Internalization of Collagen: An Important Matrix Turnover Pathway in Cancer

Abstract

Invasive tumor growth is associated with extensive remodeling of the surrounding extracellular matrix (ECM). Degradation of the original ECM scaffolds, which primarily consist of collagens, is key to the morbidity of the cancer as it leads to destruction of the original tissue and replacement with cancerous tissue. The degradation of collagen involves the cleavage of collagen fibers by extracellular proteases and the subsequent receptor-mediated internalization of large collagen fragments for lysosomal degradation. The extracellular cleavage reactions are typically mediated by matrix metalloproteinases (MMPs) that cleave the collagen strands at specific sites, thereby releasing defined collagen fragments. The intracellular collagen degradation pathway is primarily mediated by two endocytic receptors, uPARAP/Endo180 and the mannose receptor (MR), that bind collagen fragments at the cell surface and direct them to the lysosomes for complete proteolytic degradation. Macrophages and most mesenchymal cells can internalize collagen through the action of MR and uPARAP/Endo180, respectively. These receptors bind preferentially to cleaved collagen and cooperate with MMPs to degrade collagen fibers in a sequential process involving MMP-mediated collagen cleavage followed by receptor-mediated internalization of collagen fragments for lysosomal degradation. In vivo, MR-mediated collagen uptake has been suggested to be dominant in many situations with uPARAP/Endo180 playing a smaller role. In connection to cancer, uPARAP/Endo180 is often upregulated and mostly restricted to cancer-associated fibroblasts, and the action of uPARAP/Endo180 promotes tumor growth and counteracts the development of fibrosis. MR is expressed by M2 macrophages in healthy dermis and in solid tumors and mediates the efficient internalization of collagen. However, the direct functional consequences of this MR-mediated collagen degradation for cancer growth and invasion still need to be investigated.