title: Angiotensin II facilitates breast cancer cell migration and metastasis.
abstract: 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.
authors.affiliation: Inserm, Institut Cochin, Paris, France.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Rodrigues-Ferreira
authors.forename: Mohamed
authors.initials: M
authors.lastname: Abdelkarim
authors.forename: Patricia
authors.initials: P
authors.lastname: Dillenburg-Pilla
authors.forename: Anny-Claude
authors.initials: AC
authors.lastname: Luissint
authors.forename: Anne
authors.initials: A
authors.lastname: di-Tommaso
authors.forename: Frédérique
authors.initials: F
authors.lastname: Deshayes
authors.forename: Carmen Lucia S
authors.initials: CL
authors.lastname: Pontes
authors.forename: Angie
authors.initials: A
authors.lastname: Molina
authors.forename: Nicolas
authors.initials: N
authors.lastname: Cagnard
authors.forename: Franck
authors.initials: F
authors.lastname: Letourneur
authors.forename: Marina
authors.initials: M
authors.lastname: Morel
authors.forename: Rosana I
authors.initials: RI
authors.lastname: Reis
authors.forename: Dulce E
authors.initials: DE
authors.lastname: Casarini
authors.forename: Benoit
authors.initials: B
authors.lastname: Terris
authors.forename: Pierre-Olivier
authors.initials: PO
authors.lastname: Couraud
authors.forename: Claudio M
authors.initials: CM
authors.lastname: Costa-Neto
authors.forename: Mélanie
authors.initials: M
authors.lastname: Di Benedetto
authors.forename: Clara
authors.initials: C
authors.lastname: Nahmias
mesh_terms: D000804:Angiotensin II / Q000502:physiology*; D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D001859:Bone Neoplasms / Q000556:secondary*; D001932:Brain Neoplasms / Q000556:secondary*; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology*; D002448:Cell Adhesion / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D018920:Coculture Techniques; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D053263:Gene Regulatory Networks; D006801:Humans; D008175:Lung Neoplasms / Q000556:secondary*; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D057705:Transendothelial and Transepithelial Migration / Q000235:genetics
chemical_list: D051017:Apoptosis Regulatory Proteins; D000804:Angiotensin II; C522361:MMP2 protein, human; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9