升高。相反，从低氧条件培养基中去除 HGF 可以降低 PK8 细胞中升高的癌症侵袭、MMP 活性和 c-Met 磷酸化。在免疫组织化学研究中，在周围基质细胞和胰腺癌细胞中观察到HIF-1α表达，从而表明癌细胞和基质细胞中均存在缺氧。此外，发现基质HGF表达不仅与基质HIF-1a表达显着相关，而且与癌细胞中的c-Met表达显着相关。这些结果表明基质细胞和癌细胞内的缺氧环境激活 HGF/c-Met 系统，从而导致胰腺癌的侵袭性侵袭特征。 (c) 2006 Wiley-Liss, Inc.
The hypoxic environment in tumor is reported to play an important role in pancreatic cancer progression. The interaction between stromal and cancer cells also contributes to the malignant behavior of pancreatic cancer. In the present study, we investigated whether hypoxic stimulation affects stromal as well as pancreatic cancer cells. Our findings demonstrated that hypoxia remarkably elevated the HIF-1 alpha expression in both pancreatic cancer (PK8) and fibroblast cells (MRC5). Hypoxic stimulation accelerated the invasive activity of PK8 cells, and invasiveness was thus further accelerated when the hypoxic PK8 cells were cultured with conditioned medium prepared from hypoxic MRC5 cells (hypoxic conditioned medium). MMP-2, MMP-7, MT1-MMP and c-Met expressions were increased in PK8 cells under hypoxia. Hypoxic stimulation also increased the hepatocyte growth factor (HGF) secretion from MRC5 cells, which led to an elevation of c-Met phosphorylation in PK8 cells. Conversely, the elevated cancer invasion, MMP activity and c-Met phosphorylation of PK8 cells were reduced by the removal of HGF from hypoxic conditioned medium. In immunohistochemical study, the HIF-1 alpha expression was observed in surrounding stromal as well as pancreatic cancer cells, thus indicating hypoxia exists in both of cancer and stromal cells. Moreover, the stromal HGF expression was found to significantly correlate with not only the stromal HIF-1a expression but also the c-Met expression in cancer cells. These results indicate that the hypoxic environment within stromal as well as cancer cells activates the HGF/c-Met system, thereby contributing to the aggressive invasive features of pancreatic cancer. (c) 2006 Wiley-Liss, Inc.