Inhibitory role of Gas6 in intestinal tumorigenesis

Abstract

Growth arrest-specific gene (Gas) 6 is a γ-carboxyglutamic acid domain-containing protein, which shares 43% amino acid identity with protein S. Gas6 has been shown to enhance cancer cell proliferation in vitro. On the other hand, recent studies have demonstrated that Gas6 inhibits toll-like receptor-mediated immune reactions. Immune reactions are known to affect intestinal tumorigenesis. In this study, we investigated how Gas6 contributes to tumorigenesis in the intestine. Administration of recombinant Gas6 weakly, but significantly, enhanced proliferation of intestinal cancer cells (SW480 and HT29), whereas it suppressed the inflammatory responses of Lipopolysaccharide (LPS)-stimulated monocytes (THP-1). Compared with Gas6(+/+) mice, Gas6(-/-) mice exhibited enhanced azoxymethane/dextran sulfate sodium (DSS)-induced tumorigenesis and had a shorter survival. Gas6(-/-) mice also exhibited more severe DSS-induced colitis. DSS-treated Gas6(-/-) mice showed attenuated Socs1/3 messenger RNA expression and enhanced nuclear factor-kappaB activation in the colonic stroma, suggesting that the target of Gas6 is stromal cells. Bone marrow transplantation experiments indicated that both epithelial cells and bone marrow-derived cells are Gas6 sources. Furthermore, the number of intestinal tumors in Apc(Min) Gas6(-/-) mice was higher than that in Apc(Min) Gas6(+/+) mice, resulting in shorter survival. In a group of 62 patients with advanced colorectal cancer, Gas6 immunoreactivity in cancer tissues was positively correlated with prognosis. Thus, we revealed a unique in vivo inhibitory role of Gas6 during the progression of intestinal tumors associated with suppression of stromal immune reactions. These results suggest a novel therapeutic approach for colorectal cancer patients by regulation of stromal immune responses.

Tyro3, Axl, and Mertk Receptor Signaling in Inflammatory Bowel Disease and Colitis-associated Cancer

“…68 Additionally, in a model of mouse colon cancer driven by mutations in the Apc loci ( Apc Min ), the loss of Gas6 rendered the animal more susceptible. 77 Apc Min Gas6 −/− mice had increased tumor load and reduced survival in comparison to Apc Min Gas6 +/+ mice. Therefore, the role of TAM signaling in the gut in a mouse model of CAC and CRC is consistent with its anti-inflammatory function, but contrary to its prooncogenic role.…”

“…Gas6 −/− mice are more susceptible to DSS. 77 DSS-treated Gas6 −/− mice display reduced Socs1/3 gene expression and increased NF-κB activation in colon tissue. The cellular compartment producing Gas6 to engage the TAMs within the intestinal mucosa is not well defined.…”

“…However, bone marrow-transplant approaches have suggested that both radioresistant and radiosensitive cells can be the source of Gas6 during induced-inflammatory responses in the gut. 77 …”

“…Gas6 −/− mice were more susceptible to azoxy-methane–dextran sodium sulfate (AOM-DSS)-induced CAC. 77 Gas6 −/− mice developed a significantly greater number of Proliferating cell nuclear antigen (PCNA)- and c-Myc- positive polyps, produced higher levels of TNFα, CXCL1, and CCL2 and increased NF-κB activation after AOM-DSS treatment, in comparison with wild-type mice. Gas6 −/− mice also had reduced survival after AOM-DSS treatment.…”

TAM Receptor Signaling in Immune Homeostasis

“…Similarly, in mice, a single dose of the procarcinogen azoxymethane, which is metabolized into its active form by the gut microbiota, followed by repeated dosing with the proinflammatory agent dextran sodium sulfate in the drinking water (AOM-DSS treatment), results in the induction of colon cancer. Gas6 −/− mice showed increased susceptibility to AOM-DSS treatment in comparison to wild-type mice (174). Gas6 −/− mice displayed a significantly greater number of PCNA- and c-Myc-positive polyps, higher levels of the proinflammatory cytokine TNF-α and the chemokines CXCL1 and CCL2, increased NF-κB activation, and reduced survival.…”