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

Article

关键词: LEWIS-LUNG-CARCINOMA;    CANCER METASTASIS;    PROSTATE-CANCER;    INNATE IMMUNITY;    TUMOR-GROWTH;    PROTEOGLYCAN;    INFLAMMATION;    MACROPHAGES;    ANGIOGENESIS;    HYALURONAN;   

DOI  :  10.1038/nature07623

来源: SCIE

【 摘 要 】

Metastatic progression depends on genetic alterations intrinsic to cancer cells as well as the inflammatory microenvironment of advanced tumours(1,2). 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 members(4) 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(5,6), as a macrophage activator that acts through TLR2 and its coreceptors 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(7), to generate an inflammatory microenvironment hospitable for metastatic growth.

【 授权许可】

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