**7. References**


engineered to produce anti-tumor factors, MSCs possess anti-tumoral effects and may be used as trojan horses that enter and eradicate tumor cells. Drug-carrying MSCs may have a great advantage over "naked" drugs since they may deliver drugs more selectively and

Aggarwal S. & Pittenger M. F. (2005). Human mesenchymal stem cells modulate allogeneic

Barbash I. M.; Chouraqui P.; Baron J.; Feinberg M. S.; Etzion S.; Tessone A.; Miller L.; Guetta

cell migration, and body distribution. *Circulation,* Vol.108, No.7, pp. 863-868. Bartholomew A.; Sturgeon C.; Siatskas M.; Ferrer K.; McIntosh K.; Patil S.; Hardy W.; Devine

Beyer Nardi N. & da Silva Meirelles L. (2006). Mesenchymal stem cells: isolation, in vitro expansion and characterization. *Handb Exp Pharmacol*, No.174, pp. 249-282. Bhowmick N. A.; Neilson E. G. & Moses H. L. (2004). Stromal fibroblasts in cancer initiation

Bianco P. (2011). Back to the future: moving beyond "mesenchymal stem cells". *J Cell* 

Brooke G.; Cook M.; Blair C.; Han R.; Heazlewood C.; Jones B.; Kambouris M.; Kollar K.;

Burns J. S.; Abdallah B. M.; Schroder H. D. & Kassem M. (2008). The histopathology of a

origin for Ewing's sarcoma? *Histol Histopathol,* Vol.23, No.10, pp. 1229-1240. Cano A.; Perez-Moreno M. A.; Rodrigo I.; Locascio A.; Blanco M. J.; del Barrio M. G.; Portillo

Charafe-Jauffret E.; Monville F.; Ginestier C.; Dontu G.; Birnbaum D. & Wicha M. S. (2008).

Chauhan H.; Abraham A.; Phillips J. R.; Pringle J. H.; Walker R. A. & Jones J. L. (2003). There

situ, and invasive breast lesions. *J Clin Pathol,* Vol.56, No.4, pp. 271-276.

Caplan A. I. (1991). Mesenchymal stem cells. *J Orthop Res,* Vol.9, No.5, pp. 641-650.

McTaggart S.; Pelekanos R.; Rice A.; Rossetti T. & Atkinson K. (2007). Therapeutic applications of mesenchymal stromal cells. *Semin Cell Dev Biol,* Vol.18, No.6, pp.

human mesenchymal stem cell experimental tumor model: support for an hMSC

F. & Nieto M. A. (2000). The transcription factor snail controls epithelialmesenchymal transitions by repressing E-cadherin expression. *Nat Cell Biol,* Vol.2,

Cancer stem cells in breast: current opinion and future challenges. *Pathobiology,* 

is more than one kind of myofibroblast: analysis of CD34 expression in benign, in

E.; Zipori D.; Kedes L. H.; Kloner R. A. & Leor J. (2003). Systemic delivery of bone marrow-derived mesenchymal stem cells to the infarcted myocardium: feasibility,

S.; Ucker D.; Deans R.; Moseley A. & Hoffman R. (2002). Mesenchymal stem cells suppress lymphocyte proliferation in vitro and prolong skin graft survival in vivo.

more efficiently at places where they are meant to act.

*Exp Hematol,* Vol.30, No.1, pp. 42-48.

*Biochem*, Vol.112, No.7, pp. 1713-1721.

This work was supported by the Deutsche Krebshilfe (grant # 109271)

immune cell responses. *Blood,* Vol.105, No.4, pp. 1815-1822.

and progression. *Nature,* Vol.432, No.7015, pp. 332-337.

**6. Acknowledgment** 

846-858.

No.2, pp. 76-83.

Vol.75, No.2, pp. 75-84.

**7. References** 


Involvement of Mesenchymal Stem Cells in Breast Cancer Progression 263

Gjerstorff M.; Burns J. S.; Nielsen O.; Kassem M. & Ditzel H. (2009). Epigenetic modulation

Goldstein R. H.; Reagan M. R.; Anderson K.; Kaplan D. L. & Rosenblatt M. (2010). Human

Grisendi G.; Bussolari R.; Cafarelli L.; Petak I.; Rasini V.; Veronesi E.; De Santis G.; Spano C.;

Herberts C. A.; Kwa M. S. & Hermsen H. P. (2011). Evaluation of risk factors in the

Hess D.; Li L.; Martin M.; Sakano S.; Hill D.; Strutt B.; Thyssen S.; Gray D. A. & Bhatia M.

Hombauer H. & Minguell J. J. (2000). Selective interactions between epithelial tumour cells

Ishii G.; Sangai T.; Oda T.; Aoyagi Y.; Hasebe T.; Kanomata N.; Endoh Y.; Okumura C.;

Ito T.; Suzuki A.; Imai E.; Okabe M. & Hori M. (2001). Bone marrow is a reservoir of

Jiang X. X.; Zhang Y.; Liu B.; Zhang S. X.; Wu Y.; Yu X. D. & Mao N. (2005). Human

Kale S.; Karihaloo A.; Clark P. R.; Kashgarian M.; Krause D. S. & Cantley L. G. (2003). Bone

Karnoub A. E.; Dash A. B.; Vo A. P.; Sullivan A.; Brooks M. W.; Bell G. W.; Richardson A. L.;

development of stem cell therapy. *J Transl Med,* Vol.9, No.1, pp. 29.

promote bone metastasis. *Cancer Res,* Vol.70, No.24, pp. 10044-10050. Grayson W. L.; Zhao F.; Izadpanah R.; Bunnell B. & Ma T. (2006). Effects of hypoxia on

555-567.

pp. 2821-2827.

No.9, pp. 3718-3729.

*Physiol,* Vol.207, No.2, pp. 331-339.

*Biotechnol,* Vol.21, No.7, pp. 763-770.

Vol.12, No.12, pp. 2625-2635.

*Clin Invest,* Vol.112, No.1, pp. 42-49.

563.

