C-propeptides of procollagens I alpha 1 and II that differentially accumulate in enchondromas versus chondrosarcomas regulate tumor cell survival and migration.

Chondrogenic tumors that exhibit benign or malignant behaviors synthesize variable amounts of cartilage-like extracellular matrix. To define the regulators of these phenotypes, we performed a proteomic comparison of multiple human chondrogenic tumors, which revealed differential accumulation of the C-propeptides of procollagens Ialpha1 and II (PC1CP and PC2CP) in malignant versus benign tumors, respectively. Expression patterns of PC1CP correlated with levels of tumor vascularization, whereas expression patterns of PC2CP suggested its susceptibility to immobilization within the extracellular matrix. Prompted by these observations, we investigated the functions of recombinant PC1CP and PC2CP in the extracellular matrix in soluble or immobilized states. Each induced beta1 integrin-mediated chondrocyte adhesion by distinct domains and efficacies, suggesting that they initiated distinct signaling pathways. Indeed, immobilized PC2CP, but not PC1CP, induced apoptosis of primary chondrocytes and EAhy926 endothelial cells. In contrast, soluble PC1CP, but not PC2CP, induced the migration of EAhy926 cells and increased vascular endothelial growth factor (VEGF) and CXCR4 expression in chondrocytes. Soluble PC2CP also increased VEGF expression, but along with a more pronounced effect on CXCR4 and matrix metalloproteinase 13 expression. Our findings suggest that PC1CP favors angiogenesis and tumor progression, but that PC2CP acts in a more complex manner, exerting antitumor and antiangiogenic properties through apoptosis induction when immobilized, but progression and metastasis when soluble. In summary, the relative levels of PC1CP and PC2CP and their interactions within the extracellular matrix contribute to tumor progression, angiogenesis, and metastasis in chondrogenic tumors.