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

Sunhwa, K.et al. 2009. Nature letters 457, 102-106

Presentation: In English

Speaker: Bernard Kiro (祁晨恩)                                           Time: 13:00~14:00, Dec 2^nd, 2009

Commentator: Dr. Bei-Chang Yang (楊倍昌博士)              Place: Room 601

Abstract:

Cancer cells depend on genetic and/or epigenetic alterations that are intrinsic to cancer cells, or extrinsic factors provided by the tumour microenvironment for distant-site metastasis that contribute to cancer-associated mortality¹. Some cytokines produced by inflammatory cells can enhance metastatogenesis by repressing metastasis suppressor². Furthermore, there is a positive correlation between tumour metastasis and progression and the presence of myeloid and lymphoid cells infiltration³. Condition medium collected from metastatic cells, especially Lewis lung carcinoma (LLC, a potent macrophage activator), can induce high amount of Interleukin-6(IL-6) and Tumor necrotic factor-a(TNF- a, important for LLC metastasis) secretion through the activation of the Toll-like receptor family members TLR2 and TLR6 than the conditioned medium from non-metastatic cells. Biochemical purification of LLC-conditioned medium (LCM) led to the identification of the extracellular matrix proteoglycan versican, which is upregulated in many human tumours⁴ as a macrophage activator that acts through TLR2 and its co-receptor TLR6 and CD14. By the activation of TLR2:TLR6 complex and the induction of TNF-a secretion by myeloid cells, versican strongly enhances LLC metastatic growth. From the results above can explain how advanced cancer cells can utilize components from the host innate immune system to stimulate an inflammatory microenvironment that is hospitable for tumour metastatic growth.

References:

1.          L. Kopfstein, et al. 2006. Metastasis: cell-autonomous mechanisms versuscontributions by the tumor microenvironment. Cell. Mol. Life Sci. 63 (2006) 449–468

2.          J.L., Luo, et al. Nuclear cytokine-activated IKKa controls prostate cancer metastasis by repressing Maspin. NATURE (2007) 446, 690-694

3.          D. G. DeNardo, et al. Immune cells as mediators of solid tumor metastasis. Cancer Metastasis Rev (2008) 27:11–18

4.          R. Pirinen, et al. Versican in nonsmall cell lung cancer: relation to hyaluronan, clinicopathologic factors, and prognosis. Human Pathology (2005) 36, 44–50