Kim S.Takahashi H.WAN-WAN LINDescargues P.Grivennikov S.Kim Y.Luo J.-L.Karin M.2021-03-032021-03-0320092808362-s2.0-58149269348https://scholars.lib.ntu.edu.tw/handle/123456789/550472Metastatic 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-α (TNF-α) through activation of the Toll-like receptor (TLR) family members TLR2 and TLR6. Both TNF-α 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-α 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. ?2009 Macmillan Publishers Limited. All rights reserved.[SDGs]SDG3CD14 antigen; interleukin 6; proteoglycan; toll like receptor 2; toll like receptor 6; tumor necrosis factor alpha; cancer; cytology; immune system; tumor; animal cell; animal experiment; animal model; article; biochemistry; bone marrow cell; cancer cell culture; carcinoma; controlled study; cytokine production; extracellular matrix; innate immunity; Lewis carcinoma; lung cancer; macrophage activation; metastasis; mouse; nonhuman; priority journal; protein purification; upregulationjournal article10.1038/nature0762319122641