UPCI Hillman Cancer Center, Pittsburgh, PA 15213, USA.
Cancer J. 2013 Jul-Aug;19(4):341-7. doi: 10.1097/PPO.0b013e31829da0d6.
The common clear cell subtype of renal cell carcinoma is associated with hereditary or acquired loss of function of the von Hippel-Lindau tumor suppressor, a key component in oxygen sensing, perpetuating a stressed state. Autophagy is primarily a highly conserved, catabolic process by which stressed cells shuttle damaged or effete organelles and proteins into autophagosomes for sequestration and digestion after fusion with lysosomes. Autophagy is directed by autophagy-related genes and is divided into 4 discrete steps: initiation, nucleation, maturation, and degradation. During early tumorigenesis, apoptosis is enhanced and autophagy is suppressed, allowing accumulation of mutations and emergence of genomic instability. Late, an "autophagic switch" occurs, promoting survival and limiting apoptosis. Compounds such as chloroquine and hydroxychloroquine that prevent acidification of the lysosomal compartment are the sole clinically available inhibitors of autophagy. Currently, there are more than 30 trials examining combinations of hydroxychloroquine with anticancer agents. The intricate effects of autophagy on the immune response complicate manipulation of autophagy as part of the antitumor strategy. Further understanding of basic mechanisms of renal cell carcinoma pathogenesis and of autophagy will enable development of the next generation of pharmacologic modulators of autophagy.
肾透明细胞癌的常见亚型与von Hippel-Lindau 肿瘤抑制因子的遗传性或获得性功能丧失有关，该因子是氧感应的关键组成部分，使细胞处于持续的应激状态。自噬主要是一种高度保守的分解代谢过程，通过该过程，应激细胞将受损或无效的细胞器和蛋白质穿梭到自噬体中，然后与溶酶体融合进行隔离和消化。自噬由自噬相关基因指导，并分为 4 个离散步骤：起始、成核、成熟和降解。在早期肿瘤发生过程中，细胞凋亡增强而自噬受到抑制，从而导致突变积累和基因组不稳定性的出现。晚期，发生“自噬开关”，促进存活并限制细胞凋亡。氯喹和羟氯喹等可阻止溶酶体腔酸化的化合物是唯一临床上可用于抑制自噬的化合物。目前，有 30 多项试验正在研究羟氯喹与抗癌药物的联合应用。自噬对免疫反应的复杂影响使自噬作为抗肿瘤策略的一部分的操纵变得复杂。进一步了解肾透明细胞癌发病机制和自噬的基本机制将能够开发下一代自噬的药理学调节剂。