*Biophys Res Commun,* Vol.309, No.1, pp. 232-240.

dendritic cells. *Blood,* Vol.105, No.10, pp. 4120-4126.

stem cells and a predictor of poor clinical outcome. *Cell Stem Cell,* Vol.1, No.5, pp.

of cancer-germline antigen gene expression in tumorigenic human mesenchymal stem cells: implications for cancer therapy. *Am J Pathol,* Vol.175, No.1, pp. 314-323. Glennie S.; Soeiro I.; Dyson P. J.; Lam E. W. & Dazzi F. (2005). Bone marrow mesenchymal

stem cells induce division arrest anergy of activated T cells. *Blood,* Vol.105, No.7,

bone marrow-derived MSCs can home to orthotopic breast cancer tumors and

human mesenchymal stem cell expansion and plasticity in 3D constructs. *J Cell* 

Tagliazzucchi M.; Barti-Juhasz H.; Scarabelli L.; Bambi F.; Frassoldati A.; Rossi G.; Casali C.; Morandi U.; Horwitz E. M.; Paolucci P.; Conte P. & Dominici M. (2010). Adipose-derived mesenchymal stem cells as stable source of tumor necrosis factorrelated apoptosis-inducing ligand delivery for cancer therapy. *Cancer Res,* Vol.70,

(2003). Bone marrow-derived stem cells initiate pancreatic regeneration. *Nat* 

and bone marrow mesenchymal stem cells. *Br J Cancer,* Vol.82, No.7, pp. 1290-1296.

Okuhara Y.; Magae J.; Emura M.; Ochiya T. & Ochiai A. (2003). Bone-marrowderived myofibroblasts contribute to the cancer-induced stromal reaction. *Biochem* 

repopulating mesangial cells during glomerular remodeling. *J Am Soc Nephrol,* 

mesenchymal stem cells inhibit differentiation and function of monocyte-derived

marrow stem cells contribute to repair of the ischemically injured renal tubule. *J* 

Polyak K.; Tubo R. & Weinberg R. A. (2007). Mesenchymal stem cells within tumour stroma promote breast cancer metastasis. *Nature,* Vol.449, No.7162, pp. 557-

3D-cultures of MCF-7, a human breast cancer cell line, and its multidrug resistant variant. *Clin Exp Metastasis,* Vol.19, No.2, pp. 161-168.


Dittmer A.; Hohlfeld K.; Lutzkendorf J.; Muller L. P. & Dittmer J. (2009). Human

Dittmer A.; Fuchs A.; Oerlecke I.; Leyh B.; Kaiser S.; Martens J. W. M.; Lützkendorf J.;

do Amaral J. B.; Urabayashi M. S. & Machado-Santelli G. M. (2010). Cell death and lumen formation in spheroids of MCF-7 cells. *Cell Biol Int,* Vol.34, No.3, pp. 267-274. Dominici M.; Le Blanc K.; Mueller I.; Slaper-Cortenbach I.; Marini F.; Krause D.; Deans R.;

Dontu G.; Abdallah W. M.; Foley J. M.; Jackson K. W.; Clarke M. F.; Kawamura M. J. &

mammary stem/progenitor cells. *Genes Dev,* Vol.17, No.10, pp. 1253-12570. Dvorak H. F. (1986). Tumors: wounds that do not heal. Similarities between tumor stroma generation and wound healing. *N Engl J Med,* Vol.315, No.26, pp. 1650-1659. Dwyer R. M.; Potter-Beirne S. M.; Harrington K. A.; Lowery A. J.; Hennessy E.; Murphy J.

Ehninger A. & Trumpp A. (2011). The bone marrow stem cell niche grows up: mesenchymal stem cells and macrophages move in. *J Exp Med,* Vol.208, No.3, pp. 421-428. Fierro F. A.; Sierralta W. D.; Epunan M. J. & Minguell J. J. (2004). Marrow-derived

Fillmore C. & Kuperwasser C. (2007). Human breast cancer stem cell markers CD44 and

Friedenstein A. & Kuralesova A. I. (1971). Osteogenic precursor cells of bone marrow in

Friedenstein A. J.; Chailakhyan R. K.; Latsinik N. V.; Panasyuk A. F. & Keiliss-Borok I. V.

Friedenstein A. J.; Piatetzky S., II & Petrakova K. V. (1966). Osteogenesis in transplants of bone marrow cells. *J Embryol Exp Morphol,* Vol.16, No.3, pp. 381-390. Ginestier C.; Hur M. H.; Charafe-Jauffret E.; Monville F.; Dutcher J.; Brown M.; Jacquemier

radiation chimeras. *Transplantation,* Vol.12, No.2, pp. 99-108.

Therapy position statement. *Cytotherapy,* Vol.8, No.4, pp. 315-317.

variant. *Clin Exp Metastasis,* Vol.19, No.2, pp. 161-168.

*ScientificWorldJournal,* Vol.10, pp. 1234-1238.

*Clin Cancer Res,* Vol.13, No.17, pp. 5020-5027.

*Metastasis,* Vol.21, No.4, pp. 313-319.

*Cancer Res,* Vol.9, No.3, pp. 303.

Vol.17, No.4, pp. 331-340.

*Oncol.* Vol.39, No.3, pp. 689-696.

3D-cultures of MCF-7, a human breast cancer cell line, and its multidrug resistant

mesenchymal stem cells induce E-cadherin degradation in breast carcinoma spheroids by activating ADAM10. *Cell Mol Life Sci.,* Vol.66, No.18, pp. 3053-3065. Dittmer J. (2010). Mesenchymal stem cells: "repair cells" that serve wounds and cancer?

Müller L. & Dittmer J. (2011). Mesenchymal stem cells and carincoma-associated fibroblasts sensitize breast cancer cells in 3D cultures to kinase inhibitors. *Int. J.* 

Keating A.; Prockop D. & Horwitz E. (2006). Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular

Wicha M. S. (2003). In vitro propagation and transcriptional profiling of human

M.; Barry F. P.; O'Brien T. & Kerin M. J. (2007). Monocyte chemotactic protein-1 secreted by primary breast tumors stimulates migration of mesenchymal stem cells.

mesenchymal stem cells: role in epithelial tumor cell determination. *Clin Exp* 

CD24: enriching for cells with functional properties in mice or in man? *Breast* 

(1974). Stromal cells responsible for transferring the microenvironment of the hemopoietic tissues. Cloning in vitro and retransplantation in vivo. *Transplantation,* 

J.; Viens P.; Kleer C. G.; Liu S.; Schott A.; Hayes D.; Birnbaum D.; Wicha M. S. & Dontu G. (2007). ALDH1 is a marker of normal and malignant human mammary stem cells and a predictor of poor clinical outcome. *Cell Stem Cell,* Vol.1, No.5, pp. 555-567.


