title: Mesenchymal stem cells promote mammosphere formation and decrease E-cadherin in normal and malignant breast cells.
abstract: BACKGROUND
  Normal and malignant breast tissue contains a rare population of multi-potent cells with the capacity to self-renew, referred to as stem cells, or tumor initiating cells (TIC). These cells can be enriched by growth as "mammospheres" in three-dimensional cultures.
  
  
  OBJECTIVE
  We tested the hypothesis that human bone-marrow derived mesenchymal stem cells (MSC), which are known to support tumor growth and metastasis, increase mammosphere formation.
  
  
  RESULTS
  We found that MSC increased human mammary epithelial cell (HMEC) mammosphere formation in a dose-dependent manner. A similar increase in sphere formation was seen in human inflammatory (SUM149) and non-inflammatory breast cancer cell lines (MCF-7) but not in primary inflammatory breast cancer cells (MDA-IBC-3). We determined that increased mammosphere formation can be mediated by secreted factors as MSC conditioned media from MSC spheroids significantly increased HMEC, MCF-7 and SUM149 mammosphere formation by 6.4 to 21-fold. Mammospheres grown in MSC conditioned media had lower levels of the cell adhesion protein, E-cadherin, and increased expression of N-cadherin in SUM149 and HMEC cells, characteristic of a pro-invasive mesenchymal phenotype. Co-injection with MSC in vivo resulted in a reduced latency time to develop detectable MCF-7 and MDA-IBC-3 tumors and increased the growth of MDA-IBC-3 tumors. Furthermore, E-cadherin expression was decreased in MDA-IBC-3 xenografts with co-injection of MSC.
  
  
  CONCLUSIONS
  MSC increase the efficiency of primary mammosphere formation in normal and malignant breast cells and decrease E-cadherin expression, a biologic event associated with breast cancer progression and resistance to therapy.
authors.affiliation: Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.
authors.forename: Ann H
authors.initials: AH
authors.lastname: Klopp
authors.forename: Lara
authors.initials: L
authors.lastname: Lacerda
authors.forename: Anshul
authors.initials: A
authors.lastname: Gupta
authors.forename: Bisrat G
authors.initials: BG
authors.lastname: Debeb
authors.forename: Travis
authors.initials: T
authors.lastname: Solley
authors.forename: Li
authors.initials: L
authors.lastname: Li
authors.forename: Erika
authors.initials: E
authors.lastname: Spaeth
authors.forename: Wei
authors.initials: W
authors.lastname: Xu
authors.forename: Xiaomei
authors.initials: X
authors.lastname: Zhang
authors.forename: Michael T
authors.initials: MT
authors.lastname: Lewis
authors.forename: James M
authors.initials: JM
authors.lastname: Reuben
authors.forename: Savitri
authors.initials: S
authors.lastname: Krishnamurthy
authors.forename: Mauro
authors.initials: M
authors.lastname: Ferrari
authors.forename: Rogério
authors.initials: R
authors.lastname: Gaspar
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Buchholz
authors.forename: Massimo
authors.initials: M
authors.lastname: Cristofanilli
authors.forename: Frank
authors.initials: F
authors.lastname: Marini
authors.forename: Michael
authors.initials: M
authors.lastname: Andreeff
authors.forename: Wendy A
authors.initials: WA
authors.lastname: Woodward
mesh_terms: D000818:Animals; D001940:Breast / Q000166:cytology* / Q000378:metabolism / Q000473:pathology*; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology*; D015820:Cadherins / Q000378:metabolism*; D018929:Cell Culture Techniques / Q000379:methods*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002471:Cell Transformation, Neoplastic; D017077:Culture Media, Conditioned / Q000494:pharmacology; D005786:Gene Expression Regulation; D006801:Humans; D042361:Mammary Glands, Human / Q000166:cytology / Q000473:pathology; D059630:Mesenchymal Stem Cells / Q000378:metabolism*; D051379:Mice; D009362:Neoplasm Metastasis
chemical_list: D015820:Cadherins; D017077:Culture Media, Conditioned
references.citation: Cell. 2008 May 16;133(4):704-15
references.pmid: 18485877
references.citation: Oncology. 2003;64(3):245-50
references.pmid: 12697965
references.citation: J Mammary Gland Biol Neoplasia. 2005 Jan;10(1):75-86
references.pmid: 15886888
references.citation: Acta Anat (Basel). 1995;154(1):8-20
references.pmid: 8714286
references.citation: Breast Cancer Res. 2004;6(1):R110-5
references.pmid: 14696649
references.citation: Nature. 2007 Oct 4;449(7162):557-63
references.pmid: 17914389
references.citation: Cancer Res. 2002 Jul 1;62(13):3603-8
references.pmid: 12097260
references.citation: Oncology. 2007;72(5-6):403-9
references.pmid: 18196927
references.citation: Cell Mol Life Sci. 2009 Sep;66(18):3053-65
references.pmid: 19603142
references.citation: Obes Res. 2004 Mar;12(3):488-98
references.pmid: 15044666
references.citation: Breast Cancer Res Treat. 2010 Nov;124(2):317-26
references.pmid: 20087650
references.citation: Breast Cancer Res. 2008;10(2):R25
references.pmid: 18366788
references.citation: Oncogene. 2002 May 16;21(22):3631-43
references.pmid: 12032865
references.citation: Mod Pathol. 2001 May;14(5):458-64
references.pmid: 11353057
references.citation: Genes Dev. 2003 May 15;17(10):1253-70
references.pmid: 12756227
references.citation: J Mammary Gland Biol Neoplasia. 2005 Jan;10(1):17-24
references.pmid: 15886883
references.citation: Cell. 2009 Aug 21;138(4):645-659
references.pmid: 19682730
references.citation: Cancer Res. 2008 May 15;68(10):3645-54
references.pmid: 18483246
references.citation: Breast Cancer Res Treat. 2010 Jun;121(2):293-300
references.pmid: 19597705
references.citation: Proc Natl Acad Sci U S A. 2003 Apr 1;100(7):3983-8
references.pmid: 12629218
references.citation: Cell Signal. 2009 Oct;21(10):1522-31
references.pmid: 19477269
references.citation: J Natl Cancer Inst. 2004 Nov 3;96(21):1593-603
references.pmid: 15523088
references.citation: Breast Cancer Res. 2008;10(3):R52
references.pmid: 18541018
references.citation: J Pathol. 2009 Jan;217(2):169-80
references.pmid: 19089901
references.citation: Science. 2002 Feb 1;295(5556):868-72
references.pmid: 11786607
references.citation: Curr Top Microbiol Immunol. 2000;251:3-11
references.pmid: 11036752
references.citation: Cells Tissues Organs. 2007;185(1-3):191-203
references.pmid: 17587825
references.citation: J Biol Chem. 1995 Dec 1;270(48):29012-7
references.pmid: 7499434
references.citation: Cancer Res. 2005 Apr 15;65(8):3307-18
references.pmid: 15833864
references.citation: Cancer Biomark. 2009;5(1):1-8
references.pmid: 19242056
references.citation: J Biol Chem. 2009 Sep 25;284(39):26533-46
references.pmid: 19633292