Antithetic glypican control of cancer growth and dissemination

Cell surface proteoglycans (PGs), including syndecans, glypicans and NG2, are involved in several aspects of cancer biology. However, different PG may control cancer cell behaviour differently by cooperating or counteracting each other's individual functions. To resolve these antithetic effects of PGs we are adopting human and murine sarcoma and melanoma cellular models in which we manipulate the PG profile by ectopic transduction or RNAi‐mediated knockdown of the single PGs. Model cell lines engineered to express GPC4, 5 and 6, or knockdown of SDC1 or 4 were assayed for the migratory and invasive behaviour in vitro and their growth and dissemination capabilities in vivo using wild type animals. These genetic alterations caused perturbed cell motility rates, transvascular movement capabilities and growth behaviour in vivo . GPC‐4 and ‐6 seem to promote motility, invasion and in vivo tumour growth, whereas GPC‐5 exerts the opposite effect. These sarcoma models also exhibit diverse profiles of phosphorylation of intracellular signalling components. Part of the effects of these glypicans seem to be mediated by their endocytic recycling, whereas less clear is how phenomenon of shedding influence the behaviour of the cells. These observations delineate the first correlations between a given repertoire of surface PGs and malignant behavior of sarcoma cells and are expected to define novel therapeutic strategies.