Involvement of Mesenchymal Stem Cells in Breast Cancer Progression 265

Li G. R.; Sun H.; Deng X. & Lau C. P. (2005). Characterization of ionic currents in human mesenchymal stem cells from bone marrow. *Stem Cells,* Vol.23, No.3, pp. 371-382. Li N.; Yang R.; Zhang W.; Dorfman H.; Rao P. & Gorlick R. (2009). Genetically transforming

multilineage differentiation potential. *Cancer,* Vol.115, No.20, pp. 4795-4806. Lin F.; Cordes K.; Li L.; Hood L.; Couser W. G.; Shankland S. J. & Igarashi P. (2003).

Lin S. Y.; Yang J.; Everett A. D.; Clevenger C. V.; Koneru M.; Mishra P. J.; Kamen B.; Banerjee

Ling X.; Marini F.; Konopleva M.; Schober W.; Shi Y.; Burks J.; Clise-Dwyer K.; Wang R. Y.;

Liu S.; Ginestier C.; Ou S. J.; Clouthier S. G.; Patel S. H.; Monville F.; Korkaya H.; Heath A.;

Liu S. & Wicha M. S. (2010). Targeting breast cancer stem cells. *J Clin Oncol,* Vol.28, No.25,

Locke M.; Feisst V. & Dunbar P. R. (2011). Concise review: human adipose-derived stem cells: separating promise from clinical need. *Stem Cells,* Vol.29, No.3, pp. 404-411. Loebinger M. R.; Eddaoudi A.; Davies D. & Janes S. M. (2009). Mesenchymal stem cell

Lu Y.; Cai Z.; Galson D. L.; Xiao G.; Liu Y.; George D. E.; Melhem M. F.; Yao Z. & Zhang J.

Mahmood A.; Lu D.; Lu M. & Chopp M. (2003). Treatment of traumatic brain injury in adult

Manabe Y.; Toda S.; Miyazaki K. & Sugihara H. (2003). Mature adipocytes, but not

Mani S. A.; Guo W.; Liao M. J.; Eaton E. N.; Ayyanan A.; Zhou A. Y.; Brooks M.; Reinhard F.;

properties of stem cells. *Cell,* Vol.133, No.4, pp. 704-715.

Sarcoma. *Sarcoma.,* Vol.407, No.4, pp. 741-746.

networks. *Cancer Res,* Vol.71, No.2, pp. 614-624.

*Neurosurgery,* Vol.53, No.3, pp. 697-702.

pp. 3107-3117.

No.1, pp. 83-95.

pp. 4006-4012.

4134-4142.

1318.

human mesenchymal stem cells to sarcomas: changes in cellular phenotype and

Hematopoietic stem cells contribute to the regeneration of renal tubules after renal ischemia-reperfusion injury in mice. *J Am Soc Nephrol,* Vol.14, No.5, pp. 1188-1199. Lin P. P.; Wang Y. & Lozano G. (2011). Mesenchymal Stem Cells and the Origin of Ewing's

D. & Glod J. (2008). The isolation of novel mesenchymal stromal cell chemotactic factors from the conditioned medium of tumor cells. *Exp Cell Res,* Vol.314, No.17,

Zhang W.; Yuan X.; Lu H.; Caldwell L. & Andreeff M. (2010). Mesenchymal Stem Cells Overexpressing IFN-beta Inhibit Breast Cancer Growth and Metastases through Stat3 Signaling in a Syngeneic Tumor Model. *Cancer Microenviron,* Vol.3,

Dutcher J.; Kleer C. G.; Jung Y.; Dontu G.; Taichman R. & Wicha M. S. (2011). Breast cancer stem cells are regulated by mesenchymal stem cells through cytokine

delivery of TRAIL can eliminate metastatic cancer. *Cancer Res,* Vol.69, No.10, pp.

(2006). Monocyte chemotactic protein-1 (MCP-1) acts as a paracrine and autocrine factor for prostate cancer growth and invasion. *Prostate,* Vol.66, No.12, pp. 1311-

rats with intravenous administration of human bone marrow stromal cells.

preadipocytes, promote the growth of breast carcinoma cells in collagen gel matrix culture through cancer-stromal cell interactions. *J Pathol,* Vol.201, No.2, pp. 221-228.

Zhang C. C.; Shipitsin M.; Campbell L. L.; Polyak K.; Brisken C.; Yang J. & Weinberg R. A. (2008). The epithelial-mesenchymal transition generates cells with


Kidd S.; Spaeth E.; Dembinski J. L.; Dietrich M.; Watson K.; Klopp A.; Battula V. L.; Weil M.;

Kidd S.; Spaeth E.; Klopp A.; Andreeff M.; Hall B. & Marini F. C. (2008). The (in) auspicious

Kim S. M.; Kim D. S.; Jeong C. H.; Kim D. H.; Kim J. H.; Jeon H. B.; Kwon S. J.; Jeun S. S.;

toward gliomas. *Biochem Biophys Res Commun*, Vol.407, No.4, pp. 741-746. Klopp A. H.; Gupta A.; Spaeth E.; Andreeff M. & Marini F., 3rd (2011). Dissecting a

Klopp A. H.; Lacerda L.; Gupta A.; Debeb B. G.; Solley T.; Li L.; Spaeth E.; Xu W.; Zhang X.;

Klopp A. H.; Spaeth E. L.; Dembinski J. L.; Woodward W. A.; Munshi A.; Meyn R. E.; Cox J.

Krabbe C.; Zimmer J. & Meyer M. (2005). Neural transdifferentiation of mesenchymal stem

Krampera M.; Glennie S.; Dyson J.; Scott D.; Laylor R.; Simpson E. & Dazzi F. (2003). Bone

Krinner A.; Hoffmann M.; Loeffler M.; Drasdo D. & Galle J. (2010). Individual fates of

Kucerova L.; Matuskova M.; Pastorakova A.; Tyciakova S.; Jakubikova J.; Bohovic R.;

Kurozumi K.; Nakamura K.; Tamiya T.; Kawano Y.; Kobune M.; Hirai S.; Uchida H.; Sasaki

Lee R. H.; Seo M. J.; Reger R. L.; Spees J. L.; Pulin A. A.; Olson S. D. & Prockop D. J. (2006).

