Inhibiting Autophagy in Renal Cell Cancer and the Associated Tumor Endothelium

Abstract

The clear cell subtype of kidney cancer encompasses most renal cell carcinoma cases and is associated with the loss of von Hippel-Lindau gene function or expression. Subsequent loss or mutation of the other allele influences cellular stress responses involving nutrient and hypoxia sensing. Autophagy is an important regulatory process promoting the disposal of unnecessary or degraded cellular components, tightly linked to almost all cellular processes. Organelles and proteins that become damaged or that are no longer needed in the cell are sequestered and digested in autophagosomes upon fusing with lysosomes, or alternatively, released via vesicular exocytosis. Tumor development tends to disrupt the regulation of the balance between this process and apoptosis, permitting prolonged cell survival and increased replication. Completed trials of autophagic inhibitors using hydroxychloroquine in combination with other anticancer agents including rapalogues and high-dose interleukin 2 have now been reported. The complex nature of autophagy and the unique biology of clear cell renal cell carcinoma warrant further understanding to better develop the next generation of relevant anticancer agents.

Figure 1.. Clear cell renal cancer is characterized by acquired or inherited defects in two multi-subunit E3 ligases.

The loss of functional parkin decreases mitophagy and, especially in the case of HIF stabilization, contributes to profound changes in cell biology. In conjunction with the influence of HGF and cytoskeletal molecules like actin and tubulin, VHL-dependent HIF stabilization leads to downstream transcriptional modulation in cell migration, oxidative phosphorylation, glucose metabolism, pH regulation, cellular differentiation, angiogenesis, nutrient uptake, and emergence of EPO-driven erythrocytosis.

Figure 2.. Ménage à trois in renal cancer biology.

Immune cells (T cells), endothelium, and the emergent ccRCC are involved in a complex relationship, influencing both the tumor biology and microenvironment. T cells interact, through various mechanisms and molecules, with a number of other immune cells including T regulatory cells, neutrophils, myeloid derived suppressor cells (MDSCs), dendritic cells (DCs), and B cells. The affected T cells and cancer cells interact, expressing IFN-γ, IL-4/IL-3, IL-17, and TGFβ. T cell and endothelium interaction is governed primarily with RAGE, VCAM, and ICAM upregulation subsequent to HMGB1, IL-1, TNF, and IL-4/IL-13 release. ccRCC and the endothelium interact through release of angiopoietins 2 and 4 (ANG2&4), VEGF, and profilin1. There is also the potential of mitochondrial swap between these two cell types in the setting of renal cancer. Autophagy is diminished in the tumor but enhanced in endothelial cells.