Loss of fibroblast HIF-1α accelerates tumorigenesis.
Loss of fibroblast HIF-1α accelerates tumorigenesis.
复制标题
DOI：
10.1158/0008-5472.can-12-0534
复制
发表时间：
2012-07-01
期刊：
影响因子：
11.2
通讯作者：
Johnson RS
中科院分区：
文献类型：
--
作者：
Kim JW;Evans C;Weidemann A;Takeda N;Lee YS;Stockmann C;Branco-Price C;Brandberg F;Leone G;Ostrowski MC;Johnson RS
实体瘤由恶性细胞和相关的基质成分组成，包括有助于肿瘤生长和进展的成纤维细胞。虽然肿瘤纤维化和异常血管形成导致了晚期肿瘤中常见的缺氧，但肿瘤相关成纤维细胞内缺氧信号对肿瘤发生的贡献仍然未知。在这项研究中，我们使用成纤维细胞特异性启动子来创建小鼠，其中关键的缺氧调节基因，包括VHL，HIF-1α，HIF-2α和VEGF-A，在肿瘤间质成纤维细胞中被特异性敲除。我们发现在小鼠乳腺癌模型中，HIF-1α及其靶基因VEGF-A的缺失促进了肿瘤的生长。HIF-1α和VEGF-A的丢失也导致血管密度和髓样细胞浸润的减少，这与肿瘤灌注的改善相关。总之，我们的研究结果表明，成纤维细胞HIF-1α反应是肿瘤血管形成的关键组成部分。
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.