Leung C. T. & Brugge J. S. (2009). Tumor self-seeding: bidirectional flow of tumor cells. *Cell,* 

imaging. *Stem Cells,* Vol.27, No.10, pp. 2614-2623.

tumor growth? *Stem Cells,* Vol.29, No.1, pp. 11-19.

*Res,* Vol.67, No.24, pp. 11687-11695.

*Gene Med,* Vol.10, No.10, pp. 1071-1082.

*U S A,* Vol.103, No.46, pp. 17438-17443.

Vol.139, No.7, pp. 1226-1228.

pp. 189-197.

and malignant breast cells. *PLoS One,* Vol.5, No.8, pp. e12180.

cells--a critical review. *Apmis,* Vol.113, No.11-12, pp. 831-844.

mesenchymal stem cells in vitro. *BMC Syst Biol,* Vol.4, pp. 73.

No.7, pp. 657-667.

Andreeff M. & Marini F. C. (2009). Direct evidence of mesenchymal stem cell tropism for tumor and wounding microenvironments using in vivo bioluminescent

role of mesenchymal stromal cells in cancer: be it friend or foe. *Cytotherapy,* Vol.10,

Yang Y. S.; Oh W. & Chang J. W. (2011). CXC chemokine receptor 1 enhances the ability of human umbilical cord blood-derived mesenchymal stem cells to migrate

discrepancy in the literature: do mesenchymal stem cells support or suppress

Lewis M. T.; Reuben J. M.; Krishnamurthy S.; Ferrari M.; Gaspar R.; Buchholz T. A.; Cristofanilli M.; Marini F.; Andreeff M. & Woodward W. A. (2010). Mesenchymal stem cells promote mammosphere formation and decrease E-cadherin in normal

D.; Andreeff M. & Marini F. C. (2007). Tumor irradiation increases the recruitment of circulating mesenchymal stem cells into the tumor microenvironment. *Cancer* 

marrow mesenchymal stem cells inhibit the response of naive and memory antigen-specific T cells to their cognate peptide. *Blood,* Vol.101, No.9, pp. 3722-3729.

Altanerova V. & Altaner C. (2008). Cytosine deaminase expressing human mesenchymal stem cells mediated tumour regression in melanoma bearing mice. *J* 

K.; Ito Y.; Kato K.; Honmou O.; Houkin K.; Date I. & Hamada H. (2004). BDNF gene-modified mesenchymal stem cells promote functional recovery and reduce infarct size in the rat middle cerebral artery occlusion model. *Mol Ther,* Vol.9, No.2,

Multipotent stromal cells from human marrow home to and promote repair of pancreatic islets and renal glomeruli in diabetic NOD/scid mice. *Proc Natl Acad Sci* 


Involvement of Mesenchymal Stem Cells in Breast Cancer Progression 267

Monneret G. (2009). Mesenchymal stem cells: another anti-inflammatory treatment for

Motaln H.; Schichor C. & Lah T. T. (2010). Human mesenchymal stem cells and their use in

Mueller M. M. & Fusenig N. E. (2004). Friends or foes - bipolar effects of the tumour stroma

Natsu K.; Ochi M.; Mochizuki Y.; Hachisuka H.; Yanada S. & Yasunaga Y. (2004). Allogeneic

Noth U.; Osyczka A. M.; Tuli R.; Hickok N. J.; Danielson K. G. & Tuan R. S. (2002).

Olumi A. F.; Grossfeld G. D.; Hayward S. W.; Carroll P. R.; Tlsty T. D. & Cunha G. R. (1999).

Omatsu Y.; Sugiyama T.; Kohara H.; Kondoh G.; Fujii N.; Kohno K. & Nagasawa T. (2010).

Onder T. T.; Gupta P. B.; Mani S. A.; Yang J.; Lander E. S. & Weinberg R. A. (2008). Loss of

Orimo A.; Gupta P. B.; Sgroi D. C.; Arenzana-Seisdedos F.; Delaunay T.; Naeem R.; Carey V.

Ortiz L. A.; Gambelli F.; McBride C.; Gaupp D.; Baddoo M.; Kaminski N. & Phinney D. G.

Pantel K.; Alix-Panabieres C. & Riethdorf S. (2009). Cancer micrometastases. *Nat Rev Clin* 

Parekkadan B.; van Poll D.; Suganuma K.; Carter E. A.; Berthiaume F.; Tilles A. W. &

Park K. S.; Jung K. H.; Kim S. H.; Kim K. S.; Choi M. R.; Kim Y. & Chai Y. G. (2007).

Patel S. A.; Heinrich A. C.; Reddy B. Y.; Srinivas B.; Heidaran N. & Rameshwar P. (2008).

Patel S. A.; Meyer J. R.; Greco S. J.; Corcoran K. E.; Bryan M. & Rameshwar P. (2010).

elevated SDF-1/CXCL12 secretion. *Cell,* Vol.121, No.3, pp. 335-348.

bone marrow-derived mesenchymal stromal cells promote the regeneration of injured skeletal muscle without differentiation into myofibers. *Tissue Eng,* Vol.10,

Multilineage mesenchymal differentiation potential of human trabecular bone-

Carcinoma-associated fibroblasts direct tumor progression of initiated human

The essential functions of adipo-osteogenic progenitors as the hematopoietic stem

E-cadherin promotes metastasis via multiple downstream transcriptional

J.; Richardson A. L. & Weinberg R. A. (2005). Stromal fibroblasts present in invasive human breast carcinomas promote tumor growth and angiogenesis through

(2003). Mesenchymal stem cell engraftment in lung is enhanced in response to bleomycin exposure and ameliorates its fibrotic effects. *Proc Natl Acad Sci U S A,* 

Yarmush M. L. (2007). Mesenchymal stem cell-derived molecules reverse fulminant

Functional expression of ion channels in mesenchymal stem cells derived from

Breast cancer biology: the multifaceted roles of mesenchymal stem cells. *J Oncol,* 

Mesenchymal stem cells protect breast cancer cells through regulatory T cells: role of mesenchymal stem cell-derived TGF-beta. *J Immunol,* Vol.184, No.10, pp. 5885-

cell-based therapies. *Cancer,* Vol.116, No.11, pp. 2519-2530.

in cancer. *Nat Rev Cancer,* Vol.4, No.11, pp. 839-849.

derived cells. *J Orthop Res,* Vol.20, No.5, pp. 1060-1069.

pathways. *Cancer Res,* Vol.68, No.10, pp. 3645-3654.

hepatic failure. *PLoS One,* Vol.2, No.9, pp. e941.

umbilical cord vein. *Stem Cells,* Vol.25, No.8, pp. 2044-2052.

