Investigation of the etiology and tumor biology of renal cell carcinoma

Abstract

Background: Approximately 1,300 people are diagnosed with renal cell carcinoma (RCC) in Sweden each year. The aim of this thesis was to study predisposing factors for RCC development and aspects of its tumor biology connected to cellular uptake mechanisms. Furthermore, to describe novel RCC subtypes and explore potential therapeutic implications. Materials and methods: Fresh-frozen tumor samples, histological material including tissue microarrays, primary cell cultures, and cell lines were analyzed. Whole-genome sequencing, RNA sequencing, public RCC datasets, and epidemiological registry data were evaluated. Selected metabolic features were assessed by mass spectrometry (RP-LC-MS/MS) and ToF-SIMS. Results: Paper I showed that expression of SARS-CoV-2 entry factors ACE2, TMPRSS2, and NRP1 were retained by papillary and clear cell RCC. Primary cancer cells became infected and displayed distinct virus-induced cytopathogenic effects. Paper II demonstrated that RCC risk was doubled if a parent or sibling was diagnosed with RCC. The median age at diagnosis was similar to that of sporadic RCC, with higher risk for women. Paper III showed that genomic clustering of RCC cases from The Cancer Genome Atlas (TCGA), together with TMA analyses, indicated morphological and molecular overlap between the indolent RCC with fibromyomatous stroma (RCCFMS) and clear cell papillary renal cell tumor (CCPRCT). Paper IV demonstrated that the characteristic yellow-orange colour of clear cell RCC stems from accumulation of β-carotene, potentially mediated by increased uptake via SCARB1. Enzymes involved in β-carotene and retinol metabolism were detected in tumor tissue. Conclusion: Selective targeting of RCC may be possible using virus-based delivery strategies. Familial RCC appears to be relatively common and has not yet received a complete genetic explanation. The benign clear cell tumor CCPRCT may represent part of the same spectrum of indolent clear cell tumors as RCCFMS, associated with epigenetic silencing of VHL. Increased β-carotene uptake in clear cell RCC may represent a potential target for diagnostic and therapeutic applications.