Molecular Mechanisms of Renal Cancer Stem Cells and Tumor Heterogeneity: Genetic Drivers of Resistance, Relapse, and Therapeutic Challenges

Abstract

Renal cell carcinoma (RCC) is a very aggressive form of cancer which is the most common malignancy of kidneys. RCC has proven to be a problem despite modern surgical practices and systemic therapy, since it has a high rate of relapse and is very resistant to therapy, which is usually caused by cancer stem cells (CSCs). CSCs comprise a subgroup of tumor cells that induce tumor initiation, tumor progression, tumor metastasis and tumor resistance to traditional therapies, which play an important role in tumor heterogeneity. The genetic changes and activation of important pathways were evaluated by the use of molecular assays, such as flow cytometry, gene expression analysis, and next-generation sequencing (NGS). They were conducted to measure the sensitizing of CSCs populations to chemotherapy agents through drug resistance assays. It was found that high CSC population is more prevalent in higher stages of tumor (Stage III and IV) and in the clear cell subtype. Significant genetic changes were seen in high populations of CSC and encompassed Von Hippel-Lindau (VHL) gene mutations and two signaling pathways: Wnt/b-catenin signaling pathway and Notch. The large CSCs population is strongly linked to high-stage levels of RCC, genetic mutations, and high-level resistance to chemotherapy. The inhibition of CSC pathways can become a solution to resistance and better patient outcomes. Future research must aim at establishing accurate CSC biomarkers to use in personalised therapy in addition to development of new CSC-targeting therapy.