Metastasis, or distribution of cancer cells to form tumors in new sites, is the most deadly property of cancer cells and requires not only changes in cancer cells themselves but also the capacity of these cells to influence the microenvironment around them. Kim et al. identified a mechanism by which mouse-derived Lewis lung carcinoma (LLC) cells can control the activity of macrophages in the vicinity of tumor cells and thus enhance metastasis. Kim et al. found that culture medium in which the carcinoma cells were grown contained a factor that enhanced production of tumor-supporting cytokines tumor necrosis factor–α (TNF-α) and interleukin-6 (IL-6) from cultured bone marrow–derived macrophages. TNF-α appeared to be the critical factor for metastasis, because knockout animals lacking TNF-α had increased survival compared with control animals when injected with LLC cells. The effect of culture medium from the carcinoma cells on macrophages required Toll-like receptor 2 (TLR2) and was absent in macrophages from mice lacking TLR2 or its adaptor protein Myd88. TLR2 was also implicated in metastasis because Tlr2–/– mice showed fewer tumors and greater survival than control mice when injected with the LCC cells. Purification by column chromatography of the active factor from the culture medium allowed its identification by mass spectrometry as the chondroitin sulphate proteoglycan versican. Versican can enhance growth and migration of tumor cells and angiogenesis. Immunodepletion of versican from the culture medium from LLC cells diminished the effect of the medium on cytokine production by macrophages. Furthermore, depletion of versican from LLC cells with short hairpin RNA reduced generation of tumors in animals injected with the cells and enhanced survival of the injected animals. TLR2 and its co-receptor CD14 were associated with versican immunoprecipitated from macrophages exposed to the culture medium from LCC cells, but it is not clear whether versican directly associates with the receptor. Thus, the authors propose that these lung cancer cells usurp components of the innate immune system to create conditions favorable to tumor cell growth. They note that such control points are potential targets for therapeutic strategies to block metastasis.
S. Kim, H. Takahashi, W.-W. Lin, P. Descargues, S. Grivennikov, Y. Kim, J.-L. Luo, M. Karin, Carcinoma-produced factors activate myeloid cells through TLR2 to stimulate metastasis. Nature 457, 102–106 (2009). [PubMed]