Proteoglycans-Biomarkers and Targets in Cancer Therapy

Abstract

Proteoglycans (PGs), important constituents of the extracellular matrix, have been associated with cancer pathogenesis. Their unique structure consisting of a protein core and glycosaminoglycan chains endowed with fine modifications constitutes these molecules as capable cellular effectors important for homeostasis and contributing to disease progression. Indeed, differential expression of PGs and their interacting proteins has been characterized as specific for disease evolvement in various cancer types. Importantly, PGs to a large extent regulate the bioavailability of hormones, growth factors, and cytokines as well as the activation of their respective receptors which regulate phenotypic diversibility, gene expression and rates of recurrence in specific tumor types. Defining and targeting these effectors on an individual patient basis offers ground for the development of newer therapeutic approaches which may act as either supportive or a substitute treatment to the standard therapy protocols. This review discusses the roles of PGs in cancer progression, developing technologies utilized for the defining of the PG "signature" in disease, and how this may facilitate the generation of tailor-made cancer strategies.

Keywords: biomarkers; cancer biology; cytokine signaling; molecular signature; proteoglycans.

Figure 1

Schematic presentation of proteoglycan (PG) localization and regulation of cancer relevant cytokine signaling. PGs are located to the extracellular matrix (ECM) proper, pericellular matrix, cell membrane, or intracellular granules. Decorin (Dec), bound in to collagen fibers to the ECM specifically binds growth factors including TGF to create ECM “pools”; whereas pericellular decorin binds to EGFR and/or IGFR to attenuate their downstream signaling and induce growth arrest. Versican binds to through its EFG motif to EGFR and facilitates cancer cell growth, migration, and invasion in a CDK2/GSK-3β-dependent manner whereas through hyaluronan–hyaluronan receptor interaction it regulates cancer progression in a positive or negative manner depending on the context. Pericellular matrix, perlecan regulates VEGF, SHH, KGF, Flt-1, and Flk-1 bioavailability to affect cancer progression. Cell membrane, syndecan-2 was found to regulate, in fibrosarcoma, a transforming growth factor beta-2 (TGF-β2)/Smad2-signaling axis and to propagate IGF-I/IGF-IR signaling through ezrin/erk downstream activation.