Hoffman Robert M
a AntiCancer Inc. , San Diego , CA , USA.
b Department of Surgery , University of California , San Diego , CA , USA.
Cell Cycle. 2017 May 3;16(9):825-829. doi: 10.1080/15384101.2017.1304330. Epub 2017 Mar 20.
We propose here a hypothesis of the cause of cancer that brings together fundamental changes in methyl-group metabolism resulting in methionine dependence and global DNA hypomethylation which destabilizes the genome leading to aneuploid karyotypes which evolve and stabilize into autonomous cancer. Experimental support for this hypothesis is that methioine dependence is a general metabolic defect in caner. Methionine dependence is due to excess use of methionene for aberrant transmethylation reactions that apparently divert methyl groups from DNA. The resulting global DNA hypomethylation is also a general phenomena in cancer. Global hypomethylation leads to an unstable genomes and aneuploid karyotypes, another general phenomena in cancer. The excessive and aberrant use of methionine in cancer is strongly observed in [C]methionine PET imaging, where high uptake of [C]methionine results in a very strong and selective tumor signal compared with normal tissue background. [C]methionine is superior to [C] fluorodeoxyglucose (FDG)-PET for PET imaging, suggesting methionine dependence is more tumor-specific than glucose dependence.
我们在此提出一种癌症病因假说，该假说将甲基代谢的根本变化整合在一起，这些变化导致甲硫氨酸依赖性和全基因组DNA低甲基化，进而使基因组不稳定，导致非整倍体核型，这些核型不断演变并稳定为自主性癌症。这一假说的实验依据是，甲硫氨酸依赖性是癌症中一种普遍的代谢缺陷。甲硫氨酸依赖性是由于甲硫氨酸被过度用于异常的转甲基反应，这些反应显然使甲基从DNA转移。由此产生的全基因组DNA低甲基化也是癌症中的一种普遍现象。全基因组低甲基化导致基因组不稳定和非整倍体核型，这也是癌症中的一种普遍现象。在[C]甲硫氨酸PET成像中可以强烈观察到癌症中甲硫氨酸的过度和异常使用，与正常组织背景相比，[C]甲硫氨酸的高摄取导致非常强烈且具有选择性的肿瘤信号。[C]甲硫氨酸在PET成像方面优于[C]氟脱氧葡萄糖（FDG）-PET，这表明甲硫氨酸依赖性比葡萄糖依赖性更具肿瘤特异性。
