Malignant cells fuel tumor growth by educating infiltrating leukocytes to produce the mitogen Gas6
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Malignant cells fuel tumor growth by educating infiltrating leukocytes to produce the mitogen Gas6. / Loges, Sonja; Schmidt, Thomas; Tjwa, Marc; van Geyte, Katie; Lievens, Dirk; Lutgens, Esther; Vanhoutte, Davy; Borgel, Delphine; Plaisance, Stephane; Hoylaerts, Marc; Luttun, Aernout; Dewerchin, Mieke; Jonckx, Bart; Carmeliet, Peter.
In: BLOOD, Vol. 115, No. 11, 18.03.2010, p. 2264-73.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - Malignant cells fuel tumor growth by educating infiltrating leukocytes to produce the mitogen Gas6
AU - Loges, Sonja
AU - Schmidt, Thomas
AU - Tjwa, Marc
AU - van Geyte, Katie
AU - Lievens, Dirk
AU - Lutgens, Esther
AU - Vanhoutte, Davy
AU - Borgel, Delphine
AU - Plaisance, Stephane
AU - Hoylaerts, Marc
AU - Luttun, Aernout
AU - Dewerchin, Mieke
AU - Jonckx, Bart
AU - Carmeliet, Peter
PY - 2010/3/18
Y1 - 2010/3/18
N2 - 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.
AB - 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.
KW - Animals
KW - Bone Marrow Transplantation
KW - Cell Movement
KW - Cell Proliferation
KW - Gene Expression Regulation, Neoplastic
KW - Inflammation
KW - Intercellular Signaling Peptides and Proteins
KW - Interleukin-10
KW - Leukocytes
KW - Macrophage Colony-Stimulating Factor
KW - Macrophages
KW - Mice
KW - Mitogens
KW - Neoplasm Metastasis
KW - Neoplasms
KW - Neovascularization, Pathologic
KW - Receptor Protein-Tyrosine Kinases
KW - Stromal Cells
KW - Up-Regulation
KW - Journal Article
KW - Research Support, Non-U.S. Gov't
U2 - 10.1182/blood-2009-06-228684
DO - 10.1182/blood-2009-06-228684
M3 - SCORING: Journal article
C2 - 19965679
VL - 115
SP - 2264
EP - 2273
JO - BLOOD
JF - BLOOD
SN - 0006-4971
IS - 11
ER -