Autocrine and Paracrine Interactions Between Multiple Myeloma Cells and Bone Marrow Stromal Cells By Growth Arrest-Specific Gene 6 Crosstalk with Interleukin-6

The pathogenesis of multiple myeloma (MM) has not yet been fully elucidated. Our microarray analysis and immunohistochemistry revealed significant upregulation of growth arrest-specific gene 6 (Gas6), a vitamin K-dependent protein with a structural homology with protein S, in bone marrow (BM) cells of MM patients. ELISA showed that the serum levels of soluble Gas6 and interleukin (IL)-6were significantly increased in the MM patients when compared with healthy controls. Gas6 and TAM receptor tyrosine kinases Mer were overexpressed in human CD138-positive MM cell line RPMI-8226. Exogenous Gas6 and its signaling through Mer suppressed apoptosis induced by serum deprivation and enhanced cell proliferation of the MM cells. The conditioned medium from human BM stromal cell line HS-5 induced anti-apoptosis and cell proliferation of the MM cells with ERK, Akt and NF-kappaB phosphorylation, which were reversed by the neutralizing antibody to Gas6, IL-6 or Mer siRNA. Furthermore, the Gas6 neutralizing antibody reduced the upregulation of IL-6 and intercellular cell adhesion molecule-1 induced by a HS-5 cell-conditioned medium in MM cells. The present study provides new evidence that autocrine and paracrine stimulation of Gas6 in concert with IL-6 contributes to the pathology of MM, suggesting that Gas6/Mer signaling may be a promising novel target for treating MM.