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.

Cell surface proteoglycans are involved in several aspects of cancer biology including tumor progression, angiogenesis, and metastasis formation. Using soft‐tissue sarcoma as model we are trying to understand if different combinations of cell surface PGs can modulate tumour cell interaction with the host microenvironment and metastasis formation; so we are systematically modifying the constitutive patterns of these cells by in vitro gene transduction and RNAi knockdown of individual PGs in different sarcoma cell lines. Overexpression of GPC4, 5 and 6 shows a modulation of the other surface PGs and these new patterns of expression differentially affects the cell migratory and adhesive behaviour on purified ECM molecules and native matrices. RNAi‐mediated knockdown of some SDCs and GPC6 alters cell motility in vitro. Glypicans seem to undergo complex internalisation processes suggesting that endocytic pathways associated with these PGs may control the locomotory machinery. Both syndecans and glypicans seem to influence cell adhesion depending on the matrix substrate. Phospho‐proteomic screenings are in progress. Manipulated cells are assayed for their ability to form tumours and metastasis in mice. Our present findings are starting to delineate correlations between a given repertoire of surface PGs and malignant behavior of sarcoma.

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