實(shí)體腫瘤組織包括惡性腫瘤細(xì)胞和相關(guān)基質(zhì)成分，包括成纖維細(xì)胞,、腫瘤相關(guān)巨噬細(xì)胞等,，這些非腫瘤細(xì)胞的存在有助于促進(jìn)腫瘤的生長(zhǎng)和進(jìn)展。
在晚期腫瘤組織中,，我們經(jīng)常發(fā)現(xiàn)腫瘤間質(zhì)纖維化和血管異常的存在,，而這兩種現(xiàn)象都與腫瘤組織的缺氧有關(guān),，但一直以來腫瘤相關(guān)成纖維細(xì)胞內(nèi)的缺氧信號(hào)對(duì)腫瘤發(fā)生發(fā)展的貢獻(xiàn)仍然不甚明了。
最近刊登在Cancer Research雜志上的一則新研究中,，研究人員用成纖維細(xì)胞特異性啟動(dòng)子來構(gòu)建了一種新型小鼠,，該啟動(dòng)子區(qū)域調(diào)控缺氧的關(guān)鍵基因，包括VHL,、HIF-1α,、HIF-2α、VEGF-A等,，但這種小鼠體內(nèi)的腫瘤間質(zhì)成纖維細(xì)胞被剔除,。這一樣以來有助單獨(dú)考察成纖維細(xì)胞所產(chǎn)生的缺氧調(diào)控因子的作用，而排出了該細(xì)胞產(chǎn)生的其他細(xì)胞因子,。
研究人員發(fā)現(xiàn),，在乳腺癌小鼠模型中HIF-1α及其靶基因VEGF-A的缺失加速腫瘤的生長(zhǎng)。 HIF-1α和血管內(nèi)皮生長(zhǎng)因子的缺失還導(dǎo)致血管密度減少和骨髓細(xì)胞的浸潤(rùn),，這兩者與腫瘤灌注的提高相關(guān),。總之,，這項(xiàng)研究結(jié)果表明成纖維細(xì)胞所釋放的HIF-1α是腫瘤血管生成的重要調(diào)控信號(hào)途徑,。（生物谷：Bioon.com）
doi:10.1158/0008-5472.CAN-12-0534
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PMID:
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
