title: Invading basement membrane matrix is sufficient for MDA-MB-231 breast cancer cells to develop a stable in vivo metastatic phenotype.
abstract: BACKGROUND
  The poor efficacy of various anti-cancer treatments against metastatic cells has focused attention on the role of tumor microenvironment in cancer progression. To understand the contribution of the extracellular matrix (ECM) environment to this phenomenon, we isolated ECM surrogate invading cell populations from MDA-MB-231 breast cancer cells and studied their genotype and malignant phenotype.
  
  
  METHODS
  We isolated invasive subpopulations (INV) from non invasive populations (REF) using a 2D-Matrigel assay, a surrogate of basal membrane passage. INV and REF populations were investigated by microarray assay and for their capacities to adhere, invade and transmigrate in vitro, and to form metastases in nude mice.
  
  
  RESULTS
  REF and INV subpopulations were stable in culture and present different transcriptome profiles. INV cells were characterized by reduced expression of cell adhesion and cell-cell junction genes (44% of down regulated genes) and by a gain in expression of anti-apoptotic and pro-angiogenic gene sets. In line with this observation, in vitro INV cells showed reduced adhesion and increased motility through endothelial monolayers and fibronectin. When injected into the circulation, INV cells induced metastases formation, and reduced injected mice survival by up to 80% as compared to REF cells. In nude mice, INV xenografts grew rapidly inducing vessel formation and displaying resistance to apoptosis.
  
  
  CONCLUSIONS
  Our findings reveal that the in vitro ECM microenvironment per se was sufficient to select for tumor cells with a stable metastatic phenotype in vivo characterized by loss of adhesion molecules expression and induction of pro-angiogenic and survival factors.
authors.affiliation: Université Paris 13, CNRS FRE CSPBAT, Laboratoire de Chimie Structurale Biomoléculaire, UFR SMBH, Bobigny, France.
authors.forename: Mohamed
authors.initials: M
authors.lastname: Abdelkarim
authors.forename: Nadejda
authors.initials: N
authors.lastname: Vintonenko
authors.forename: Anna
authors.initials: A
authors.lastname: Starzec
authors.forename: Aniela
authors.initials: A
authors.lastname: Robles
authors.forename: Julie
authors.initials: J
authors.lastname: Aubert
authors.forename: Marie-Laure
authors.initials: ML
authors.lastname: Martin
authors.forename: Samia
authors.initials: S
authors.lastname: Mourah
authors.forename: Marie-Pierre
authors.initials: MP
authors.lastname: Podgorniak
authors.forename: Sylvie
authors.initials: S
authors.lastname: Rodrigues-Ferreira
authors.forename: Clara
authors.initials: C
authors.lastname: Nahmias
authors.forename: Pierre-Olivier
authors.initials: PO
authors.lastname: Couraud
authors.forename: Christelle
authors.initials: C
authors.lastname: Doliger
authors.forename: Odile
authors.initials: O
authors.lastname: Sainte-Catherine
authors.forename: Nicole
authors.initials: N
authors.lastname: Peyri
authors.forename: Lei
authors.initials: L
authors.lastname: Chen
authors.forename: Jérémie
authors.initials: J
authors.lastname: Mariau
authors.forename: Monique
authors.initials: M
authors.lastname: Etienne
authors.forename: Gerard-Yves
authors.initials: GY
authors.lastname: Perret
authors.forename: Michel
authors.initials: M
authors.lastname: Crepin
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Poyet
authors.forename: Abdel-Majid
authors.initials: AM
authors.lastname: Khatib
authors.forename: Mélanie
authors.initials: M
authors.lastname: Di Benedetto
mesh_terms: D042501:Angiogenic Proteins / Q000235:genetics / Q000378:metabolism; D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D001485:Basement Membrane / Q000378:metabolism* / Q000473:pathology; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002448:Cell Adhesion / Q000235:genetics; D045744:Cell Line, Tumor; D003094:Collagen; D004338:Drug Combinations; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D007797:Laminin; D008325:Mammary Neoplasms, Experimental / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D009361:Neoplasm Invasiveness / Q000235:genetics; D009362:Neoplasm Metastasis / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D011509:Proteoglycans; D020133:Reverse Transcriptase Polymerase Chain Reaction; D059467:Transcriptome; D057705:Transendothelial and Transepithelial Migration / Q000235:genetics; D014183:Transplantation, Heterologous; D047368:Tumor Burden / Q000235:genetics
chemical_list: D042501:Angiogenic Proteins; D051017:Apoptosis Regulatory Proteins; D004338:Drug Combinations; D007797:Laminin; D011509:Proteoglycans; C059485:matrigel; D003094:Collagen