Osteopontin CD44 Interaction: A Novel Mechanism for the Selective Homing of Breast Tumor Cells into Bone
Abstract
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 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 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 PI-3 kinase, while PepL inhibits the activation of FAK, inhibits the activation of PKcp, but can activate PKCsigma. 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, PI3 Kinase and PKCbeta. We further conclude that PepL mediates its anti-tumor activity by inhibiting the activation of FAK and the activation of PKCbsigma. We Further conclude that activation of PKCsigma might result in the activation of NKnh and the induction of iNOS.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jun 01, 2001
- Accession Number
- ADA396394
Entities
People
- Samy Ashkar