Carcinoma Produced Factors Activate Myeloid Cells via TLR2 to Stimulate Metastasis

By Sunhwa Kim, Hiroyuki Takahashi, Wan-Wan Lin, P. Descargues, S. Grivennikov, Youngjun Kim, Jun-Li Luo, M. Karin. Nature, 2009

1,048 citations recorded by the source corpus.

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-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.

Subfields: Cell Biology, Immunology

View Paper: https://www.semanticscholar.org/paper/f8442980d28ea2e9fa99f660bb97cd890e05da25

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In Cell Biology

1. A. Sica
2. P. Allavena
3. F. Colotta
4. C. Garlanda
5. Carlo Maria Croce
6. J. Joyce
7. Li Yang
8. J. Pollard

In Immunology

1. A. Mantovani
2. A. Sica
3. P. Allavena
4. J. Pollard
5. J. Joyce
6. F. Balkwill
7. C. Garlanda
8. Lisa M. Coussens

Citations in the corpus

• A Distinct Macrophage Population Mediates Metastatic Breast Cancer Cell Extravasation, Establishment and Growth (2009, background): “A change of CD11b+Gr1+bone marrow derived suppressor cells probably pregranulocytes [38] were believed to be responsible for the reduced metastasis of Lewis lung carcinoma cells in TLR22/2 mice [21].”
• Tumors as organs: complex tissues that interface with the entire organism (2010, neutral): “Indeed, circulating cancer cells are able to reinfiltrate and grow in primary tumors, likely because a favorable microenvironment is already established (Kim et al., 2009a).”
• An Introduction to Proteoglycans and Their Localization (2012, background): “Versican has been identified as upregulated in many tumors, including, lung, gastric, ovarian, breast and melanoma (Kim et al. 2009; Ricciardelli et al. 2009; Du et al. 2010; Ween et al. 2011, Hernández et al. 2011).”
• Chronic Inflammation and Cytokines in the Tumor Microenvironment (2014, background): “6 mice injected with LLC cells showed improved survival and reduced lung tumormultiplicity, suggesting a critical role of TNF-α in LLC metastasis [172].”
• Cancer-related inflammation, the seventh hallmark of cancer: links to genetic instability. (2009, background): “that versican, by triggering the innate receptors TLR2/TLR6 on TAM, amplifies an inflammatory cascade leading to enhanced metastasis [99].”
• Cancer-related inflammation: common themes and therapeutic opportunities. (2012, background): “This may partly explain the ability of TNFto enhance metastatic activity of tumor cells as first reported in the 1990s and further elucidated by Michael Karin’s group in 2009 [37].”
• DAMPening Inflammation by Modulating TLR Signalling (2010, background): “Indeed, knockdown of versican expression in Lewis lung carcinoma cell lines (LLC) ablated their tumorigenic capability, promoting mouse survival and reduced metastasis, whilst overexpression of versican in LLC lines with low innate metastatic potential increased lung metastasis [25].”
• Tumor-Associated Macrophages as Major Players in the Tumor Microenvironment (2014, background): “Kim and colleagues recently found that versican activated macrophages via TLR2 and its co-receptors TLR6 and CD14 [44].”
• Macrophages, innate immunity and cancer: balance, tolerance, and diversity. (2010, background): “Tumor cell products, including extracellular matrix components, IL-10, CSF-1, activate macrophages and set them in an M2, cancer promoting mode [33 ,34–36].”
• The Ripoptosome, a signaling platform that assembles in response to genotoxic stress and loss of IAPs. (2011, background): “In this respect, it is important to note that TNF is one of the key mediators of cancer-related inflammation that drives tumor development and/or progression (Kim et al., 2009; Wu and Zhou, 2010).”