Lee Namgyu, Kim Dohoon
Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, MA, USA.
Mol Cells. 2016 Dec;39(12):847-854. doi: 10.14348/molcells.2016.0310. Epub 2016 Dec 29.
The early landmark discoveries in cancer metabolism research have uncovered metabolic processes that support rapid proliferation, such as aerobic glycolysis (Warburg effect), glutaminolysis, and increased nucleotide biosynthesis. However, there are limitations to the effectiveness of specifically targeting the metabolic processes which support rapid proliferation. First, as other normal proliferative tissues also share similar metabolic features, they may also be affected by such treatments. Secondly, targeting proliferative metabolism may only target the highly proliferating "bulk tumor" cells and not the slower-growing, clinically relevant cancer stem cell subpopulations which may be required for an effective cure. An emerging body of research indicates that altered metabolism plays key roles in supporting proliferation-independent functions of cancer such as cell survival within the ischemic and acidic tumor microenvironment, immune system evasion, and maintenance of the cancer stem cell state. As these aspects of cancer cell metabolism are critical for tumor maintenance yet are less likely to be relevant in normal cells, they represent attractive targets for cancer therapy.
癌症代谢研究中的早期标志性发现揭示了支持快速增殖的代谢过程,如有氧糖酵解(瓦伯格效应)、谷氨酰胺分解和核苷酸生物合成增加。然而,特异性靶向支持快速增殖的代谢过程的有效性存在局限性。首先,由于其他正常增殖组织也具有相似的代谢特征,它们也可能受到此类治疗的影响。其次,靶向增殖性代谢可能仅针对高度增殖的“实体瘤”细胞,而无法针对生长较慢但对有效治愈可能至关重要的临床相关癌症干细胞亚群。越来越多的研究表明,代谢改变在支持癌症的增殖非依赖性功能中起关键作用,如在缺血和酸性肿瘤微环境中的细胞存活、逃避免疫系统以及维持癌症干细胞状态。由于癌细胞代谢的这些方面对肿瘤维持至关重要,但在正常细胞中不太可能相关,因此它们是癌症治疗的有吸引力的靶点。