Osteopontin CD44 Interaction: A Novel Mechanism for the Selective Homing of Breast Tumor Cells into Bone

摘要

Osteopontin, a secreted phosphoprotein, is a major modulator of the motility of several cell types including macrophages, osteoclasts and tumor cells. Through its interaction with integrins and CD44v, osteopontin can induce metalloprotease, inhibit apoptosis, inhibit NO production and induce cytokine secretion. We have recently isolated a hexa peptide from osteopontin that is chemotactic to tumor cells. Antibodies raised against this peptide neutralize the chemotactic response of tumor cells to osteopontin it in vitro and in vivo. Our hypothesis is that osteopontin or chemotactic peptides released during bone remodeling attract circulating breast tumor cells expressing specific CD44v splice variants. We have demonstrated that expression of human CD44 (v3-v6) in non-metastatic human tumor cells, results in turning these cells into metastatic tumor cells. Further, we have also demonstrated that the novel metastatic tumor line metastasizes predominantly into bone. The expression of CD44 (v3- v6) in breast tumor is necessary but not sufficient for bone specific metastasis. Other genes need to be turned on in tumor cells for these cells to become metastatic. We have isolated a peptide analogue of the chemotactic domain (PepL) that inhibits tumor cell migration, induces Nitric Oxide production and activates apoptosis in tumor cells. We now report that the chemotactic domain of OPN induces the activation of FAK, Protein Kinase CBeta (PKCBeta) and Pl-3 kinase, while PepL inhibits the activation of FAK, inhibits the activation of PKCBeta, but can activate PKCzeta Further mutants of OPN lacking the chemotactic domain cannot stimulate the chemotaxis of tumor cells nor can they activate protein kinase Cbeta%. However, these mutants can activate P13 kinase and FAK. We concluded that OPN mediates tumor migration by regulating, FAK, Pl3 Kinase and PKCzeta.