Mesenchymal stem cells within tumour stroma promote breast cancer metastasis

Mesenchymal stem cells have been recently described to localize to breast carcinomas, where they integrate into the tumour-associated stroma. However, the involvement of mesenchymal stem cells (or their derivatives) in tumour pathophysiology has not been addressed. Here, we demonstrate that bone-marrow-derived human mesenchymal stem cells, when mixed with otherwise weakly metastatic human breast carcinoma cells, cause the cancer cells to increase their metastatic potency greatly when this cell mixture is introduced into a subcutaneous site and allowed to form a tumour xenograft. The breast cancer cells stimulate de novo secretion of the chemokine CCL5 (also called RANTES) from mesenchymal stem cells, which then acts in a paracrine fashion on the cancer cells to enhance their motility, invasion and metastasis. This enhanced metastatic ability is reversible and is dependent on CCL5 signalling through the chemokine receptor CCR5. Collectively, these data demonstrate that the tumour microenvironment facilitates metastatic spread by eliciting reversible changes in the phenotype of cancer cells.

[1]  H. Tsuda,et al.  Antitumor effect of genetically engineered mesenchymal stem cells in a rat glioma model , 2004, Gene Therapy.

[2]  M. Raffeld,et al.  Human mesenchymal stem cells exert potent antitumorigenic effects in a model of Kaposi's sarcoma , 2006, The Journal of experimental medicine.

[3]  D. Baltimore,et al.  Inhibiting HIV-1 infection in human T cells by lentiviral-mediated delivery of small interfering RNA against CCR5 , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[4]  D. Prockop,et al.  Non-hematopoietic bone marrow stem cells: molecular control of expansion and differentiation. , 2005, Experimental cell research.

[5]  D. Banerjee,et al.  Differential Gene Expression Associated with Migration of Mesenchymal Stem Cells to Conditioned Medium from Tumor Cells or Bone Marrow Cells , 2007, Stem cells.

[6]  A. Toker,et al.  Akt signaling and cancer: surviving but not moving on. , 2006, Cancer research.

[7]  Giselle Chamberlain,et al.  Recent advances into the understanding of mesenchymal stem cell trafficking , 2007, British journal of haematology.

[8]  F. Balkwill,et al.  A chemokine receptor antagonist inhibits experimental breast tumor growth. , 2003, Cancer research.

[9]  T. Steele,et al.  Human reserve pluripotent mesenchymal stem cells are present in the connective tissues of skeletal muscle and dermis derived from fetal, adult, and geriatric donors , 2001, The Anatomical record.

[10]  Manuel A. González,et al.  A role for chemokine receptor transactivation in growth factor signaling , 2001, EMBO reports.

[11]  R. Weinberg,et al.  Chemokine networks and breast cancer metastasis. , 2006, Breast disease.

[12]  W. Hahn,et al.  Human breast cancer cells generated by oncogenic transformation of primary mammary epithelial cells. , 2001, Genes & development.

[13]  J. Thiery.  Epithelial–mesenchymal transitions in tumour progression , 2002, Nature Reviews Cancer.

[14]  Rameen Beroukhim,et al.  Molecular characterization of the tumor microenvironment in breast cancer. , 2004, Cancer cell.

[15]  Anandan Palani,et al.  Discovery and development of small-molecule chemokine coreceptor CCR5 antagonists. , 2006, Journal of medicinal chemistry.

[16]  M. Andreeff,et al.  The participation of mesenchymal stem cells in tumor stroma formation and their application as targeted-gene delivery vehicles. , 2007, Handbook of experimental pharmacology.

[17]  Robert A. Weinberg,et al.  Creation of human tumour cells with defined genetic elements , 1999, Nature.

[18]  M. Andreeff,et al.  Bone marrow-derived mesenchymal stem cells as vehicles for interferon-beta delivery into tumors. , 2002, Cancer research.

[19]  F. Balkwill.  Cancer and the chemokine network , 2004, Nature Reviews Cancer.

[20]  R. Weinberg,et al.  Reconstruction of functionally normal and malignant human breast tissues in mice. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[21]  S. Hung,et al.  Mesenchymal Stem Cell Targeting of Microscopic Tumors and Tumor Stroma Development Monitored by Noninvasive In vivo Positron Emission Tomography Imaging , 2005, Clinical Cancer Research.

[22]  L. Shihabuddin,et al.  Systematic analysis of reportedly distinct populations of multipotent bone marrow-derived stem cells reveals a lack of distinction. , 2002, Tissue engineering.

[23]  Mina J. Bissell,et al.  Putting tumours in context , 2001, Nature Reviews Cancer.

[24]  Dennis C. Sgroi,et al.  Stromal Fibroblasts Present in Invasive Human Breast Carcinomas Promote Tumor Growth and Angiogenesis through Elevated SDF-1/CXCL12 Secretion , 2005, Cell.

[25]  Shridar Ganesan,et al.  X chromosomal abnormalities in basal-like human breast cancer. , 2006, Cancer cell.

[26]  M. Pittenger,et al.  Multilineage potential of adult human mesenchymal stem cells. , 1999, Science.

[27]  M. Miyasaka,et al.  Chemokines in tumor progression and metastasis , 2005, Cancer science.

[28]  D. Male,et al.  Expression of chemokines on the surface of different human endothelia , 2005, Immunology and cell biology.

[29]  John B. Shoven,et al.  I , Edinburgh Medical and Surgical Journal.

[30]  C. Duplàa,et al.  Clonogenic analysis reveals reserve stem cells in postnatal mammals: I. Pluripotent mesenchymal stem cells , 2001, The Anatomical record.

[31]  A. Ben-Baruch,et al.  Elevated expression of the CC chemokine regulated on activation, normal T cell expressed and secreted (RANTES) in advanced breast carcinoma. , 1999, Cancer research.

[32]  M. Weil,et al.  The CC chemokine RANTES in breast carcinoma progression: regulation of expression and potential mechanisms of promalignant activity. , 2002, Cancer research.

[33]  D. Curiel,et al.  Mesenchymal progenitor cells as cellular vehicles for delivery of oncolytic adenoviruses , 2006, Molecular Cancer Therapeutics.

[34]  M. Andreeff,et al.  Human bone marrow-derived mesenchymal stem cells in the treatment of gliomas. , 2005, Cancer research.

[35]  Tina Hernandez-Boussard,et al.  Determination of Stromal Signatures in Breast Carcinoma , 2005, PLoS biology.

[36]  Y. Ozaki,et al.  Correlation of tissue and plasma RANTES levels with disease course in patients with breast or cervical cancer. , 2001, Clinical cancer research : an official journal of the American Association for Cancer Research.

[37]  M J Bissell,et al.  The influence of the microenvironment on the malignant phenotype. , 2000, Molecular medicine today.