Breast cancer stem cells are regulated by mesenchymal stem cells through cytokine networks.

We have used in vitro and mouse xenograft models to examine the interaction between breast cancer stem cells (CSC) and bone marrow-derived mesenchymal stem cells (MSC). We show that both of these cell populations are organized in a cellular hierarchy in which primitive aldehyde dehydrogenase expressing mesenchymal cells regulate breast CSCs through cytokine loops involving IL6 and CXCL7. In NOD/SCID mice, labeled MSCs introduced into the tibia traffic to sites of growing breast tumor xenografts where they accelerated tumor growth by increasing the breast CSC population. With immunochemistry, we identified MSC-CSC niches in these tumor xenografts as well as in frozen sections from primary human breast cancers. Bone marrow-derived MSCs may accelerate human breast tumor growth by generating cytokine networks that regulate the CSC population.

[1]  D. Birnbaum,et al.  CXCR1 blockade selectively targets human breast cancer stem cells in vitro and in xenografts. , 2010, The Journal of clinical investigation.

[2]  A. Kate Sasser,et al.  Mesenchymal Stem Cell Transition to Tumor-Associated Fibroblasts Contributes to Fibrovascular Network Expansion and Tumor Progression , 2009, PloS one.

[3]  M. Endres,et al.  Gene expression profile of adult human bone marrow-derived mesenchymal stem cells stimulated by the chemokine CXCL7. , 2009, The international journal of biochemistry & cell biology.

[4]  F. Bertucci,et al.  Breast cancer cell lines contain functional cancer stem cells with metastatic capacity and a distinct molecular signature. , 2009, Cancer research.

[5]  M. Karin,et al.  IL-6 and Stat3 are required for survival of intestinal epithelial cells and development of colitis-associated cancer. , 2009, Cancer cell.

[6]  C. Shao,et al.  Human mesenchymal stem cells inhibit cancer cell proliferation by secreting DKK-1 , 2009, Leukemia.

[7]  G. Tromp,et al.  Increased invasion through basement membrane by CXCL7-transfected breast cells. , 2008, American journal of surgery.

[8]  A. Uccelli,et al.  Mesenchymal stem cells in health and disease , 2008, Nature Reviews Immunology.

[9]  Anna E. Lokshin,et al.  Drug-Selected Human Lung Cancer Stem Cells: Cytokine Network, Tumorigenic and Metastatic Properties , 2008, PloS one.

[10]  Max S Wicha,et al.  Implications of the cancer stem-cell hypothesis for breast cancer prevention and therapy. , 2008, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[11]  S. Merajver,et al.  BRCA1 regulates human mammary stem/progenitor cell fate , 2008, Proceedings of the National Academy of Sciences.

[12]  D. Santini,et al.  IL-6 triggers malignant features in mammospheres from human ductal breast carcinoma and normal mammary gland. , 2007, The Journal of clinical investigation.

[13]  Utpal Banerjee,et al.  The hematopoietic stem cell and its niche: a comparative view. , 2007, Genes & development.

[14]  Daniel Birnbaum,et al.  ALDH1 is a marker of normal and malignant human mammary stem cells and a predictor of poor clinical outcome. , 2007, Cell stem cell.

[15]  Ross Tubo,et al.  Mesenchymal stem cells within tumour stroma promote breast cancer metastasis , 2007, Nature.

[16]  R. Vessella,et al.  The role of tumor microenvironment in prostate cancer bone metastasis , 2007, Journal of cellular biochemistry.

[17]  M. Sporn,et al.  The tumour microenvironment as a target for chemoprevention , 2007, Nature Reviews Cancer.

[18]  Wen-Lin Kuo,et al.  A collection of breast cancer cell lines for the study of functionally distinct cancer subtypes. , 2006, Cancer cell.

[19]  Harikrishna Nakshatri,et al.  CD44+/CD24- breast cancer cells exhibit enhanced invasive properties: an early step necessary for metastasis , 2006, Breast Cancer Research.

[20]  G. Dontu,et al.  Hedgehog signaling and Bmi-1 regulate self-renewal of normal and malignant human mammary stem cells. , 2006, Cancer research.

[21]  D. Prockop,et al.  A Crosstalk Between Myeloma Cells and Marrow Stromal Cells Stimulates Production of DKK1 and Interleukin‐6: A Potential Role in the Development of Lytic Bone Disease and Tumor Progression in Multiple Myeloma , 2006, Stem cells.

[22]  Mamoru Ito,et al.  Reconstitution of the functional human hematopoietic microenvironment derived from human mesenchymal stem cells in the murine bone marrow compartment. , 2006, Blood.

[23]  H. Clevers,et al.  Wnt signalling in stem cells and cancer , 2005, Nature.

[24]  G. Dontu,et al.  Mammary stem cells, self-renewal pathways, and carcinogenesis , 2005, Breast Cancer Research.

[25]  G. Dontu,et al.  Role of Notch signaling in cell-fate determination of human mammary stem/progenitor cells , 2004, Breast Cancer Research.

[26]  Stefano Landi,et al.  Association of common polymorphisms in inflammatory genes interleukin (IL)6, IL8, tumor necrosis factor alpha, NFKB1, and peroxisome proliferator-activated receptor gamma with colorectal cancer. , 2003, Cancer research.

[27]  Rafael A Irizarry,et al.  Exploration, normalization, and summaries of high density oligonucleotide array probe level data. , 2003, Biostatistics.

[28]  S. Morrison,et al.  Prospective identification of tumorigenic breast cancer cells , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[29]  P. Fu,et al.  Expansion of LTC‐ICs and Maintenance of p21 and BCL‐2 Expression in Cord Blood CD34+/CD38− Early Progenitors Cultured over Human MSCs as a Feeder Layer , 2002, Stem cells.

[30]  S. Ikehara,et al.  Intra-bone marrow injection of allogeneic bone marrow cells: a powerful new strategy for treatment of intractable autoimmune diseases in MRL/lpr mice. , 2001, Blood.

[31]  A. Spradling,et al.  A niche maintaining germ line stem cells in the Drosophila ovary. , 2000, Science.

[32]  A I Caplan,et al.  Cytokine expression by human marrow‐derived mesenchymal progenitor cells in vitro: Effects of dexamethasone and IL‐1α , 1996, Journal of cellular physiology.

[33]  J. Soulier,et al.  Phenotypic and functional characterization of bone marrow mesenchymal stem cells derived from patients with multiple myeloma , 2007, Leukemia.