Abstract
Fibrin(ogen) mediates sustained tumor cell adhesion and survival in the pulmonary vasculature, thereby facilitating the metastatic dissemination of tumor cells. CD44 is the major functional fibrin receptor on colon carcinoma cells. Growth factors, such as platelet-derived growth factor (PDGF), induce post-translational protein modifications, which modulate ligand binding activity. In view of the roles of PDGF, fibrin(ogen) and CD44 in cancer metastasis, we aimed to delineate the effect of PDGF on CD44-fibrin recognition. By immunoprecipitating CD44 from PDGF-treated and untreated LS174T colon carcinoma cells, which express primarily CD44v, we demonstrate that PDGF enhances the adhesion of CD44v-coated beads to immobilized fibrin. Enzymatic inhibition studies coupled with flow-based adhesion assays and autoradiography reveal that PDGF augments the binding of CD44v to fibrin by significantly attenuating the extent of CD44 sulfation primarily on chondroitin and dermatan sulfate chains. Surface plasmon resonance assays confirm that PDGF enhances the affinity of CD44v-fibrin binding by markedly reducing its dissociation rate while modestly increasing the association rate. PDGF mildly reduces the affinity of CD44v-hyaluronan binding without affecting selectin-CD44v recognition. The latter is attributed to the fact that CD44v binds to selectins via sialofucosylated O-linked residues independent of heparan, dermatan and chondroitin sulfates. Interestingly, PDGF moderately reduces the sulfation of CD44s and CD44s-fibrin recognition. Collectively, these data offer a novel perspective into the mechanism by which PGDF regulates CD44-dependent binding of metastatic colon carcinoma cells to fibrin(ogen).
Highlights
Fibrinogen is a 340-kDa glycoprotein composed of two identical disulfide-linked subunits, each of which is formed by three distinct polypeptide chains, Aa, Bb, and c [1]
We recently reported that CD44 transcript known as standard form (CD44s) is the primary fibrin, but not fibrinogen, receptor on LS174T colon carcinoma cells [8]
In view of observations suggesting that chondroitin/dermatan sulfate glycosaminoglycans on CD44 are important fibrin binding determinants [8] and that platelet-derived growth factor (PDGF) induces the expression of chondroitin/dermatan sulfate chains on CD44s in human dermal fibroblasts [11], we sought to evaluate the effect of PDGF on CD44-fibrin binding under flow
Summary
Fibrinogen is a 340-kDa glycoprotein composed of two identical disulfide-linked subunits, each of which is formed by three distinct polypeptide chains, Aa, Bb, and c [1]. The contribution of fibrin(ogen) to metastasis has been established by the use of fibrinogen-deficient mice, which exhibit a profound inhibition of experimental and spontaneous metastasis relative to wild-type control mice [2]; [3]; [4]; [5]. It is believed that plateletfibrin(ogen) clots surrounding tumor cells protect them from immunological and physiological stresses in the bloodstream and facilitate their lodging to the pulmonary vasculature [6]. This hypothesis is corroborated by in vivo data, which reveal that in mice lacking functional natural killer (NK) cells, fibrin(ogen) deficiency was no longer a significant determinant of metastatic potential [3]
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