title: 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.
authors: Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, 54 Shogoin-Kawahara-cho, Sakyo-ku, Kyoto 606–8507, Japan.
authors: Reiko
authors: R
authors: Akitake-Kawano
authors: Hiroshi
authors: H
authors: Seno
authors: Masato
authors: M
authors: Nakatsuji
authors: Yuto
authors: Y
authors: Kimura
authors: Yuki
authors: Y
authors: Nakanishi
authors: Takuto
authors: T
authors: Yoshioka
authors: Keitaro
authors: K
authors: Kanda
authors: Mayumi
authors: M
authors: Kawada
authors: Kenji
authors: K
authors: Kawada
authors: Yoshiharu
authors: Y
authors: Sakai
authors: Tsutomu
authors: T
authors: Chiba
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D001397:Azoxymethane / Q000009:adverse effects; D001853:Bone Marrow / Q000378:metabolism; D016026:Bone Marrow Transplantation / Q000379:methods; D049109:Cell Proliferation / Q000187:drug effects; D002471:Cell Transformation, Neoplastic; D003092:Colitis / Q000139:chemically induced / Q000473:pathology; D015179:Colorectal Neoplasms / Q000378:metabolism / Q000473:pathology*; D016264:Dextran Sulfate / Q000494:pharmacology; D018450:Disease Progression; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D019073:HT29 Cells; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000008:administration & dosage / Q000378:metabolism* / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008875:Middle Aged; D009000:Monocytes / Q000187:drug effects; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D011379:Prognosis; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000494:pharmacology; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000235:genetics / Q000378:metabolism; D000099255:Growth Arrest-Specific Protein 6
chemical_list: D001397:Azoxymethane; D016264:Dextran Sulfate; D036341:Intercellular Signaling Peptides and Proteins; D008070:Lipopolysaccharides; D016328:NF-kappa B; D012333:RNA, Messenger; D011994:Recombinant Proteins; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D000099255:Growth Arrest-Specific Protein 6; C491590:Socs1 protein, mouse