Carcinoma-produced factors activate myeloid cells through TLR2 to stimulate metastasis
Open accessAbstract
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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Both IL-6 and TNF produced by myeloid cells in the TME can directly stimulate metastasis and invasion.
“Both IL-6 and TNF produced by myeloid cells in the TME can directly stimulate metastasis and invasion (58, 75–78).”
From Tumor-Induced Inflammatory Cytokines and the Emerging Diagnostic Devices for Cancer Detection and Prognosis (2021) · cites this paper as [75]
The indexed copy’s Abstract reports that myeloid-cell TNF-α promotes Lewis lung carcinoma metastasis, but its knockout comparison concludes that TNF-α, not IL-6, is important for metastasis in this model. It does not establish that either cytokine directly stimulates invasion. (LLM, conf=0.90)
Experimental — accuracy not yet measuredThere is evidence for a role of TLR2 and/or TLR4 in the induction of cytokine and chemokine production in response to extracellular matrix components, including hyaluronan fragments or soluble proteoglycan components, in vitro and in vivo.
“For example, there is evidence for a role of TLR2 and/or TLR4 in the induction of cytokine and chemokine production in response to extracellular matrix components, including hyaluronan fragments or soluble proteoglycan components, in vitro and in vivo31–34.”
From Sterile inflammation: sensing and reacting to damage (2010) · cites this paper as [34]
TLR2 signalling by the endogenous extracellular matrix-derived proteoglycan versican can promote tumour metastasis.
“Furthermore, it was shown that TLR2 signalling by the endogenous extracellular matrix-derived proteoglycan versican can promote tumour metastasis34.”
From Sterile inflammation: sensing and reacting to damage (2010) · cites this paper as [34]
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Self-citation
- Authors
- Kim, S., Takahashi, H., Lin, W.-W., Descargues, P., Grivennikov, S., Kim, Y., Luo, J.-L., & Karin, M.
- Affiliations
- University of California San Diego (US)
- National Taiwan University (TW)
- Corresponding author
- Karin, Michael
- Venue
- Nature
- Published
- 2009-01-01
- Volume
- 457
- Issue
- 7225
- Pages
- 102-106
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC2746432
- OpenAlex
- W2161091841
- Cited by
- 1,100
- References
- 28
- Citations by year
- 2026: 18 · 2025: 27 · 2024: 46 · 2023: 38 · 2022: 46 · 2021: 53 · 2020: 68 · 2019: 59 · 2018: 57 · 2017: 58 · 2016: 74 · 2015: 69 · 2014: 73 · 2013: 85 · 2012: 80
- FWCI
- 34.35
- Type
- journal article
- Language
- en
- Update notices
- expression_of_concern (2026-07-28)
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- National Cancer Institute (R01CA118165, R01CA132586, T32CA121938)
- National Institute of Environmental Health Sciences (R01ES006376)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Proteoglycans and glycosaminoglycans research
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Keywords
- versican, TLR2, TLR6, CD14, macrophage activation, tumour metastasis, Lewis lung carcinoma, TNF-α, interleukin-6, extracellular matrix proteoglycans, innate immune system, bone marrow-derived myeloid cells
- MeSH terms
- Animals, Liver Neoplasms, Lung Neoplasms, Macrophage Activation, Macrophages, Mice, Inbred C57BL, Neoplasm Metastasis, Neoplasm Transplantation, Tumor Necrosis Factor-alpha, Interleukin-6, Culture Media, Serum-Free, Culture Media, Conditioned, Carcinoma, Lewis Lung, Lipopolysaccharide Receptors, Toll-Like Receptor 2, Toll-Like Receptor 6, Mice, Versicans
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