Malignant cells fuel tumor growth by educating infiltrating leukocytes to produce the mitogen Gas6

Abstract

The transforming and tumor growthpromoting 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 upregulate 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. IntroductionGrowth arrest-specific gene 6 (Gas6) was discovered because its expression is up-regulated in fibroblasts under growth-arrest conditions. 1,2 This factor exerts pleiotropic functions in health and disease: it amplifies platelet aggregation during thrombus formation, 3,4 enhances erythropoiesis, 5 and increases leukocyte extravasation in inflammatory conditions, 6 among other functions. 7,8 Gas6 binds to the Tyro3, Axl, and Mer (TAM) family of receptor tyrosine kinases (TAMRs), which consists of Tyro3 (Sky/Rse), Axl (Ufo/ Ark), and Mer (Eyk), although the binding affinity of this ligand differs for each receptor (AxlϾTyro3Ͼ ϾMer). 9,10 TAMRs, in particular Axl, have transforming properties. Indeed, overexpression of a truncated version of Axl in premalignant cells is sufficient to induce tumors in mice. 11 Axl is also highly expressed in human tumor cells in vitro, [12][13][14][15] as well as in a large variety of primary human cancers, including leukemia, 16 gastric cancer, 17 colon cancer, 18 breast cancer, 19 ovarian cancer, 20 and glioblastoma, 21 among others. In gastric cancer, Axl expression is associated with lymph node metastasis, an adverse prognostic factor. 17 However, little is known about the role of Gas6 in cancer. Gas6 is overexpressed in human ovarian, endometrial, gastric, thyroid, and glioblastoma tumors. 17,[20][21][22][23] In those studies, expression of Gas6 was detected in tumor cells, endothelial cells, and astrocytes, 20-24 but expression of Gas6 in tumor-infiltrated leukocytes has not been studied. Gas6 promotes proliferation and survival of different cancer cell lines, including prostate and melanoma tumor cells. 13,14 Interestingly, when glioma tumors coexpress high levels of Axl and Gas6, the survival of cancer patients is shortened. 21 Inhibition of Gas6 by a soluble Axl trap in vitro or a dominantneg...

An anti-Axl monoclonal antibody attenuates xenograft tumor growth and enhances the effect of multiple anticancer therapies

“…As Axl mAbs do not seem to have a significant effect on the expression of Axl on TAMs, but downregulate receptor expression on tumor cells, it is likely that anti-Axl mAbs modulate cytokine/ chemokine secretion from TAMs by blocking the crosstalk between tumor and stromal cells. These results are consistent with the recent reports that tumor cells could promote their growth by educating infiltrating leukocytes to induce the expression of Gas6 (Loges et al, 2010); and a small-molecule inhibitor of Axl reduced the expression of granulocyte macrophage colony-stimulating factor in 4T1 breast tumor cells (Holland et al, 2010).…”

Direct regulation of GAS6/AXL signaling by HIF promotes renal metastasis through SRC and MET

“…The ccRCC cell lines examined in our study expressed low to high levels of endogenous GAS6. Infiltrating immune cells including leukocytes also have the capacity to produce GAS6 and stimulate TAM receptor signaling on tumor cells (41). Thus, both autocrine and paracrine production of GAS6 may contribute to SRC activation in kidney cancer.…”

“…Previous studies have shown that both tumor-and stromalderived GAS6 contributes to tumor growth and metastasis. Loges et al used GAS6-deficient mice to demonstrate that bone marrow-derived GAS6 promotes the growth and metastasis of a variety of cancer cell lines deficient for endogenous GAS6 (41). In these models, the tumor microenvironment stimulated the upregulation of GAS6 in leukocytes, which in turn mediate the growth and metastasis of GAS6-deficient tumor cells.…”

Origin and Functions of Tumor-Associated Myeloid Cells (TAMCs)

“…tumor necrosis factor, TNF; reactive oxygen species, ROS) appears to support neoplastic transformation [6], whereas in established cancers the expression of M2-like phenotypes with immunosuppressive, pro-angiogenic and tissue remodelling activities promotes immune escape, tumor growth and malignancy [1,6,[52][53][54][55]. Recent addition to the molecular repertoire of TAMs includes semaphorin 4D (Sema4D) [56] and growth arrest-specific 6 (Gas6) [57], which are respectively involved in promoting tumor angiogenesis and cancer cell proliferation. Of note, Src homology 2-containing inositol-5′-phosphatase-1 (SHIP1)-deficient mice, which exhibit a spontaneous macrophage drift towards M2 polarization, display increased growth of transplanted tumors [58].…”