The S100A8-serum amyloid A3-TLR4 paracrine cascade establishes a pre-metastatic phase

Sachie, H. et al. Nature Cell Biology. Published online: Sep. 28 2008

Speaker: Cheng-Yu Wang (王政育)                       Time: 13:00~14:00, Dec. 3 , 2008

Commentator: Dr. Pin Ling (凌斌老師)    Place: Room 601

Abstract：

    Metastasis is the major issue to be solved for the clinical treatment of cancer. In addition, there is the predisposition for certain tumour cells to colonize in particular organs. Scientists propose the seed-and-soil theory of metastasis, but the underlying mechanism is unclear yet. The tumour microenvironment contains varies type of resident cell including adipocytes, fibroblasts, and hematopoietic cells (most notably macrophages, neutrophils and mast cells). These hematopoietic cells have pivotal roles in the progression and metastasis of tumours¹. In the previous work, the authors showed that distant primary tumours induce the expression of the chemoattractants S100A8 and S100A9 in the lungs of mice, thereby recruiting MAC1⁺ myeloid cells ². This time, they found that serum amyloid A (SAA) 3 might be a downstream molecule of S100A8-SAA3 cascade, because SAA3 expression in the lung is induced by S100A8. Based on their results, the authors suggested that Toll-like receptor 4 (TLR4) might be a functional receptor for SAA3. SAA3-GST fusion protein induced chemotaxis of TLR4-expressing Ba/F3 cells and primary mouse macrophages from wild-type, but not Tlr4–/–, mice. SAA3–GST also induced NFκB activation through TLR4 in primary mouse macrophages. There was also a positive feedback regulation that SAA3–GST induced further secretion of SAA3 in wild-type, but not Tlr4–/–, mice. So the authors suggested the S100A8-SAA3-TLR4 paracrine cascade might play a key role in tumour metastasis. Results from in vivo studies showed that primary tumour sizes were not significantly different between wild-type and Tlr4–/– mice; however, there were fewer MAC1⁺ myeloid cells in the lungs of tumour-bearing Tlr4–/–mice. A neutralizing antibody against SAA3 reduced the numbers of MAC1⁺ myeloid cells in the lungs of wild-type mice. Furthermore, during the metastatic phase there was a reduction in tumour cell colonization in the lungs in wild-type mice treated with the anti-SAA3 antibody. In brief, these findings provide evidence that the distant primary tumour may prepare the “soil” for the further metastasis phase.

References：

1.      Jeffery W, P. et al. Tumour-educated macrophages promote tumour progression and metastasis. Nat. Rev. Cancer. 4. 71~78 (2004).

2.      Sachie, H. et al. Tumour-mediated upregulation of chemoattractants and recruitment of myeloid cells predetermines lung metastasis. Nat. Cell Biology. Published online: Nov. 26 2006.