title: Induction of proinflammatory mediators by CHI3L1 is reduced by chitin treatment: decreased tumor metastasis in a breast cancer model.
abstract: Disseminated metastasis accounts for over 90% of breast cancer deaths. Recently, elevated serum levels of a glycoprotein known as chitinase-3 like-protein-1 (CHI3L1) has been correlated with poor prognosis and shorter survival of patients with metastatic breast cancer. In this study, we show that there are increased levels of CHI3L1 in plasma of tumor-bearing mice and that both tumor cells and immune cells express and secrete CHI3L1. However, the biological and physiological functions of CHI3L1 are still unclear. We demonstrate that while CHI3L1 has an inhibitory role in the expression of interferon-gamma (IFN-γ), CHI3L1 up-regulates pro-inflammatory mediators, C-chemokine ligand 2 (CCL2), chemokine CX motif ligand 2 (CXCL2) and matrix metalloproteinase-9 (MMP-9) all of which contribute to tumor growth and metastasis. We found that in vitro inhibition of CHI3L1 by siRNA suppressed the production of CCL2, CXCL2 and MMP-9 by macrophages. In vivo treatment of mammary tumor-bearing mice with chitin (β-(1-4)-poly-N-acetyl D-glucosamine), a TH(1)  adjuvant and a ligand for CHI3L1, promoted immune effector functions with increased production of IFN-γ and decreased CCL2, CXCL2 and MMP-9 expression. In vivo administration of chitin to mammary tumor-bearing mice significantly decreased lung metastasis. These studies show that CHI3L1 plays a role in tumor progression and that chitin can inhibit the pleiotropic effects of CHI3L1 giving support to the idea that CHI3L1 is a useful therapeutic target for treatment of breast cancer.
authors.affiliation: Department of Biomedical Sciences, Charles E. Schmidt College of Medicine, Florida Atlantic University, Boca Raton, FL 33431-0991, USA.
authors.forename: Stephania
authors.initials: S
authors.lastname: Libreros
authors.forename: Ramon
authors.initials: R
authors.lastname: Garcia-Areas
authors.forename: Yoshimi
authors.initials: Y
authors.lastname: Shibata
authors.forename: Roberto
authors.initials: R
authors.lastname: Carrio
authors.forename: Marta
authors.initials: M
authors.lastname: Torroella-Kouri
authors.forename: Vijaya
authors.initials: V
authors.lastname: Iragavarapu-Charyulu
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D018932:Chemokine CCL2 / Q000378:metabolism; D054426:Chemokine CXCL2 / Q000378:metabolism; D002686:Chitin / Q000494:pharmacology* / Q000627:therapeutic use; D000071451:Chitinase-3-Like Protein 1; D018450:Disease Progression; D005260:Female; D006023:Glycoproteins / Q000097:blood / Q000378:metabolism*; D007371:Interferon-gamma / Q000378:metabolism; D008175:Lung Neoplasms / Q000556:secondary; D008264:Macrophages / Q000378:metabolism; D015674:Mammary Neoplasms, Animal / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D009362:Neoplasm Metastasis; D034622:RNA Interference; D034741:RNA, Small Interfering
chemical_list: C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D054426:Chemokine CXCL2; C509289:Chil1 protein, mouse; D000071451:Chitinase-3-Like Protein 1; C404915:Cxcl2 protein, mouse; D006023:Glycoproteins; D034741:RNA, Small Interfering; D002686:Chitin; D007371:Interferon-gamma; D020780:Matrix Metalloproteinase 9