Vol.100, No.14, pp. 8407-8411.

*Oncol,* Vol.6, No.6, pp. 339-351.

Vol.2008, pp. 425895.

5894.

prostatic epithelium. *Cancer Res,* Vol.59, No.19, pp. 5002-5011.

and progenitor cell niche. *Immunity.,* Vol.33, No.3, pp. 387-399.

sepsis? *Nat Med,* Vol.15, No.6, pp. 601-602.

No.7-8, pp. 1093-1112.


Marchini C.; Montani M.; Konstantinidou G.; Orru R.; Mannucci S.; Ramadori G.; Gabrielli

Martin F. T.; Dwyer R. M.; Kelly J.; Khan S.; Murphy J. M.; Curran C.; Miller N.; Hennessy

May C. D.; Sphyris N.; Evans K. W.; Werden S. J.; Guo W. & Mani S. A. (2011). Epithelial-

Medici D.; Shore E. M.; Lounev V. Y.; Kaplan F. S.; Kalluri R. & Olsen B. R. (2010).

Mei S. H.; Haitsma J. J.; Dos Santos C. C.; Deng Y.; Lai P. F.; Slutsky A. S.; Liles W. C. &

Mendez-Ferrer S.; Michurina T. V.; Ferraro F.; Mazloom A. R.; Macarthur B. D.; Lira S. A.;

Menon L. G.; Kelly K.; Yang H. W.; Kim S. K.; Black P. M. & Carroll R. S. (2009). Human

Menon L. G.; Picinich S.; Koneru R.; Gao H.; Lin S. Y.; Koneru M.; Mayer-Kuckuk P.; Glod J.

Mi Z.; Bhattacharya S. D.; Kim V.; Guo H.; Talbot L. J. & Kuo P. C. (2011). Osteopontin

Mishra P. J. & Banerjee D. (2011). Activation and differentiation of mesenchymal stem cells.

Mishra P. J.; Humeniuk R.; Medina D. J.; Alexe G.; Mesirov J. P.; Ganesan S.; Glod J. W. &

Mohseny A. B. & Hogendoorn P. C. (2011). Concise review: mesenchymal tumors: when

Molloy A. P.; Martin F. T.; Dwyer R. M.; Griffin T. P.; Murphy M.; Barry F. P.; O'Brien T. &

mesenchymal stem cells. *Cancer Res,* Vol.68, No.11, pp. 4331-4339.

with breast cancer cells. *Int J Cancer,* Vol.124, No.2, pp. 326-332.

stem cells go mad. *Stem Cells,* Vol.29, No.3, pp. 397-403.

breast cancer progression. *Breast Cancer Res,* Vol.13, No.1, pp. 202.

resistance to therapies. *PLoS One,* Vol.5, No.11, pp. e14131.

Vol.124, No.2, pp. 317-326.

Vol.16, No.12, pp. 1400-1406.

Vol.182, No.8, pp. 1047-1057.

cells. *Stem Cells,* Vol.25, No.2, pp. 520-528.

*Carcinogenesis*, Vol.32, No.4, pp. 477-487.

*Methods Mol Biol,* Vol.717, pp. 245-253.

No.7308, pp. 829-834.

F.; Baruzzi A.; Berton G.; Merigo F.; Fin S.; Iezzi M.; Bisaro B.; Sbarbati A.; Zerani M.; Galie M. & Amici A. (2010). Mesenchymal/stromal gene expression signature relates to basal-like breast cancers, identifies bone metastasis and predicts

E.; Dockery P.; Barry F. P.; O'Brien T. & Kerin M. J. (2010). Potential role of mesenchymal stem cells (MSCs) in the breast tumour microenvironment: stimulation of epithelial to mesenchymal transition (EMT). *Breast Cancer Res Treat,* 

mesenchymal transition and cancer stem cells: a dangerously dynamic duo in

Conversion of vascular endothelial cells into multipotent stem-like cells. *Nat Med,* 

Stewart D. J. (2010). Mesenchymal stem cells reduce inflammation while enhancing bacterial clearance and improving survival in sepsis. *Am J Respir Crit Care Med,* 

Scadden D. T.; Ma'ayan A.; Enikolopov G. N. & Frenette P. S. (2010). Mesenchymal and haematopoietic stem cells form a unique bone marrow niche. *Nature,* Vol.466,

bone marrow-derived mesenchymal stromal cells expressing S-TRAIL as a cellular delivery vehicle for human glioma therapy. *Stem Cells,* Vol.27, No.9, pp. 2320-2330.

& Banerjee D. (2007). Differential gene expression associated with migration of mesenchymal stem cells to conditioned medium from tumor cells or bone marrow

Promotes CCL5-Mesenchymal Stromal Cell Mediated Breast Cancer Metastasis.

Banerjee D. (2008). Carcinoma-associated fibroblast-like differentiation of human

Kerin M. J. (2009). Mesenchymal stem cell secretion of chemokines during differentiation into osteoblasts, and their potential role in mediating interactions


Involvement of Mesenchymal Stem Cells in Breast Cancer Progression 269

Rhodes L. V.; Antoon J. W.; Muir S. E.; Elliott S.; Beckman B. S. & Burow M. E. (2010). Effects

mediated through ER-SDF-1/CXCR4 crosstalk. *Mol Cancer,* Vol.9, pp. 295. Rhodes L. V.; Muir S. E.; Elliott S.; Guillot L. M.; Antoon J. W.; Penfornis P.; Tilghman S. L.;

Riggi N.; Suva M. L.; Suva D.; Cironi L.; Provero P.; Tercier S.; Joseph J. M.; Stehle J. C.;

Ritter E.; Perry A.; Yu J.; Wang T.; Tang L. & Bieberich E. (2008). Breast cancer cell-derived

Rojas M.; Xu J.; Woods C. R.; Mora A. L.; Spears W.; Roman J. & Brigham K. L. (2005). Bone

Romieu-Mourez R.; Francois M.; Abate A.; Boivin M. N.; Birman E.; Bailey D.; Bramson J. L.;

Rosland G. V.; Svendsen A.; Torsvik A.; Sobala E.; McCormack E.; Immervoll H.; Mysliwietz

Ryniers F.; Stove C.; Goethals M.; Brackenier L.; Noe V.; Bracke M.; Vandekerckhove J.;

Sanchez C.; Penfornis P.; Oskowitz A. Z.; Boonjindasup A. G.; Cai D. Z.; Dhule S.; Rowan B.

