Malignant cells fuel tumor growth by educating infiltrating leukocytes to produce the mitogen Gas6.
The transforming and tumor growth-promoting properties of Axl, a member of the Tyro3, Axl, and Mer (TAM) family of receptor tyrosine kinases (TAMRs), are well recognized. In contrast, little is known about the role of the TAMR ligand growth arrest-specific gene 6 (Gas6) in tumor biology. By using Gas6-deficient (Gas6(-/-)) mice, we show that bone marrow-derived Gas6 promotes growth and metastasis in different experimental cancer models, including one resistant to vascular endothelial growth factor inhibitors. Mechanistic studies reveal that circulating leukocytes produce minimal Gas6. However, once infiltrated in the tumor, leukocytes up-regulate Gas6, which is mitogenic for tumor cells. Consistent herewith, impaired tumor growth in Gas6(-/-) mice is rescued by transplantation of wild-type bone marrow and, conversely, mimicked by transplantation of Gas6(-/-) bone marrow into wild-type hosts. These findings highlight a novel role for Gas6 in a positive amplification loop, whereby tumors promote their growth by educating infiltrating leukocytes to up-regulate the production of the mitogen Gas6. Hence, inhibition of Gas6 might offer novel opportunities for the treatment of cancer.
Loges
Sonja
S
Vesalius Research Center (VRC), Vlaams Instituut voor Biotechnologie (VIB), Leuven, Belgium.
Schmidt
Thomas
T
Tjwa
Marc
M
van Geyte
Katie
K
Lievens
Dirk
D
Lutgens
Esther
E
Vanhoutte
Davy
D
Borgel
Delphine
D
Plaisance
Stephane
S
Hoylaerts
Marc
M
Luttun
Aernout
A
Dewerchin
Mieke
M
Jonckx
Bart
B
Carmeliet
Peter
P
D000818:Animals; D016026:Bone Marrow Transplantation; D002465:Cell Movement; D049109:Cell Proliferation; D015972:Gene Expression Regulation, Neoplastic; D007249:Inflammation / Q000150:complications / Q000473:pathology; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis* / Q000172:deficiency / Q000235:genetics; D016753:Interleukin-10 / Q000378:metabolism; D007962:Leukocytes / Q000378:metabolism* / Q000473:pathology*; D016173:Macrophage Colony-Stimulating Factor / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008934:Mitogens / Q000096:biosynthesis*; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000098:blood supply / Q000201:enzymology / Q000235:genetics / Q000473:pathology*; D009389:Neovascularization, Pathologic / Q000150:complications / Q000235:genetics; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D017154:Stromal Cells / Q000378:metabolism / Q000473:pathology; D015854:Up-Regulation / Q000235:genetics; D000099255:Growth Arrest-Specific Protein 6
D036341:Intercellular Signaling Peptides and Proteins; D016753:Interleukin-10; D016173:Macrophage Colony-Stimulating Factor; D008934:Mitogens; D020794:Receptor Protein-Tyrosine Kinases; D000099255:Growth Arrest-Specific Protein 6