Autocrine and Paracrine Interactions between Multiple Myeloma Cells and Bone Marrow Stromal Cells by Growth Arrest-specific Gene 6 Cross-talk with Interleukin-6.
The pathogenesis of multiple myeloma (MM) has not yet been fully elucidated. Our microarray analysis and immunohistochemistry revealed significant up-regulation 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 were significantly increased in the MM patients when compared with healthy controls. Gas6 was overexpressed in the human CD138-positive MM cell line RPMI-8226. Exogenous Gas6 suppressed apoptosis induced by serum deprivation and enhanced cell proliferation of the MM cells. The conditional medium from the human BM stromal cell line HS-5 induced cell proliferation and anti-apoptosis of the MM cells with extracellular signal-regulated kinase, Akt, and nuclear factor-κB phosphorylation, which were reversed by the neutralizing antibody to Gas6 or IL-6. The TAM family receptor Mer, which has been identified as a Gas6 receptor, was overexpressed in BM cells of MM patients. The knockdown of Mer by siRNA inhibited cell proliferation, anti-apoptosis, and up-regulation of intercellular cell adhesion molecule-1 (ICAM-1) in MM cells stimulated by an HS-5 cell-conditioned medium. Furthermore, the Gas6-neutralizing antibody reduced the up-regulation of IL-6 and ICAM-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 pathogenesis of MM, suggesting that Gas6-Mer-related signaling pathways may be a promising novel target for treating MM.
From the Departments of Hematology.
Miki
M
Furukawa
From the Departments of Hematology, ohkawara@fmu.ac.jp.
Hiroshi
H
Ohkawara
From the Departments of Hematology.
Kazuei
K
Ogawa
From the Departments of Hematology.|Blood Transfusion and Transplantation Immunology, and.
Kazuhiko
K
Ikeda
From the Departments of Hematology.
Koki
K
Ueda
From the Departments of Hematology.
Akiko
A
Shichishima-Nakamura
the Translational Research Center, Fukushima Medical University, Fukushima 960-1295 and.
Emi
E
Ito
the Translational Research Center, Fukushima Medical University, Fukushima 960-1295 and.
Jun-Ichi
JI
Imai
the Translational Research Center, Fukushima Medical University, Fukushima 960-1295 and.
Yuka
Y
Yanagisawa
NIPPON GENE Co., Ltd., Tokyo 101-0054 Japan.
Reiko
R
Honma
the Translational Research Center, Fukushima Medical University, Fukushima 960-1295 and.
Shinya
S
Watanabe
the Translational Research Center, Fukushima Medical University, Fukushima 960-1295 and.
Satoshi
S
Waguri
From the Departments of Hematology.
Takayuki
T
Ikezoe
Cardiovascular Medicine and.
Yasuchika
Y
Takeishi
D019898:Autocrine Communication / Q000502:physiology*; D049109:Cell Proliferation; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D015850:Interleukin-6 / Q000378:metabolism*; D059630:Mesenchymal Stem Cells / Q000378:metabolism / Q000473:pathology*; D009101:Multiple Myeloma / Q000378:metabolism / Q000473:pathology*; D016328:NF-kappa B / Q000378:metabolism; D019899:Paracrine Communication / Q000502:physiology*; D010766:Phosphorylation; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D000099255:Growth Arrest-Specific Protein 6
D036341:Intercellular Signaling Peptides and Proteins; D015850:Interleukin-6; D016328:NF-kappa B; D000099255:Growth Arrest-Specific Protein 6; C508600:IL6 protein, human
apoptosis; bone marrow; cell proliferation; interleukin 6 (IL-6); multiple myeloma; stromal cell