Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review
  • Published:

Cancer stem cells and tumor-associated macrophages: a roadmap for multitargeting strategies

Oncogene volume 35, pages 671–682 (2016)Cite this article

Subjects

Abstract

The idea that tumor initiation and progression are driven by a subset of cells endowed with stem-like properties was first described by Rudolf Virchow in 1855. ‘Cancer stem cells’, as they were termed more than a century later, represent a subset of tumor cells that are able to generate all tumorigenic and nontumorigenic cell types within the malignancy. Although their existence was hypothesized >150 years ago, it was only recently that stem-like cells started to be isolated from different neoplastic malignancies. Interestingly, Virchow, in suggesting a correlation between cancer and the inflammatory microenvironment, also paved the way for the ‘Seed and Soil’ theory proposed by Paget a few years later. Despite the time that has passed since these two important concepts were suggested, the relationships between Virchow’s ‘stem-like cells’ and Paget’s ‘soil’ are far from being fully understood. One emerging topic is the importance of a stem-like niche in modulating the biological properties of stem-like cancer cells and thus in affecting the response of the tumor to drugs. This review aims to summarize the recent molecular data concerning the multilayered relationship between cancer stem cells and tumor-associated macrophages that form a key component of the tumor microenvironment. We also discuss the therapeutic implications of targeting this synergistic interplay.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2

Similar content being viewed by others

Abbreviations

c-Myc:

avian myelocytomatosis virus oncogene cellular homolog

CCL-2:

chemokine C-C motif ligand 2

CSC:

cancer stem cell

CSF-1:

colony-stimulating factor 1

EMT:

epithelial-to-mesenchymal transition

M-CSF:

macrophage colony-stimulating factor

NF-κB:

nuclear factor-κB

SOX2:

sex-determining region-Y-related high-mobility group box 2

TAM:

tumor-associated macrophage

Wnt:

wingless-type MMTV integration site family member

References

  1. Fidler IJ, Hart IR . Biological diversity in metastatic neoplasms: origins and implications. Science 1982; 217: 998–1003.

    CAS  PubMed  Google Scholar 

  2. Heppner GH, Miller BE . Tumor heterogeneity: biological implications and therapeutic consequences. Cancer Metastasis Rev 1983; 2: 5–23.

    CAS  PubMed  Google Scholar 

  3. Kreso A, Dick JE . Evolution of the cancer stem cell model. Cell Stem Cell 2014; 14: 275–291.

    CAS  PubMed  Google Scholar 

  4. Morrison SJ, Kimble J . Asymmetric and symmetric stem-cell divisions in development and cancer. Nature 2006; 441: 1068–1074.

    CAS  PubMed  Google Scholar 

  5. Clarke MF, Dick JE, Dirks PB, Eaves CJ, Jamieson CH, Jones DL et al. Cancer stem cells—perspectives on current status and future directions: AACR Workshop on cancer stem cells. Cancer Res 2006; 66: 9339–9344.

    Article  CAS  PubMed  Google Scholar 

  6. Beachy PA, Karhadkar SS, Berman DM . Tissue repair and stem cell renewal in carcinogenesis. Nature 2004; 432: 324–331.

    CAS  PubMed  Google Scholar 

  7. Virchow R . An address on the value of pathological experiments. Br Med J 1881; 2: 198–203.

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Rais Y, Zviran A, Geula S, Gafni O, Chomsky E, Viukov S et al. Deterministic direct reprogramming of somatic cells to pluripotency. Nature 2013; 502: 65–70.

    CAS  PubMed  Google Scholar 

  9. Chaffer CL, Brueckmann I, Scheel C, Kaestli AJ, Wiggins PA, Rodrigues LO et al. Normal and neoplastic nonstem cells can spontaneously convert to a stem-like state. Proc Natl Acad Sci USA 2011; 108: 7950–7955.

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Takahashi K, Yamanaka S . Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 2006; 126: 663–676.

    CAS  PubMed  Google Scholar 

  11. Schoenhals M, Kassambara A, De Vos J, