Heterogeneity of monocarboxylate transporter 1 and 4 (MCT1/MCT4) in clear cell renal cell carcinoma (ccRCC) and metastasis

Abstract

Renal cell carcinoma is the most common kidney cancer and its subtype clear cell renal cell carcinoma (ccRCC) is responsible for the majority of kidney cancer deaths. One metabolic characteristic of ccRCC is the shift to aerobic glycolysis that causes an increase of lactate production and export. Lactate is involved in various processes of carcinogenesis. Responsible for lactate transport in ccRCC are the monocarboxylate transporters (MCT) MCT1 (SLC16A1) and MCT4 (SLC16A3). The expression of both transmembrane proteins was found to correlate with tumour-dependent survival in renal cell carcinoma. For MCT4 it was shown that CpG methylation in the SLC16A3 promotor region is an epigenetic mechanism for MCT4 regulation and a predictor for clinical outcome. In this context, the lactate transporters are of interest as promising candidates as treatment target. This work aimed to elucidate the role of the lactate transporter MCT4 for ccRCC intra-tumour heterogeneity and inter-tumour heterogeneity of metastasis. Moreover, MCT1/MCT4 inhibitors were evaluated as synergistic treatment partners together with metformin or phenformin, which have been suggested to be novel RCC therapeutic options.