title: Suppression of SOCS3 in macrophages prevents cancer metastasis by modifying macrophage phase and MCP2/CCL8 induction.
abstract: Inflammation has been demonstrated to play important roles in tumorigenesis, tumor progression, and metastasis. STAT3 has been shown to be frequently activated in a variety of human cancer cells and STAT3 signaling promotes the growth and survival of tumor cells. However, the role of STAT3 of myeloid cells associated with tumors is currently unknown. Suppressor of cytokine signaling-3 (SOCS3) has been shown to be a negative regulator of STAT3. In this study, we used macrophage specific SOCS3 conditional knockout (cKO) mice to investigate the effect of the hyperactivation of STAT3 in macrophages on tumor development and metastasis. In a subcutaneous transplantation model of B16F10 melanoma cells, although tumor sizes were not significantly different, SOCS3-cKO mice survived longer than wild-type (WT) mice did. SOCS3-cKO mice exhibited fewer lung and liver metastatic tumor nodules than WT mice when B16F10 was challenged intravenously. SOCS3(-/-) macrophages stimulated with tumor lysates in vitro exhibited prolonged STAT3 phosphorylation and produced less amount of TNFα and IL-6, and higher amount of MCP2/CCL8 than WT macrophages. MCP/CCL8 was induced via STAT3 and exhibited anti-tumor metastatic effect in WT mice. These data suggest that hyperactivation of STAT3 in myeloid cells simultaneously exerted an anti-inflammatory as well as anti-tumor effects. Thus, the targeted inhibition of SOCS3 activity in macrophages may be therapeutic for the suppression of tumor metastasis.
authors.affiliation: Department of Microbiology and Immunology, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan.
authors.forename: Kiyokazu
authors.initials: K
authors.lastname: Hiwatashi
authors.forename: Taiga
authors.initials: T
authors.lastname: Tamiya
authors.forename: Eiichi
authors.initials: E
authors.lastname: Hasegawa
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Fukaya
authors.forename: Masayuki
authors.initials: M
authors.lastname: Hashimoto
authors.forename: Kyosuke
authors.initials: K
authors.lastname: Kakoi
authors.forename: Ikko
authors.initials: I
authors.lastname: Kashiwagi
authors.forename: Akihiro
authors.initials: A
authors.lastname: Kimura
authors.forename: Naoko
authors.initials: N
authors.lastname: Inoue
authors.forename: Rimpei
authors.initials: R
authors.lastname: Morita
authors.forename: Hideo
authors.initials: H
authors.lastname: Yasukawa
authors.forename: Akihiko
authors.initials: A
authors.lastname: Yoshimura
mesh_terms: D000818:Animals; D015153:Blotting, Western; D054412:Chemokine CCL8 / Q000235:genetics / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D007150:Immunohistochemistry; D008264:Macrophages / Q000378:metabolism*; D008546:Melanoma, Experimental / Q000503:physiopathology*; D051379:Mice; D018345:Mice, Knockout; D009362:Neoplasm Metastasis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D054412:Chemokine CCL8; C106644:SOCS3 protein, human; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins