Sharifi Nima, Farrar William L
Cytokine Molecular Mechanisms Section, Laboratory of Molecular Immunoregulation, Center for Cancer Research, National Cancer Institute at Frederick, Bldg. 560, Room 21-81, Frederick, MD 21702, USA.
Med Hypotheses. 2006;66(4):732-5. doi: 10.1016/j.mehy.2005.11.003. Epub 2005 Dec 20.
The discovery and characterization of the von Hippel Lindau (VHL) syndrome has brought about tremendous advances in understanding the molecular mechanisms of renal cell carcinoma. VHL mutations are known to act through hypoxia inducible factor, which has a physiologic role in detecting hypoxia. Recent investigations into other hereditary forms of kidney cancer with mutations in genes involving energy metabolism and oxidative changes, such as fumarate hydratase, suggest that metabolic changes related to hypoxia detection may be a common mechanism of tumorigenesis. This implicates aberrations in the kidney's physiologic role in detection of hypoxia in tumor formation. Germline mutations of genes involved in energy metabolism and oxidative perturbations lead to tumors in other tissues that detect hypoxia, such as head and neck paragangliomas that occur in the area of the carotid body. Therefore, aberrations in physiologic detection of hypoxia that predispose to tumor formation may not be a mechanism unique to the kidney. Furthermore, inducers of hypoxic perturbations other than germline mutations in metabolic genes may predispose to cancers in organs that have a physiologic role in detecting hypoxia. Conditions that effectively lead to tissue hypoxia in hypoxia detecting tissues is one such mechanism. We propose that some of the common molecular and physiologic mechanisms in heritable forms of kidney cancer, namely detection of hypoxia, may play a role in the genesis of sporadic kidney cancer. We survey evidence suggesting that the mechanism of some recognized risk factors of kidney cancer, such as smoking and obesity, may be due in part to tissue hypoxia, reflecting physiologic detection of hypoxia gone awry.
冯·希佩尔-林道（VHL）综合征的发现与特征描述，在理解肾细胞癌分子机制方面带来了巨大进展。已知VHL突变通过缺氧诱导因子发挥作用，该因子在检测缺氧方面具有生理作用。最近对其他遗传性肾癌形式的研究，这些肾癌涉及能量代谢和氧化变化相关基因（如延胡索酸水合酶）的突变，表明与缺氧检测相关的代谢变化可能是肿瘤发生的常见机制。这暗示了肾脏在肿瘤形成过程中检测缺氧的生理作用存在异常。参与能量代谢和氧化扰动的基因的种系突变会导致其他检测缺氧的组织发生肿瘤，如发生在颈动脉体区域的头颈部副神经节瘤。因此，易引发肿瘤形成的缺氧生理检测异常可能并非肾脏特有的机制。此外，除了代谢基因的种系突变外，缺氧扰动的诱导因素可能会使在检测缺氧方面具有生理作用的器官易患癌症。在检测缺氧的组织中有效导致组织缺氧的情况就是这样一种机制。我们提出，遗传性肾癌的一些常见分子和生理机制，即缺氧检测机制，可能在散发性肾癌的发生中起作用。我们调查了证据，表明肾癌一些公认的风险因素（如吸烟和肥胖）的机制可能部分归因于组织缺氧，这反映了缺氧生理检测出现了偏差。