Sasser A. K.; Mundy B. L.; Smith K. M.; Studebaker A. W.; Axel A. E.; Haidet A. M.;

3D tumor environments. *Cancer Lett,* Vol.254, No.2, pp. 255-264.

stimulates cancer cell invasion. *Biol Chem,* Vol.383, No.1, pp. 159-165. Sacchetti B.; Funari A.; Michienzi S.; Di Cesare S.; Piersanti S.; Saggio I.; Tagliafico E.; Ferrari

*Res Treat,* Vol.121, No.2, pp. 293-300.

*Cancer Res,* Vol.68, No.7, pp. 2176-2185.

*Cell Mol Biol,* Vol.33, No.2, pp. 145-152.

priming. *Cancer Res,* Vol.70, No.20, pp. 7742-7747.

310-314.

No.13, pp. 5331-5339.

Vol.131, No.2, pp. 324-336.

Vol.32, No.7, pp. 964-972.

of human mesenchymal stem cells on ER-positive human breast carcinoma cells

Salvo V. A.; Fonseca J. P.; Lacey M. R.; Beckman B. S.; McLachlan J. A.; Rowan B. G.; Pochampally R. & Burow M. E. (2009). Adult human mesenchymal stem cells enhance breast tumorigenesis and promote hormone independence. *Breast Cancer* 

Baumer K.; Kindler V. & Stamenkovic I. (2008). EWS-FLI-1 expression triggers a Ewing's sarcoma initiation program in primary human mesenchymal stem cells.

fibroblast growth factor 2 and vascular endothelial growth factor are chemoattractants for bone marrow stromal stem cells. *Ann Surg,* Vol.247, No.2, pp.

marrow-derived mesenchymal stem cells in repair of the injured lung. *Am J Respir* 

Forner K.; Young Y. K.; Medin J. A. & Galipeau J. (2010). Mesenchymal stromal cells expressing ErbB-2/neu elicit protective antibreast tumor immunity in vivo, which is paradoxically suppressed by IFN-gamma and tumor necrosis factor-alpha

J.; Tonn J. C.; Goldbrunner R.; Lonning P. E.; Bjerkvig R. & Schichor C. (2009). Long-term cultures of bone marrow-derived human mesenchymal stem cells frequently undergo spontaneous malignant transformation. *Cancer Res,* Vol.69,

Mareel M. & Bruyneel E. (2002). Plasmin produces an E-cadherin fragment that

S.; Robey P. G.; Riminucci M. & Bianco P. (2007). Self-renewing osteoprogenitors in bone marrow sinusoids can organize a hematopoietic microenvironment. *Cell,* 

G.; Kelekar A.; Krause D. S. & Pochampally R. R. (2011). Activation of Autophagy in Mesenchymal Stem Cells Provides Tumor Stromal Support. *Carcinogenesis*,

Fernandez S. A. & Hall B. M. (2007a). Human bone marrow stromal cells enhance breast cancer cell growth rates in a cell line-dependent manner when evaluated in


Patki S.; Kadam S.; Chandra V. & Bhonde R. (2010). Human breast milk is a rich source of multipotent mesenchymal stem cells. *Hum Cell,* Vol.23, No.2, pp. 35-40. Phinney D. G. (2002). Building a consensus regarding the nature and origin of mesenchymal

Pinzone J. J.; Hall B. M.; Thudi N. K.; Vonau M.; Qiang Y. W.; Rosol T. J. & Shaughnessy J.

Pittenger M. F.; Mackay A. M.; Beck S. C.; Jaiswal R. K.; Douglas R.; Mosca J. D.; Moorman

Prockop D. J. & Olson S. D. (2007). Clinical trials with adult stem/progenitor cells for tissue

Pulukuri S. M.; Gorantla B.; Dasari V. R.; Gondi C. S. & Rao J. S. (2010). Epigenetic

Qiao L.; Xu Z. L.; Zhao T. J.; Ye L. H. & Zhang X. D. (2008a). Dkk-1 secreted by

Qiao L.; Zhao T. J.; Wang F. Z.; Shan C. L.; Ye L. H. & Zhang X. D. (2008b). NF-kappaB

Raffaghello L.; Bianchi G.; Bertolotto M.; Montecucco F.; Busca A.; Dallegri F.; Ottonello L. &

Ramasamy R.; Fazekasova H.; Lam E. W.; Soeiro I.; Lombardi G. & Dazzi F. (2007).

preventing entry into the cell cycle. *Transplantation,* Vol.83, No.1, pp. 71-76. Rasmusson I. (2006). Immune modulation by mesenchymal stem cells. *Exp Cell Res,* Vol.312,

Rasmusson I.; Ringden O.; Sundberg B. & Le Blanc K. (2003). Mesenchymal stem cells inhibit

Rattigan Y.; Hsu J. M.; Mishra P. J.; Glod J. & Banerjee D. (2010). Interleukin 6 mediated

D., Jr. (2009). The role of Dickkopf-1 in bone development, homeostasis, and

M. A.; Simonetti D. W.; Craig S. & Marshak D. R. (1999). Multilineage potential of adult human mesenchymal stem cells. *Science,* Vol.284, No.5411, pp. 143-147. Ponte A. L.; Marais E.; Gallay N.; Langonne A.; Delorme B.; Herault O.; Charbord P. &

Domenech J. (2007). The in vitro migration capacity of human bone marrow mesenchymal stem cells: comparison of chemokine and growth factor chemotactic

repair: let's not overlook some essential precautions. *Blood,* Vol.109, No.8, pp. 3147-

upregulation of urokinase plasminogen activator promotes the tropism of mesenchymal stem cells for tumor cells. *Mol Cancer Res,* Vol.8, No.8, pp. 1074-1083.

mesenchymal stem cells inhibits growth of breast cancer cells via depression of Wnt

downregulation may be involved the depression of tumor cell proliferation mediated by human mesenchymal stem cells. *Acta Pharmacol Sin,* Vol.29, No.3, pp.

