title: Carcinoma-produced factors activate myeloid cells through TLR2 to stimulate metastasis.
abstract: Metastatic progression depends on genetic alterations intrinsic to cancer cells as well as the inflammatory microenvironment of advanced tumours. To understand how cancer cells affect the inflammatory microenvironment, we conducted a biochemical screen for macrophage-activating factors secreted by metastatic carcinomas. Here we show that, among the cell lines screened, Lewis lung carcinoma (LLC) were the most potent macrophage activators leading to production of interleukin-6 (IL-6) and tumour-necrosis factor-alpha (TNF-alpha) through activation of the Toll-like receptor (TLR) family members TLR2 and TLR6. Both TNF-alpha and TLR2 were found to be required for LLC metastasis. Biochemical purification of LLC-conditioned medium (LCM) led to identification of the extracellular matrix proteoglycan versican, which is upregulated in many human tumours including lung cancer, as a macrophage activator that acts through TLR2 and its co-receptors TLR6 and CD14. By activating TLR2:TLR6 complexes and inducing TNF-alpha secretion by myeloid cells, versican strongly enhances LLC metastatic growth. These results explain how advanced cancer cells usurp components of the host innate immune system, including bone-marrow-derived myeloid progenitors, to generate an inflammatory microenvironment hospitable for metastatic growth.
authors.affiliation: Department of Pharmacology and Cancer Center, School of Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093-0723, USA.
authors.forename: Sunhwa
authors.initials: S
authors.lastname: Kim
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Takahashi
authors.forename: Wan-Wan
authors.initials: WW
authors.lastname: Lin
authors.forename: Pascal
authors.initials: P
authors.lastname: Descargues
authors.forename: Sergei
authors.initials: S
authors.lastname: Grivennikov
authors.forename: Youngjun
authors.initials: Y
authors.lastname: Kim
authors.forename: Jun-Li
authors.initials: JL
authors.lastname: Luo
authors.forename: Michael
authors.initials: M
authors.lastname: Karin
mesh_terms: D000818:Animals; D018827:Carcinoma, Lewis Lung / Q000378:metabolism* / Q000473:pathology; D017077:Culture Media, Conditioned / Q000378:metabolism / Q000494:pharmacology; D016895:Culture Media, Serum-Free / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D018950:Lipopolysaccharide Receptors / Q000378:metabolism; D008113:Liver Neoplasms / Q000556:secondary; D008175:Lung Neoplasms / Q000378:metabolism / Q000473:pathology / Q000556:secondary; D008262:Macrophage Activation; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009362:Neoplasm Metastasis / Q000473:pathology; D009368:Neoplasm Transplantation; D051195:Toll-Like Receptor 2 / Q000819:agonists / Q000378:metabolism*; D051216:Toll-Like Receptor 6 / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D053675:Versicans / Q000378:metabolism / Q000494:pharmacology
chemical_list: D017077:Culture Media, Conditioned; D016895:Culture Media, Serum-Free; D015850:Interleukin-6; D018950:Lipopolysaccharide Receptors; C493486:Tlr2 protein, mouse; C495369:Tlr6 protein, mouse; D051195:Toll-Like Receptor 2; D051216:Toll-Like Receptor 6; D014409:Tumor Necrosis Factor-alpha; D053675:Versicans