Axl is required for TGF-β2-induced dormancy of prostate cancer cells in the bone marrow.
Disseminated prostate cancer (PCa) cells in the marrow survive for years without evidence of proliferation, while maintaining the capacity to develop into metastatic lesions. These dormant disseminated tumor cells (DTCs) may reside in close proximity to osteoblasts, while expressing high levels of Axl, one of the tyrosine kinase receptors for growth arrest specific 6 (Gas6). Yet how Axl regulates DTC proliferation in marrow remains undefined. Here, we explored the impact of the loss of Axl in PCa cells (PC3 and DU145) on the induction of their dormancy when they are co-cultured with a pre-osteoblastic cell line, MC3T3-E1. MC3T3-E1 cells dramatically decrease the proliferation of PCa cells, however this suppressive effect of osteoblasts is significantly reduced by the reduction of Axl expression in PCa cells. Interestingly, expression of both TGF-β and its receptors were regulated by Axl expression in PCa cells, while specific blockade of TGF-β signaling limited the ability of the osteoblasts to induce dormancy of PCa cells. Finally, we found that both Gas6 and Axl are required for TGF-β2-mediated cell growth suppression. Taken together, these data suggest that a loop between the Gas6/Axl axis and TGF-β2 signaling plays a significant role in the induction of PCa cell dormancy.
Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, MI 48109, USA.
Kenji
K
Yumoto
Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, MI 48109, USA.|Department of Cancer Biology and Comprehensive Cancer, Wake Forest University School of Medicine, Winston-Salem, NC, USA.
Matthew R
MR
Eber
Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, MI 48109, USA.
Jingcheng
J
Wang
Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, MI 48109, USA.|Department of Internal Medicine, Division of Hematology and Oncology, University of Michigan School of Medicine, Ann Arbor, MI 48109, USA.
Frank C
FC
Cackowski
Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, MI 48109, USA.
Ann M
AM
Decker
Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, MI 48109, USA.
Eunsohl
E
Lee
Departments of Medicine, Division of Hematology and Oncology, Otolaryngology and Oncological Sciences, Head and Neck Cancer Basic Research, Departments of Otolaryngology, NCI-Designated Tisch Cancer Institute at Mount Sinai, Icahn School of Medicine at Mount Sinai New York, NY10029, USA.
Ana Rita
AR
Nobre
Departments of Medicine, Division of Hematology and Oncology, Otolaryngology and Oncological Sciences, Head and Neck Cancer Basic Research, Departments of Otolaryngology, NCI-Designated Tisch Cancer Institute at Mount Sinai, Icahn School of Medicine at Mount Sinai New York, NY10029, USA.
Julio A
JA
Aguirre-Ghiso
Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, MI 48109, USA.
Younghun
Y
Jung
Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, MI 48109, USA.
Russell S
RS
Taichman
D000818:Animals; D001853:Bone Marrow / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000502:physiology; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D008297:Male; D051379:Mice; D010006:Osteoblasts / Q000378:metabolism; D011467:Prostate / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000378:metabolism*; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D053781:Transforming Growth Factor beta2 / Q000378:metabolism*
D036341:Intercellular Signaling Peptides and Proteins; D053781:Transforming Growth Factor beta2; D020794:Receptor Protein-Tyrosine Kinases