Pistoia V. (2008). Human mesenchymal stem cells inhibit neutrophil apoptosis: a model for neutrophil preservation in the bone marrow niche. *Stem Cells,* Vol.26,

Mesenchymal stem cells inhibit dendritic cell differentiation and function by

the formation of cytotoxic T lymphocytes, but not activated cytotoxic T lymphocytes or natural killer cells. *Transplantation,* Vol.76, No.8, pp. 1208-1213. Rasmusson I.; Ringden O.; Sundberg B. & Le Blanc K. (2005). Mesenchymal stem cells inhibit

lymphocyte proliferation by mitogens and alloantigens by different mechanisms.

recruitment of mesenchymal stem cells to the hypoxic tumor milieu. *Exp Cell Res,* 

stem cells. *J Cell Biochem Suppl,* Vol.38, pp. 7-12.

activities. *Stem Cells,* Vol.25, No.7, pp. 1737-1745.

signalling. *Cancer Lett,* Vol.269, No.1, pp. 67-77.

3151.

333-340.

No.1, pp. 151-162.

No.12, pp. 2169-2179.

*Exp Cell Res,* Vol.305, No.1, pp. 33-41.

Vol.316, No.20, pp. 3417-3424.

disease. *Blood,* Vol.113, No.3, pp. 517-525.


Involvement of Mesenchymal Stem Cells in Breast Cancer Progression 271

Sun B.; Yu K. R.; Bhandari D. R.; Jung J. W.; Kang S. K. & Kang K. S. (2010). Human

Theillet C. (2010). What do we learn from HER2-positive breast cancer genomic profiles?

Tlsty T. D. & Coussens L. M. (2006). Tumor stroma and regulation of cancer development.

Tocci A. & Forte L. (2003). Mesenchymal stem cell: use and perspectives. *Hematol J,* Vol.4,

Toma C.; Pittenger M. F.; Cahill K. S.; Byrne B. J. & Kessler P. D. (2002). Human

Tondreau T.; Lagneaux L.; Dejeneffe M.; Massy M.; Mortier C.; Delforge A. & Bron D. (2004).

proteins before any differentiation. *Differentiation,* Vol.72, No.7, pp. 319-326. Uccelli A.; Moretta L. & Pistoia V. (2008). Mesenchymal stem cells in health and disease. *Nat* 

Visvader J. E. & Lindeman G. J. (2008). Cancer stem cells in solid tumours: accumulating evidence and unresolved questions. *Nat Rev Cancer,* Vol.8, No.10, pp. 755-768. Walczak H.; Miller R. E.; Ariail K.; Gliniak B.; Griffith T. S.; Kubin M.; Chin W.; Jones J.;

apoptosis-inducing ligand in vivo. *Nat Med,* Vol.5, No.2, pp. 157-163. Wang J. S.; Shum-Tim D.; Chedrawy E. & Chiu R. C. (2001). The coronary delivery of

mesenchymal stem cells differentiate to a cardiomyocyte phenotype in the adult

Bone marrow-derived mesenchymal stem cells already express specific neural

Woodward A.; Le T.; Smith C.; Smolak P.; Goodwin R. G.; Rauch C. T.; Schuh J. C. & Lynch D. H. (1999). Tumoricidal activity of tumor necrosis factor-related

marrow stromal cells for myocardial regeneration: pathophysiologic and therapeutic implications. *J Thorac Cardiovasc Surg.,* Vol.122, No.4, pp. 699-705. Wang L.; Li Y.; Chen J.; Gautam S. C.; Zhang Z.; Lu M. & Chopp M. (2002). Ischemic cerebral

tissue and MCP-1 enhance rat bone marrow stromal cell migration in interface

Adult bone marrow is a rich source of human mesenchymal 'stem' cells but umbilical cord and mobilized adult blood are not. *Br J Haematol,* Vol.121, No.2, pp.

K. M. (2010). Breast cancer dormancy can be maintained by small numbers of

Plasticity of cultured mesenchymal stem cells: switch from nestin-positive to

intrahepatic injection of bone-derived GFP-murine mesenchymal stem cells infected with the recombinant retrovirus-carrying human insulin gene. *World J* 

Wexler S. A.; Donaldson C.; Denning-Kendall P.; Rice C.; Bradley B. & Hows J. M. (2003).

Willis L.; Alarcon T.; Elia G.; Jones J. L.; Wright N. A.; Tomlinson I. P.; Graham T. A. & Page

Wislet-Gendebien S.; Hans G.; Leprince P.; Rigo J. M.; Moonen G. & Rogister B. (2005).

excitable neuron-like phenotype. *Stem Cells,* Vol.23, No.3, pp. 392-402. Xu J.; Lu Y.; Ding F.; Zhan X.; Zhu M. & Wang Z. (2007). Reversal of diabetes in mice by

178-185.

368-374.

No.2, pp. 92-96.

*Breast,* Vol.12, No.3, pp. 107.

*Annu Rev Pathol,* Vol.1, pp. 119-150.

*Rev Immunol,* Vol.8, No.9, pp. 726-736.

culture. *Exp Hematol,* Vol.30, No.7, pp. 831-836.

*Surg,* Vol.31, No.9, pp. 1872-1882.

micrometastases. *Cancer Res,* Vol.70, No.11, pp. 4310-4307.

murine heart. *Circulation,* Vol.105, No.1, pp. 93-98.

umbilical cord blood mesenchymal stem cell-derived extracellular matrix prohibits metastatic cancer cell MDA-MB-231 proliferation. *Cancer Lett,* Vol.296, No.2, pp.


Sasser A. K.; Sullivan N. J.; Studebaker A. W.; Hendey L. F.; Axel A. E. & Hall B. M. (2007b).

Schor S. L.; Schor A. M. & Rushton G. (1988). Fibroblasts from cancer patients display a

Seeberger K. L.; Dufour J. M.; Shapiro A. M.; Lakey J. R.; Rajotte R. V. & Korbutt G. S. (2006).

