The Biological Role of the Collagen Alpha-3 (VI) Chain and Its Cleaved C5 Domain Fragment Endotrophin in Cancer

The collagen alpha-3 (VI) chain encoded by the gene COL6A3 is one of the 3 subunits of collagen VI which is a microfibrillar component of the extracellular matrix and is essential for the stable assembly process of collagen VI. The collagen alpha-3 (VI) chain and the cleaved C5 domain fragment, called endotrophin, are highly expressed in a variety of cancers and play a crucial role in cancer progression. The biological functions of endotrophin in tumors can be driven by adipocytes. Studies have demonstrated that endotrophin can directly affect the malignancy of cancer cells through TGF-β-dependent mechanisms, inducing epithelial–mesenchymal transition and fibrosis of the tumor microenvironment. In addition, endotrophin can also recruit macrophages and endothelial cells through chemotaxis to regulate the tumor microenvironment and ultimately promote tumor inflammation and angiogenesis. Furthermore, COL6A3 and endotrophin serve as novel diagnostic and prognostic biomarkers in cancer and contribute to clinical therapeutic applications in the future. In summary, in this review, we discuss the importance of the collagen alpha-3 (VI) chain and endotrophin in cancer progression, the future clinical applications of endotrophin and the remaining challenges in this field.