Cell surface chondroitin sulfate proteoglycans in tumor cell adhesion, motility and invasion Joji Iida*, Alexandra M. L. Meijne *, JenniferR. Knutson *, LeoT. Furcht*†‡ and James B. McCarthy *†‡ Tumor cell invasion and metastasis is highly dependent on dynamic changes in the adhesion and migration of transformed and malignant cells. As with normal cell adhesion, the adhesion of tumor cells influences their cytoskeletal organization, activation of signal transduction pathways within the cell, and nuclear events leading to changes in mRNA transcription and protein synthesis. Furthermore, as tumor cells invade the circulation, they adhere to activated endothelial cells at sites within the vasculature during arrest and extravasation. Studies in the area of tumor cell adhesion and migration have demonstrated that the recognition of extracellular matrix ligands, or adhesion promoting ligands expressed on neighboring cells (i.e. counter-receptors), involves complex molecular recognition mechanisms. The complexity arises, in part, from the multiple recognition sites that are present within adhesion promoting ligands. Some of these structures within ECM components act by binding integrins, whereas others bind additional receptors such as cell surface proteoglycans. In this sense, adhesion promoting ligands may be considered as informational arrays, that function to modulate cell phenotype by engaging specific combinations of adhesion receptors on the cell surface. Understanding the mechanism(s) by which these receptor ‘cluster’ modify cell adhesion, motility and growth may lead to novel therapeutic strategies to control tumor cell invasion and metastasis formation. This review will highlight the role that cell surface chondroitin sulfate proteoglycans may play in modulating tumor cell adhesion, migration and invasion, with an emphasis on the relationship between cell surface chondroitin sulfate proteoglycans and integrins. Key words: cell adhesion / integrins / metastasis / signal transduction / tumor ©1996 Academic Press Ltd Tumor cell adhesion is a fundamental consideration in tumor cell invasion and metastasis Tumor cells must adhere to a variety of extracellular matrix (ECM) components and cell surface molecules as they invade and metastasize. These interactions of tumor cells have a profound effect on their pheno- typic behavior. Over the last 15 years, extensive progress has been made in identifying ECM compo- nents and particular sites on these components that mediate cellular recognition/ adhesion. 1-10 Similar progress has been made in the area of cell–cell adhesion, with a significant number of specific recep- tor/ counter-receptor pairs having been identified and partially characterized. Several types of adhesion receptors can function in both cell–ECM and cell–cell adhesion, and therefore both types of adhesion may share common mechanisms. Integrins are a family of receptors that are funda- mentally important for mediating cell adhesion. 1,2,7 Integrins are transmembrane heterodimers, consist- ing of noncovalently associated α and  subunits. The combination of particular integrin α and  subunits is important for determining ligand-binding specific- ities. Crosslinking of integrins by the appropriate ligands leads to the generation of intracellular signals by outside-in mechanisms. Several approaches point to an importance of the -subunit cytoplasmic tail for mediating signals (see reviews by La Flamme and Sanchez-Madrid, this issue, also ref 10). Such outside- in signals include tyrosine phosphorylation of several cytoplasmic/ cytoskeletal proteins such as FAK, pax- illin, tensin, and activation of Na + /H + antiporter. Furthermore, integrin activation leads to physical changes in cell shape brought about by changes in cytoskeletal organization. Outside-in signal transduc- tion by integrins is a complex process, involving both ligand binding and receptor clustering on the cell surface. Activation of signalling pathways inside cells can also modulate integrin function by inside-out mechanisms. 3,6,7,9,10 Inside-out mechanisms of signal From the University of Minnesota, Box 609 UMHC *Department of Laboratory Medicine and Pathology, †Biomedical Engineering Cen ter, and ‡University of Minnesota Cancer Center, Minneapolis, MN 55455, USA seminars in CANCER BIOLOGY, Vol 7, 1996: pp 155–162 ©1996 Academic Press Ltd 1044-579X/ 96/ 030155 +08$18.00/ 0 155