Selmani Z.; Naji A.; Zidi I.; Favier B.; Gaiffe E.; Obert L.; Borg C.; Saas P.; Tiberghien P.;

Shin S. Y.; Nam J. S.; Lim Y. & Lee Y. H. (2010). TNFalpha-exposed bone marrow-derived

Sonabend A. M.; Ulasov I. V.; Tyler M. A.; Rivera A. A.; Mathis J. M. & Lesniak M. S. (2008).

Sotiropoulou P. A.; Perez S. A.; Gritzapis A. D.; Baxevanis C. N. & Papamichail M. (2006).

Spaeth E. L.; Dembinski J. L.; Sasser A. K.; Watson K.; Klopp A.; Hall B.; Andreeff M. &

Spaggiari G. M.; Capobianco A.; Abdelrazik H.; Becchetti F.; Mingari M. C. & Moretta L.

Stoff-Khalili M. A.; Rivera A. A.; Mathis J. M.; Banerjee N. S.; Moon A. S.; Hess A.; Rocconi

Studeny M.; Marini F. C.; Dembinski J. L.; Zompetta C.; Cabreira-Hansen M.; Bekele B. N.;

Sun B.; Roh K. H.; Park J. R.; Lee S. R.; Park S. B.; Jung J. W.; Kang S. K.; Lee Y. S. & Kang K.

carcinoma. *Breast Cancer Res Treat,* Vol.105, No.2, pp. 157-167.

cancer metastasis model. *Cytotherapy,* Vol.11, No.3, pp. 289-298.

*Faseb J,* Vol.21, No.13, pp. 3763-3770.

*Lab Invest,* Vol.86, No.2, pp. 141-153.

Vol.285, No.40, pp. 30731-30740.

*Cells,* Vol.24, No.1, pp. 74-85.

Vol.4, No.4, pp. e4992.

glioma. *Stem Cells,* Vol.26, No.3, pp. 831-841.

E2. *Blood,* Vol.111, No.3, pp. 1327-1333.

*Inst,* Vol.96, No.21, pp. 1593-1603.

regulatory T cells. *Stem Cells,* Vol.26, No.1, pp. 212-222.

No.Pt 3, pp. 401-407.

Interleukin-6 is a potent growth factor for ER-alpha-positive human breast cancer.

mixture of both foetal and adult-like phenotypic characteristics. *J Cell Sci,* Vol.90,

Expansion of mesenchymal stem cells from human pancreatic ductal epithelium.

Rouas-Freiss N.; Carosella E. D. & Deschaseaux F. (2008). Human leukocyte antigen-G5 secretion by human mesenchymal stem cells is required to suppress T lymphocyte and natural killer function and to induce CD4+CD25highFOXP3+

mesenchymal stem cells promote locomotion of MDA-MB-231 breast cancer cells through transcriptional activation of CXCR3 ligand chemokines. *J Biol Chem,* 

Mesenchymal stem cells effectively deliver an oncolytic adenovirus to intracranial

Interactions between human mesenchymal stem cells and natural killer cells. *Stem* 

Marini F. (2009). Mesenchymal stem cell transition to tumor-associated fibroblasts contributes to fibrovascular network expansion and tumor progression. *PLoS One,* 

(2008). Mesenchymal stem cells inhibit natural killer-cell proliferation, cytotoxicity, and cytokine production: role of indoleamine 2,3-dioxygenase and prostaglandin

R. P.; Numnum T. M.; Everts M.; Chow L. T.; Douglas J. T.; Siegal G. P.; Zhu Z. B.; Bender H. G.; Dall P.; Stoff A.; Pereboeva L. & Curiel D. T. (2007). Mesenchymal stem cells as a vehicle for targeted delivery of CRAds to lung metastases of breast

Champlin R. E. & Andreeff M. (2004). Mesenchymal stem cells: potential precursors for tumor stroma and targeted-delivery vehicles for anticancer agents. *J Natl Cancer* 

S. (2009). Therapeutic potential of mesenchymal stromal cells in a mouse breast


**13** 

**Breast Cancer Stem Cells** 

*Sun Yat-Sen University, Guangzhou* 

*People's Republic of China* 

Fengyan Yu, Qiang Liu, Yujie Liu, Jieqiong Liu and Erwei Song *Department of Breast Tumor Center, Sun Yat-Sen Memorial Hospital* 

Over 150 years ago, Cohnheim and Durante formalized the concept that cancers might arise from a small subset of cells with stem cell properties 1-3, and in 1961, Till and McCulloch demonstrated for the first time that the existence of hematopoietic stem cells (HSC) in the bone marrow, which was postulated that stem-like cells might be the origin of cancer 4. However, only recently did an increased interest in cancer stem cells (CSC) occur, thus spurring great advances in cancer stem cell biology. The CSC model was first developed in 1994 when malignant initiating cells were discerned in human acute myeloid leukemia (AML) 5. Afterwards, similar CSC model was extended to some solid tumors that originated in the breast, brain, lung, prostate, colon, head and neck, and pancreas 6-12. Most importantly, the development of CSC hypothesis has fundamental implications in terms of understanding the biology of muti-step tumorigenesis, the prevention of cancer, and the

It is well documented that tumors contain cancer cells with heterogeneous phenotypes reflecting aspects of their apparent state of differentiation. In a tumor, the mutable expression of normal differentiation markers by cancer cells implies that some of the heterogeneity arises as a result of this altered manifestation. Also, cancer is known to be the product of the accumulation of multiple genetic mutations and epigenetic alterations in a single target cell, the occurrences of which can sometimes take place over many decades. Furthermore, chemotherapy and radiation therapy for cancers have limited effectiveness in long-term scenarios, and the possible recurrence of tumors after years of disease-free survival exists in great majority of cancers. All these observations provide persuasive evidence that tumors are not mere monoclonal expansions of cells but might contain a subset of long-lived tumor-initiating cells with the ability to self-renew indefinitely and to regenerate the phenotypic diversity of original tumor 13. This subpopulation is now widely termed as cancer stem cells (CSCs), also named tumor-initiating cells (T-IC). The exist of CSCs within a tumor was also supported by *in vitro* ''clonogenic assays'' that showed subpopulations of tumor cells (with increased proliferative capacity) using cells isolated from tumor specimens, as well as by *in vivo* self-renewal assays that indicated only a small specific subset of cancer cell population had tumorigenic potential when injected into

creation of novel effective strategies for cancer therapy.

**1.1 The definition of cancer stem cells** 

immunodeficient mice 13, 14.

**1. Introduction** 

