Inflammatory Networks in Renal Cell Carcinoma

SIMPLE SUMMARY: Inflammation is an important hallmark of advanced renal cell carcinoma and plays a pivotal role in tumor progression, metastasis, and anti-cancer resistance. Inflammation regulates the crosstalk between tumor cells and the surrounding tumor microenvironment, thereby promoting immune cell infiltration and release of inflammatory mediators and inducing immunosuppressive functions. Although inflammatory pathways sustain the function of renal cancer cells, the activatory effects are highly dependent on the immune cell landscape and the stage of RCC tumors. The aim of this review is to summarize the recent works describing the role of inflammation in the growth and metastasis of RCC tumors. This review also critically discusses the clinically relevant inflammatory pathways as potential targets for disease prevention and treatment. ABSTRACT: Cancer-associated inflammation has been established as a hallmark feature of almost all solid cancers. Tumor-extrinsic and intrinsic signaling pathways regulate the process of cancer-associated inflammation. Tumor-extrinsic inflammation is triggered by many factors, including infection, obesity, autoimmune disorders, and exposure to toxic and radioactive substances. Intrinsic inflammation can be induced by genomic mutation, genome instability and epigenetic remodeling in cancer cells that promote immunosuppressive traits, inducing the recruitment and activation of inflammatory immune cells. In RCC, many cancer cell-intrinsic alterations are assembled, upregulating inflammatory pathways, which enhance chemokine release and neoantigen expression. Furthermore, immune cells activate the endothelium and induce metabolic shifts, thereby amplifying both the paracrine and autocrine inflammatory loops to promote RCC tumor growth and progression. Together with tumor-extrinsic inflammatory factors, tumor-intrinsic signaling pathways trigger a Janus-faced tumor microenvironment, thereby simultaneously promoting or inhibiting tumor growth. For therapeutic success, it is important to understand the pathomechanisms of cancer-associated inflammation, which promote cancer progression. In this review, we describe the molecular mechanisms of cancer-associated inflammation that influence cancer and immune cell functions, thereby increasing tumor malignancy and anti-cancer resistance. We also discuss the potential of anti-inflammatory treatments, which may provide clinical benefits in RCCs and possible avenues for therapy and future research.