Carcinoma-produced factors activate myeloid cells through TLR2 to stimulate metastasis.
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.
Kim
Sunhwa
S
Department of Pharmacology and Cancer Center, School of Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093-0723, USA.
Takahashi
Hiroyuki
H
Lin
Wan-Wan
WW
Descargues
Pascal
P
Grivennikov
Sergei
S
Kim
Youngjun
Y
Luo
Jun-Li
JL
Karin
Michael
M
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
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