Abstract 1353: Malignant cells fuel tumor growth by educating infiltrating leukocytes to produce the mitogen Gas6

Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC Growth arrest-specific gene 6 (Gas6) binds to the TAM family of receptor tyrosine kinases (TAMRs) and exerts pleiotropic functions in health and disease. TAMRs, in particular Axl, have transforming properties, and are highly expressed in human tumor cells. In contrast, little is known about the role of Gas6 in cancer. Previous studies indicate that Gas6 stimulates proliferation of cancer cells in vitro and that it is present in human tumor tissue. By using Gas6-deficient mice, we explored the role of Gas6 in tumor biology in vivo in detail and here unravel a previously unknown mechanism, how malignant cells educate infiltrating leukocytes, in particular macrophages, to upregulate Gas6 and as such promote their growth. By analyzing Gas6 expression, we found that in murine syngeneic tumor models (colonic CT26, pancreatic Panc02 and breast 4T1 tumors) Gas6 is exclusively expressed in host cells, most notably in tumor-infiltrating leukocytes, and to a lesser extent in tumor endothelial cells, but was beyond threshold of detection in tumor cells. Investigation of Gas6 expression in different intratumoral leukocyte subfractions (macrophages, monocytes, granulocytes, T-cells, B-cells, dendritic cells, NK cells) revealed highest Gas6 expression in tumor-associated macrophages (TAMs) and dendritic cells. Importantly, by comparing Gas6 expression in TAMs to resident tissue macrophages (isolated from spleen, lung and peritoneum), we found that tumors specifically educate TAMs to upregulate Gas6, which is mediated by IL-10. To analyze a potential impact of Gas6 on tumor progression, we studied growth of different tumor models (see above) in Gas6-/- mice, and found impaired tumor growth and metastasis in all studied models, including one resistant to VEGF inhibitors (lymphoma EL4), by 35-55%. Phenotypic analyses of tumors grown in wt mice in comparison to Gas6-deficient mice revealed reduced proliferation of tumor cells in Gas6-/- hosts. Angiogenesis, lymphangiogenesis, apoptosis and intra-tumoral coagulation were similar in both genotypes. Based on these findings we put forward the hypothesis that tumors educate infiltrating leukocytes to upregulate Gas6, which stimulates their growth. To functionally proof this concept, we performed cross-over bone marrow transplantation (BMT) studies in 3 different tumor models. These experiments revealed that transplantation of wt bone marrow into Gas6-/- hosts rescues impaired tumor growth, conversely transplantation of Gas6-/- bone marrow into wt hosts phenocopies decreased tumor growth in Gas6-/- mice. Hence, bone marrow-derived cells indeed deliver growth-promoting Gas6 into tumors, which stimulates their growth. This concept was further underscored by strongly reduced capability of Gas6-/- TAMs to stimulate proliferation of tumor cells compared to wt TAMs. In summary, our studies identify Gas6 as potential novel target in cancer. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1353.