Antithetic roles of proteoglycans in cancer

Abstract

Proteoglycans (PGs), a family of complex post-translationally sculptured macromolecules, are fundamental regulators of most normal and aberrant cellular functions. The unparalleled structural-functional diversity of PGs endows them with the ability to serve as critical mediators of the tumor cells' interaction with the host microenvironment, while directly contributing to the organization and dynamic remodeling of this milieu. Despite their indisputable importance during embryonic development and in the adult organism, and their frequent dysregulation in tumor lesions, their precise involvement in tumorigenesis awaits a more decisive demonstration. Particularly challenging is to ascertain to what extent selected PGs may catalyze tumor progression and to what extent they may inhibit it, implying antithetic functions of individual PGs. Integrated efforts are needed to consolidate the routine use of PGs in the clinical monitoring of cancer patients and to broaden the exploitation of these macromolecules as therapeutic targets. Several PGs have the required attributes to be contemplated as effective antigens for immunotherapeutic approaches, while the tangible results obtained in recent clinical trials targeting the NG2/CSPG4 transmembrane PG urge further development of PG-based cancer treatment modalities.

Fig. 1

Schematic overview of the documented molecular interactions exhibited by glypicans at the cellular and subcellular level and their down-stream consequences. Information is primarily available for GPC1, GPC3, GPC4, and GPC5 hints at agonizing co-receptor functions affecting at least five different signaling systems. This in turn implies that glypicans may be capable of influencing a number of biological events that are instrumental for tumor progression. In many cases, the signaling molecule docking effects of glypicans are mediated by their HS side chains, leaving to be unfolded the actual contribution of the core proteins in determining the specificity of these molecular interactions. Yet another obscure issue is modes through which GPC3 and GPC5 may influence multiple signaling pathways critically involved in tumor growth and dissemination and more precisely how they may counterbalance the up-stream regulation of these signal transductions to eventually elicit tumor-promoting or tumor-inhibiting outputs

Fig. 2

Schematic overview of the putative PG involvement in the different phases of tumorigenesis. A number of PGs expressed by the tumor cells themselves or by the intralesional stroma promote local growth (and may also affect intra-lesional angiogenesis). By contrast, very little is known about to what extent PGs may contribute to local tissue invasion, the entrance (intravasation) of disseminating cells into the hematic and lymphatic circuits, and their exit from these circuits in target organs (extravasation). HS-bearing PGs have been proposed to be implicated in the process of leukocyte/lymphocyte extravasation (which is thought to be regulated by mechanisms analogous to those governing tumor cell trafficking), but the identity of these PGs has not yet been disclosed. Cell surface PGs, in their membrane-associated or shedded form, are similarly believed to the implicated in this phenomenon and our preliminary findings assigns a pivotal role to NG2 in this process and the recycling disseminating cancer cells through the circulation. A number of PGs have also been demonstrated to be associated with metastasis formation in various experimental models and most of these PG are accordingly found to be up-regulated in human metastatic lesions