The anti-tumor mechanism of tyrosine kinase inhibitors in clear cell renal cell carcinomas: insights from a pathologic assessment

Abstract

Angiogenesis occurs during tumor development and plays a critical role in the progression of clear cell renal cell carcinoma (CCRCC). Tyrosine kinase inhibitors (TKIs) are multi-target inhibitors of TK receptors that are standard first-line drugs for the treatment of advanced or recurrent CCRCC. Although their efficacy in preventing CCRCC progression is well established, the pathologic features of tumors treated with TKIs are rarely described in the literature. We recently reported that TKIs induced two types of vasculopathy in tumor vessels: type A in large and/or medium-sized vessels, in which there is a concentric intimal thickening that results in the narrowing or occlusion of the lumen; and type B in small vessels, which consist of hyalinized fibrous vessel walls, leading to occlusion of the lumen. TKI-induced vasculopathy was observed in or adjacent to necrotic or degenerative areas in CCRCCs, with tumor vessels showing decreased endothelial cell density; the consequent reduction in the blood supply to CCRCCs had anti-tumorigenic effects. These findings indicate that vasculopathy can serve as a prognostic marker for predicting the effectiveness of TKIs as well as patients outcome, and highlight the relevance of pathologic assessments for pharmaceutical development.