Angiotensin II facilitates breast cancer cell migration and metastasis

• Published in: PloS one Vol. 7; no. 4; p. e35667
• Main Authors: Rodrigues-Ferreira, Sylvie, Abdelkarim, Mohamed, Dillenburg-Pilla, Patricia, Luissint, Anny-Claude, di-Tommaso, Anne, Deshayes, Frédérique, Pontes, Carmen Lucia S, Molina, Angie, Cagnard, Nicolas, Letourneur, Franck, Morel, Marina, Reis, Rosana I, Casarini, Dulce E, Terris, Benoit, Couraud, Pierre-Olivier, Costa-Neto, Claudio M, Di Benedetto, Mélanie, Nahmias, Clara
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 20.04.2012; Public Library of Science (PLoS)
• Subjects: Adhesion; Angiogenesis; Angiotensin; Angiotensin II; Angiotensin II - physiology; Angiotensinogen; Angiotensins; Animals; Apoptosis Regulatory Proteins - genetics; Apoptosis Regulatory Proteins - metabolism; Biochemistry; Biology; Bone Neoplasms - secondary; Brain Neoplasms - secondary; Breast cancer; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Cancer; Cancer metastasis; Cell adhesion; Cell adhesion & migration; Cell Adhesion - genetics; Cell Line, Tumor; Cell migration; Cell Proliferation; Cloning; Coculture Techniques; Collaboration; Colonization; Deoxyribonucleic acid; Development and progression; DNA; DNA microarrays; Endothelial cells; Endothelium; Enzymes; Extracellular matrix; Extravasation; Female; Gelatinase A; Gelatinase B; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Gene Regulatory Networks; Genes; Hostages; Humans; Immunology; Intercellular adhesion molecule 1; Invasiveness; Kinases; Life Sciences; Lung Neoplasms - secondary; Malignancy; Matrix Metalloproteinase 2 - genetics; Matrix Metalloproteinase 2 - metabolism; Matrix Metalloproteinase 9 - genetics; Matrix Metalloproteinase 9 - metabolism; Medical prognosis; Medicine; Meta-analysis; Metastases; Metastasis; Mice; Mice, Nude; Neoplasm Transplantation; Organs; Transendothelial and Transepithelial Migration - genetics; Tumor cells; Tumors; Vasoactive agents; France
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0035667

Breast cancer metastasis is a leading cause of death by malignancy in women worldwide. Efforts are being made to further characterize the rate-limiting steps of cancer metastasis, i.e. extravasation of circulating tumor cells and colonization of secondary organs. In this study, we investigated whether angiotensin II, a major vasoactive peptide both produced locally and released in the bloodstream, may trigger activating signals that contribute to cancer cell extravasation and metastasis. We used an experimental in vivo model of cancer metastasis in which bioluminescent breast tumor cells (D3H2LN) were injected intra-cardiacally into nude mice in order to recapitulate the late and essential steps of metastatic dissemination. Real-time intravital imaging studies revealed that angiotensin II accelerates the formation of metastatic foci at secondary sites. Pre-treatment of cancer cells with the peptide increases the number of mice with metastases, as well as the number and size of metastases per mouse. In vitro, angiotensin II contributes to each sequential step of cancer metastasis by promoting cancer cell adhesion to endothelial cells, trans-endothelial migration and tumor cell migration across extracellular matrix. At the molecular level, a total of 102 genes differentially expressed following angiotensin II pre-treatment were identified by comparative DNA microarray. Angiotensin II regulates two groups of connected genes related to its precursor angiotensinogen. Among those, up-regulated MMP2/MMP9 and ICAM1 stand at the crossroad of a network of genes involved in cell adhesion, migration and invasion. Our data suggest that targeting angiotensin II production or action may represent a valuable therapeutic option to prevent metastatic progression of invasive breast tumors.