GAS6/AXL axis regulates prostate cancer invasion, proliferation, and survival in the bone marrow niche.
Our recent studies have shown that annexin II, expressed on the cell surface of osteoblasts, plays an important role in the adhesion of hematopoietic stem cells (HSCs) to the endosteal niche. Similarly, prostate cancer (PCa) cells express the annexin II receptor and seem to use the stem cell niche for homing to the bone marrow. The role of the niche is thought to be the induction and sustenance of HSC dormancy. If metastatic PCa cells occupy a similar or the same ecological niche as HSCs, then it is likely that the initial role of the HSC niche will be to induce dormancy in metastatic cells. In this study, we demonstrate that the binding of PCa to annexin II induces the expression of the growth arrest-specific 6 (GAS6) receptors AXL, Sky, and Mer, which, in the hematopoietic system, induce dormancy. In addition, GAS6 produced by osteoblasts prevents PCa proliferation and protects PCa from chemotherapy-induced apoptosis. Our results suggest that the activation of GAS6 receptors on PCa in the bone marrow environment may play a critical role as a molecular switch, establishing metastatic tumor cell dormancy.
Shiozawa
Yusuke
Y
Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, MI 48109-1078, USA.
Pedersen
Elisabeth A
EA
Patel
Lalit R
LR
Ziegler
Anne M
AM
Havens
Aaron M
AM
Jung
Younghun
Y
Wang
Jingcheng
J
Zalucha
Stephanie
S
Loberg
Robert D
RD
Pienta
Kenneth J
KJ
Taichman
Russell S
RS
D000818:Animals; D017306:Annexin A2 / Q000378:metabolism; D017209:Apoptosis / Q000502:physiology; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002469:Cell Separation; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D006801:Humans; D007150:Immunohistochemistry; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D008297:Male; D051379:Mice; D009361:Neoplasm Invasiveness; D010006:Osteoblasts / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D020794:Receptor Protein-Tyrosine Kinases; D020133:Reverse Transcriptase Polymerase Chain Reaction; D055153:Stem Cell Niche / Q000166:cytology / Q000378:metabolism*; D046888:Tissue Array Analysis; D000099255:Growth Arrest-Specific Protein 6
D017306:Annexin A2; D036341:Intercellular Signaling Peptides and Proteins; D020794:Receptor Protein-Tyrosine Kinases; D000099255:Growth Arrest-Specific Protein 6; C472822:ANXA2 protein, human; C084944:TYRO3 protein, human