Annexin II interactions with the annexin II receptor enhance multiple myeloma cell adhesion and growth in the bone marrow microenvironment.
Multiple myeloma (MM) is an incurable B-cell malignancy in which the marrow microenvironment plays a critical role in our inability to cure MM. Marrow stromal cells in the microenvironment support homing, lodging, and growth of MM cells through activation of multiple signaling pathways in both MM and stromal cells. Recently, we identified annexin II (AXII) as a previously unknown factor produced by stromal cells and osteoclasts (OCL) that is involved in OCL formation, HSC and prostate cancer (PCa) homing to the BM as well as mobilization of HSC and PCa cells. AXII expressed on stromal cells supports PCa cell lodgment via the AXII receptor (AXIIR) on PCa cells, but the role of AXII and AXIIR in MM is unknown. In this study, we show that MM cells express AXIIR, that stromal/osteoblast-derived AXII facilitates adhesion of MM cells to stromal cells via AXIIR, and OCL-derived AXII enhances MM cell growth. Finally, we demonstrate that AXII activates the ERK1/2 and AKT pathways in MM cells to enhance MM cell growth. These results demonstrate that AXII and AXIIR play important roles in MM and that targeting the AXII/AXIIR axis may be a novel therapeutic approach for MM.
Department of Medicine, Division of Hematology/Oncology and Bone Biology Center of University of Pittsburgh Medical Center, University of Pittsburgh and Veterans Administration Healthcare System, Pittsburgh, PA, USA.
Sonia
S
D'Souza
Noriyoshi
N
Kurihara
Yusuke
Y
Shiozawa
Jeena
J
Joseph
Russell
R
Taichman
Deborah L
DL
Galson
G David
GD
Roodman
D000818:Animals; D017306:Annexin A2 / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D015153:Blotting, Western; D001853:Bone Marrow / Q000378:metabolism*; D001854:Bone Marrow Cells / Q000378:metabolism; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002478:Cells, Cultured; D060833:Cellular Microenvironment; D018920:Coculture Techniques; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009101:Multiple Myeloma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D010010:Osteoclasts / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034622:RNA Interference; D018000:Receptors, Peptide / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction
D017306:Annexin A2; D018000:Receptors, Peptide; C514873:annexin II receptor, human; D051057:Proto-Oncogene Proteins c-akt; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3