Modulation of sarcoma cell movement and matrix interaction following manipulation of cell surface proteoglycans

Abstract

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.