Endothelial Progenitor Cells Control the Angiogenic Switch in Mouse Lung Metastasis

Science 319: 195-198, 2008

Speaker: Chen, Chian-Yi (陳倩怡)                           Time:14:00~15:00, April 30, 2008

Commentator: Wang, Yi-Ching (王憶卿老師)王憶卿       Place: Room 601

Abstract:

Angiogenesis-mediated progression of micrometastasis to lethal macrometastasis is the major cause of death in cancer patients. The authors hypothesis that endothelial progenitor cells control the angiogenic switch in mouse lung metastasis. The authors use mouse models of pulmonary metastasis to mimic human lung cancers. They focus on BM-derived endothelial progenitor cells (EPCs) contribute to angiogenesis-mediated progression of micrometastases into deadly macrometastases.The authors implanted Lewis lung carcinoma cells stably expressing red fluorescent protein (LLC-RFP) into syngeneic mice reconstituted with BM cells expressing green fluorescent protein (GFP+ BM). Next the authors determined whether this window of metastasis progression was associated with the angiogenic switch. As expected, many BM-derived GFP+ cells were recruited to both micro- and macrometastases. Histology revealed vessel-incorporated GFP+ CD31+ BM-derived endothelial cells. To determine the mechanism underlying EPC recruitment to the sites of neovascularization, the authors examined metastatic lesions for the expression of adhesion molecules. Following dissect the role of Id1 in EPC-mediated progression of metastatic lesions, the authors used a lentiviral-based synthetic microRNA (miR-30)–based short hairpin RNA (shRNA) expression system whose activity could be induced by doxycycline (Dox) to target Id1 expression in vivo. Doxmediated induction of Id1 shRNA expression substantially reduced the total number of metastases in animals having an Id1 shRNA bone marrow transplant (BMT) (28 ± 6 in –Dox versus 8 ± 5 in +Dox) as compared with nonspecific shRNA BMT animals [32 ± 7 in –Dox versus 33 ± 6 in +Dox. In conclusion, This study illustrates the critical role of EPCs as novel regulators of the angiogenic switch in metastatic progression and points to a direct role of Id1 in mediating EPC mobilization and recruitment. These findings establish the role of EPCs in metastatic progression in preclinical models and suggest that selective targeting of EPCs may merit investigation as a therapy for cancer patients with lung metastases.

References:

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

2.     D. J. Nolan et al., 2007. Bone marrow-derived endothelial progenitor cells are a major determinant of nascent tumor neovascularization. Genes Dev .21, 1546.