The Extracellular Matrix Environment of Clear Cell Renal Cell Carcinoma

Simple Summary The extracellular matrix (ECM) controls fundamental properties of tumors, including growth, blood vessel investment, and invasion. The ECM defines rigidity of tumor tissue and individual ECM proteins have distinct biological effects on tumor cells. This article reviews the composition and biological functions of the ECM of clear cell renal cell carcinoma (ccRCC). The most frequent initiating genetic mutation in ccRCC inactivates the VHL gene, which plays a direct role in organizing the ECM. This is predicted to result in local ECM modification, which promotes the growth of tumor cells and the invasion of blood vessels. Later in tumor growth, connective tissue cells are recruited, which are predicted to produce large amounts of ECM, affecting the growth and invasive behaviors of tumor cells. Strategies to therapeutically control the ECM are under active investigation and a better understanding of the ccRCC ECM will determine the applicability of ECM-modifying drugs to this type of cancer. The extracellular matrix (ECM) of tumors is a complex mix of components characteristic of the tissue of origin. In the majority of clear cell renal cell carcinomas (ccRCCs), the tumor suppressor VHL is inactivated. VHL controls matrix organization and its loss promotes a loosely organized and angiogenic matrix, predicted to be an early step in tumor formation. During tumor evolution, cancer-associated fibroblasts (CAFs) accumulate, and they are predicted to produce abundant ECM. The ccRCC ECM composition qualitatively resembles that of the healthy kidney cortex in which the tumor arises, but there are important differences. One is the quantitative difference between a healthy cortex ECM and a tumor ECM; a tumor ECM contains a higher proportion of interstitial matrix components and a lower proportion of basement membrane components. Another is the breakdown of tissue compartments in the tumor with mixing of ECM components that are physically separated in healthy kidney cortex. Numerous studies reviewed in this work reveal effects of specific ECM components on the growth and invasive behaviors of ccRCCs, and extrapolation from other work suggests an important role for ECM in controlling ccRCC tumor rigidity, which is predicted to be a key determinant of invasive behavior.