Blais Jaime D, Addison Christina L, Edge Robert, Falls Theresa, Zhao Huijun, Wary Kishore, Koumenis Costas, Harding Heather P, Ron David, Holcik Martin, Bell John C
Ottawa Health Research Institute, Ottawa, ON K1H 1C4, Canada.
Mol Cell Biol. 2006 Dec;26(24):9517-32. doi: 10.1128/MCB.01145-06. Epub 2006 Oct 9.
It has been well established that the tumor microenvironment can promote tumor cell adaptation and survival. However, the mechanisms that influence malignant progression have not been clearly elucidated. We have previously demonstrated that cells cultured under hypoxic/anoxic conditions and transformed cells in hypoxic areas of tumors activate a translational control program known as the integrated stress response (ISR). Here, we show that tumors derived from K-Ras-transformed Perk(-/-) mouse embryonic fibroblasts (MEFs) are smaller and exhibit less angiogenesis than tumors with an intact ISR. Furthermore, Perk promotes a tumor microenvironment that favors the formation of functional microvessels. These observations were corroborated by a microarray analysis of polysome-bound RNA in aerobic and hypoxic Perk(+/+) and Perk(-/-) MEFs. This analysis revealed that a subset of proangiogenic transcripts is preferentially translated in a Perk-dependent manner; these transcripts include VCIP, an adhesion molecule that promotes cellular adhesion, integrin binding, and capillary morphogenesis. Taken with the concomitant Perk-dependent translational induction of additional proangiogenic genes identified by our microarray analysis, this study suggests that Perk plays a role in tumor cell adaptation to hypoxic stress by regulating the translation of angiogenic factors necessary for the development of functional microvessels and further supports the contention that the Perk pathway could be an attractive target for novel antitumor modalities.
肿瘤微环境可促进肿瘤细胞适应和存活，这一点已得到充分证实。然而，影响恶性进展的机制尚未完全阐明。我们之前已证明，在缺氧/无氧条件下培养的细胞以及肿瘤缺氧区域的转化细胞会激活一种名为综合应激反应（ISR）的翻译控制程序。在此，我们表明，源自K-Ras转化的Perk基因敲除小鼠胚胎成纤维细胞（MEF）的肿瘤比具有完整ISR的肿瘤更小，血管生成也更少。此外，Perk可促进有利于功能性微血管形成的肿瘤微环境。通过对有氧和缺氧条件下的Perk基因野生型（Perk(+/+)）和Perk基因敲除型（Perk(-/-)）MEF中多核糖体结合RNA进行微阵列分析，这些观察结果得到了证实。该分析表明，一部分促血管生成转录本以Perk依赖的方式优先翻译；这些转录本包括VCIP，一种促进细胞黏附、整合素结合和毛细血管形态发生的黏附分子。结合我们微阵列分析确定的其他促血管生成基因伴随的Perk依赖性翻译诱导，本研究表明，Perk通过调节功能性微血管发育所需的血管生成因子的翻译，在肿瘤细胞对缺氧应激的适应中发挥作用，并进一步支持了Perk通路可能是新型抗肿瘤治疗有吸引力的靶点这一观点。
