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

Sunhwa Ki, Hiroyuki Takahashi, Wan-Wan Lin, Pascal Descargues, Sergei Grivennikov, Youngjun Kim, Jun-Li Luo & Michael Karin

Nature 457, 102-107 (2009)

Speaker: 張竣泓                                                        Time: 14:00~15:00, April 08, 2009

Commentator: 楊倍昌 老師                          Place: Room 601

Abstract:

Distant-site metastasis of malignant tumors depends on the intrinsic gene alteration of tumor cells as well as extrinsic factors derived from the tumor microenvironment, especially the tumor-associated inflammatory milieu consisting of immune cells, their secreted products, and scaffolds in the form of the extracellular matrix for further tumor growth. Furthermore, tumor progression and metastasis positively correlate with the presence of infiltrating myeloid cells and the cytokines they produced. In order to understand how cancer cells affected the inflammatory microenvironment, the authors screened for potential macrophage-activating factors secreted by metastatic carcinoma. Among the cell lines screened, they showed that the condition medium where highly metastatic tumor cells (Lewis lung carcinoma, LLC) grew could lead to the production of IL-6 and TNF-α by macrophages in a TLR2-dependent manner. Moreover, TLR2 and TNF-α were shown to be necessary for LLC metastasis. By purifying the components from LLC condition medium, they found versican, a proteoglycan of the extracellular matrix that is frequently upregulated in human tumors, could function as a macrophage activator through the engagement of TLR2 and its coreceptor TLR6 and CD14. Usage of the RNA interference approach and TLR2 knockout mice showed that versican strongly enhance LLC metastatic growth through activating TLR2 and inducing cytokine secretion by myeloid cells. These results explain how cancer cells control bone marrow derived myeloid cells to induce proinflammatory molecules and make the microenvironment suitable for tumor metastasis.

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