Glycosaminoglycans in cancer treatment

Abstract

Studies aimed at the identification of biomarkers and treatment targets of cancer have focused on mRNAs, miRNAs, and proteins expressed by malignant cells, while glycoproteins mainly produced by stromal cells remain relatively unexplored. Glycans lack a given template for their biosynthesis that involves the concerted action of several, sometimes >15 different enzymes. This fact complicates the analysis at the genomic level of the role of glycoproteins in clinical oncology. The glycosaminoglycans (GAGs) stand out as highly polyanionic components at the surface of malignant and stromal tumor cells as well as their surrounding matrix. Published data thus describe a multifaceted regulatory role of GAGs and GAG-conjugated proteins, proteoglycans, in e.g. tumor associated angiogenesis, coagulation, invasion, and metastasis. Relatively small, randomized clinical trials suggest that heparin, an over-sulfated variant of the GAG heparan sulfate, may have direct, anti-tumor effects. Several ongoing trials aim at establishing whether heparin and its derivatives should be added to standard treatment of cancer patients or not, based on progression free- and overall survival end-point data. Given the potential bleeding complications with this treatment, other strategies to block GAG function should provide interesting alternatives. In the emerging era of personalized medicine, one can foresee the development of predictive biomarkers to select patients that may benefit from GAG-targeted treatments, aiming at individualized prevention of thromboembolic complications as well as inhibition of tumor development and progression. Here, the role of GAGs as targets and vehicles of cancer treatment is discussed with special emphasis on angiogenesis and coagulation associated mechanisms.

Keywords: Cancer; Coagulation; Heparan sulfate; Heparin; Proteoglycan.