Mesenchymal stem cells promote mammosphere formation and decrease E-cadherin in normal and malignant breast cells.
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.
Klopp
Ann H
AH
Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.
Lacerda
Lara
L
Gupta
Anshul
A
Debeb
Bisrat G
BG
Solley
Travis
T
Li
Li
L
Spaeth
Erika
E
Xu
Wei
W
Zhang
Xiaomei
X
Lewis
Michael T
MT
Reuben
James M
JM
Krishnamurthy
Savitri
S
Ferrari
Mauro
M
Gaspar
Rogério
R
Buchholz
Thomas A
TA
Cristofanilli
Massimo
M
Marini
Frank
F
Andreeff
Michael
M
Woodward
Wendy A
WA
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
D015820:Cadherins; D017077:Culture Media, Conditioned
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