Tumour-mediated upregulation of chemoattractants and recruitment of myeloid cells predetermines lung metastasis

Nature Cell Biology 8, 1639-1375 (2006)

Speaker: Jheng-Liang Cai               Time: 14:00~15:00, May. 2, 2007

Commentator: Dr. Hung-Chi Cheng      Place: Room 601

Abstract:

In 2002, the authors performed an “experimental” metastasis model that intravenously inject lung cancer cells into the tumor-bearing (with/without) mice¹. They found MMP9 is specifically induced in premetastatic lung endothelial cells and macrophages by distant primary tumors via VEGFR-1/Flt-1 tyrosine kinase (TK) and that it significantly promotes lung metastasis. Three years later, another report found bone marrow-derived haematopoietic progenitor cells that express VEGFR-1/Flt-1 home to tumour-specific pre-metastatic sites and form cellular clusters before the arrival of tumour cells². According to above-mentioned studies, the authors hypothesize that the lungs are sensitized by primary tumors at an early stage and searched for molecules that are induced by primary tumors and directly regulate the migration of tumor cells, as well as cells associated with them. They found that primary tumors stimulate S100A8 and S100A9 expression in lung endothelial cells and Mac 1⁺-myeloid cells through VEGF-A, TNFa, and TGFb. In the bargain, S100A8 and S100A9 induce the migration activities of myeloid cells and tumor cells through activation of MAPK p38. Finally, activated endothelial cells and Mac 1⁺-myeloid cells release MIP2, TNFa, and TGFb to attract tumor cell metastasize from distant primary tumor site to the lungs.

Reference

1.         Hiratsuka, S. et al. MMP9 induction by vascular endothelial growth factor receptor-1 is involved in lung-specific metastasis. Cancer Cell 2, 289-300 (2002).

2.         Kaplan, R. N. et al. VEGFR1-positive haematopoietic bone marrow progenitors initiate the pre-metastatic niche. Nature 438, 820-7 (2005).