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.
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Authors | Sunhwa Kim, Hiroyuki Takahashi, Wan-Wan Lin, Pascal Descargues, Sergei Grivennikov, Youngjun Kim, Jun-Li Luo, Michael Karin |
Journal | Nature
(Nature)
Vol. 457
Issue 7225
Pg. 102-6
(Jan 01 2009)
ISSN: 1476-4687 [Electronic] England |
PMID | 19122641
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
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Chemical References |
- Culture Media, Conditioned
- Culture Media, Serum-Free
- Interleukin-6
- Lipopolysaccharide Receptors
- Tlr2 protein, mouse
- Tlr6 protein, mouse
- Toll-Like Receptor 2
- Toll-Like Receptor 6
- Tumor Necrosis Factor-alpha
- Versicans
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Topics |
- Animals
- Carcinoma, Lewis Lung
(metabolism, pathology)
- Culture Media, Conditioned
(metabolism, pharmacology)
- Culture Media, Serum-Free
(metabolism)
- Interleukin-6
(metabolism)
- Lipopolysaccharide Receptors
(metabolism)
- Liver Neoplasms
(secondary)
- Lung Neoplasms
(metabolism, pathology, secondary)
- Macrophage Activation
- Macrophages
(metabolism)
- Mice
- Mice, Inbred C57BL
- Neoplasm Metastasis
(pathology)
- Neoplasm Transplantation
- Toll-Like Receptor 2
(agonists, metabolism)
- Toll-Like Receptor 6
(metabolism)
- Tumor Necrosis Factor-alpha
(metabolism)
- Versicans
(metabolism, pharmacology)
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