Nature 457, 102-106 (1 January 2009) | doi:10.1038/nature07623; Received 1 August 2008; Accepted 20 October 2008

Carcinoma-produced factors activate myeloid cells through TLR2 to stimulate metastasis

Sunhwa Kim1, Hiroyuki Takahashi1, Wan-Wan Lin1,2, Pascal Descargues1, Sergei Grivennikov1, Youngjun Kim1,3, Jun-Li Luo1,3 & Michael Karin1

  1. Department of Pharmacology and Cancer Center, School of Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093-0723, USA
  2. Department of Pharmacology, College of Medicine, National Taiwan University, Taipei, China
  3. Present addresses: Department of Applied Biochemistry, Konkuk University, 322 Danwol-dong, Chungju-City, Chungbuk 380-701, Korea (Y.K.); Department of Cancer Biology, The Scripps Research Institute, 5353 Parkside Drive, Jupiter, Florida 33458, USA (J.-L.L.).

Correspondence to: Michael Karin1 Correspondence and requests for materials should be addressed to M.K. (Email: karinoffice@ucsd.edu).

Metastatic progression depends on genetic alterations intrinsic to cancer cells as well as the inflammatory microenvironment of advanced tumours1, 2. 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)3 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 members4 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 cancer5, 6, 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 progenitors7, to generate an inflammatory microenvironment hospitable for metastatic growth.


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