Cancer Res：成纤维细胞HIF-1α的作用被揭示

实体肿瘤组织包括恶性肿瘤细胞和相关基质成分，包括成纤维细胞、肿瘤相关巨噬细胞等，这些非肿瘤细胞的存在有助于促进肿瘤的生长和进展。

在晚期肿瘤组织中，我们经常发现肿瘤间质纤维化和血管异常的存在，而这两种现象都与肿瘤组织的缺氧有关，但一直以来肿瘤相关成纤维细胞内的缺氧信号对肿瘤发生发展的贡献仍然不甚明了。

最近刊登在Cancer Research杂志上的一则新研究中，研究人员用成纤维细胞特异性启动子来构建了一种新型小鼠，该启动子区域调控缺氧的关键基因，包括VHL、HIF-1α、HIF-2α、VEGF-A等，但这种小鼠体内的肿瘤间质成纤维细胞被剔除。这一样以来有助单独考察成纤维细胞所产生的缺氧调控因子的作用，而排出了该细胞产生的其他细胞因子。

研究人员发现，在乳腺癌小鼠模型中HIF-1α及其靶基因VEGF-A的缺失加速肿瘤的生长。 HIF-1α和血管内皮生长因子的缺失还导致血管密度减少和骨髓细胞的浸润，这两者与肿瘤灌注的提高相关。总之，这项研究结果表明成纤维细胞所释放的HIF-1α是肿瘤血管生成的重要调控信号途径。

doi:10.1158/0008-5472.CAN-12-0534
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Loss of Fibroblast HIF-1α Accelerates Tumorigenesis

Jung-whan Kim, Colin Evans, Alexander Weidemann, Norihiko Takeda, Yun Sok Lee, Christian Stockmann, Cristina Branco-Price, Filip Brandberg, Gustavo Leone, Michael C. Ostrowski, and Randall S. Johnson

Solid tumors consist of malignant cells and associated stromal components, including fibroblastic cells that contribute to tumor growth and progression. Although tumor fibrosis and aberrant vascularization contribute to the hypoxia often found in advanced tumors, the contribution of hypoxic signaling within tumor-associated fibroblasts to tumorigenesis remains unknown. In this study, we used a fibroblast-specific promoter to create mice in which key hypoxia regulatory genes, including VHL, HIF-1α, HIF-2α, and VEGF-A, were knocked out specifically in tumor stromal fibroblasts. We found that loss of HIF-1α and its target gene VEGF-A accelerated tumor growth in murine model of mammary cancer. HIF-1α and VEGF-A loss also led to a reduction in vascular density and myeloid cell infiltration, which correlated with improved tumor perfusion. Together, our findings indicate that the fibroblast HIF-1α response is a critical component of tumor vascularization