Division of Medical Oncology, Mayo Clinic, Rochester, USA
Division of Medical Oncology, Mayo Clinic, Rochester, USA.
Ann Oncol. 2016 Sep;27(9):1685-95. doi: 10.1093/annonc/mdw241. Epub 2016 Jun 20.
Clear cell renal cell carcinoma (ccRCC) accounts for ∼80% of all RCC, and biallelic Von Hippel-Lindau (VHL) gene defects occur in ∼75% of sporadic ccRCC. The etiopathogenesis of VHL mutant metastatic RCC, based on our understanding to date of molecular mechanisms involved, is a sequence of events which can be grouped under the following: (i) loss of VHL activity (germline/somatic mutation + inactivation of the wild-type copy); (ii) constitutive activation of the hypoxia-inducible factor (HIF) pathway due to loss of VHL activity and transcription of genes involved in angiogenesis, epithelial-mesenchymal transition, invasion, metastasis, survival, anaerobic glycolysis and pentose phosphate pathway; (iii) interactions of the HIF pathway with other oncogenic pathways; (iv) genome-wide epigenetic changes (potentially driven by an overactive HIF pathway) and the influence of epigenetics on various oncogenic, apoptotic, cell cycle regulatory and mismatch repair pathways (inhibition of multiple tumor suppressor genes); (v) immune evasion, at least partially caused by changes in the epigenome. These mechanisms interact throughout the pathogenesis and progression of disease, and also confer chemoresistance and radioresistance, making it one of the most difficult metastatic cancers to treat. This article puts together the sequential pathogenesis of VHL mutant ccRCC by elaborating these mechanisms and the interplay of oncogenic pathways, epigenetics, metabolism and immune evasion, with a perspective on potential therapeutic strategies. We reflect on the huge gap between our understanding of the molecular biology and currently accepted standard of care in metastatic ccRCC, and present ideas for better translational research involving therapeutic strategies with combinatorial drug approach, targeting different aspects of the pathogenesis.
透明细胞肾细胞癌（ccRCC）占所有 RCC 的约 80%，散发性 ccRCC 中约有 75%存在双等位基因 Von Hippel-Lindau（VHL）基因缺陷。基于我们目前对所涉及的分子机制的理解，VHL 突变转移性 RCC 的病因发病机制是一系列事件，可以分为以下几类：（i）VHL 活性丧失（种系/体细胞突变+野生型拷贝失活）；（ii）由于 VHL 活性丧失和参与血管生成、上皮-间充质转化、侵袭、转移、存活、无氧糖酵解和戊糖磷酸途径的基因转录，导致低氧诱导因子（HIF）通路的组成性激活；（iii）HIF 通路与其他致癌途径的相互作用；（iv）全基因组表观遗传变化（可能由过度活跃的 HIF 通路驱动）以及表观遗传学对各种致癌、凋亡、细胞周期调节和错配修复途径的影响（抑制多个肿瘤抑制基因）；（v）免疫逃避，至少部分由表观基因组的改变引起。这些机制在疾病的发病机制和进展过程中相互作用，并赋予化学耐药性和放射耐药性，使其成为最难治疗的转移性癌症之一。本文通过阐述这些机制以及致癌途径、表观遗传学、代谢和免疫逃避的相互作用，阐述了 VHL 突变型 ccRCC 的序贯发病机制，并探讨了潜在的治疗策略。我们反思了我们对分子生物学的理解与转移性 ccRCC 目前公认的标准治疗之间的巨大差距，并提出了一些想法，以更好地进行涉及联合药物治疗策略的转化研究，针对发病机制的不同方面。
