Dayan Frédéric, Mazure Nathalie M, Brahimi-Horn M Christiane, Pouysségur Jacques
Institute of Signaling, Developmental Biology and Cancer Research, University of Nice, CNRS UMR 6543, Centre A. Lacassagne, 33 Avenue Valombrose, Nice, France.
Cancer Microenviron. 2008 Dec;1(1):53-68. doi: 10.1007/s12307-008-0006-3. Epub 2008 Mar 19.
The hypoxia-inducible factor is the key protein responsible for the cellular adaptation to low oxygen tension. This transcription factor becomes activated as a result of a drop in the partial pressure of oxygen, to hypoxic levels below 5% oxygen, and targets a panel of genes involved in maintenance of oxygen homeostasis. Hypoxia is a common characteristic of the microenvironment of solid tumors and, through activation of the hypoxia-inducible factor, is at the center of the growth dynamics of tumor cells. Not only does the microenvironment impact on the hypoxia-inducible factor but this factor impacts on microenvironmental features, such as pH, nutrient availability, metabolism and the extracellular matrix. In this review we discuss the influence the tumor environment has on the hypoxia-inducible factor and outline the role of this factor as a modulator of the microenvironment and as a powerful actor in tumor remodeling. From a fundamental research point of view the hypoxia-inducible factor is at the center of a signaling pathway that must be deciphered to fully understand the dynamics of the tumor microenvironment. From a translational and pharmacological research point of view the hypoxia-inducible factor and its induced downstream gene products may provide information on patient prognosis and offer promising targets that open perspectives for novel "anti-microenvironment" directed therapies.
缺氧诱导因子是负责细胞适应低氧张力的关键蛋白。由于氧分压下降至低于5%氧气的缺氧水平，这种转录因子被激活，并靶向一组参与维持氧稳态的基因。缺氧是实体瘤微环境的一个共同特征，通过激活缺氧诱导因子，它处于肿瘤细胞生长动力学的中心位置。微环境不仅影响缺氧诱导因子，而且该因子也影响微环境特征，如pH值、营养物质可用性、代谢和细胞外基质。在本综述中，我们讨论了肿瘤环境对缺氧诱导因子的影响，并概述了该因子作为微环境调节剂和肿瘤重塑中有力参与者的作用。从基础研究的角度来看，缺氧诱导因子处于一个信号通路的中心，必须对其进行解读才能充分理解肿瘤微环境的动态变化。从转化研究和药理学研究的角度来看，缺氧诱导因子及其诱导的下游基因产物可能提供有关患者预后的信息，并提供有前景的靶点，为新型“抗微环境”定向治疗开辟前景。
