Proteoglycans as miscommunication biomarkers for cancer diagnosis

Cancer cells reside in a microenvironment comprising of fibroblasts, endothelial cells, pericytes, macrophages, and other immune cells. All these cells coevolve with the cancer cells into a clinically manifested tumor. The immune system of the host should eliminate the tumor but fails to do so until it develops into a deadly disease. Based on these facts, cancer is a system disorder caused by miscommunications among cancer cells, its microenvironment, and host immune system. Therefore, identifying communication-related biomarkers will be important for cancer diagnosis and treatment. Proteoglycans are important communication molecules made by all types of mammalian cells and present both at cell surfaces and in extracellular matrix. Proteoglycans consist of a core protein to which one or more glycosaminoglycan (GAG) chains are covalently attached. GAGs are long linear anionic polysaccharides. They interact with hundreds of growth factors, chemokines, cytokines, proteases, protease inhibitors, and facilitate many signaling transduction pathways in a GAG composition and/or sequence-specific manner. When the GAG network goes awry, the problem cannot be defined by conventional genomic or proteomic approaches because GAGs are assembled without a genetic template. This review will summarize all GAG- and proteoglycan-related cancer biomarkers as well as GAG modification enzymes including sulfotransferase-, heparanase-, hyaluronidase-, and sulfatase-based biomarkers identified during the past 20 years. The published data demonstrate that the proteoglycan- and GAG-related cancer biomarkers are not produced by cancer cells alone, and they are indicators of a miscommunicated system during cancer development.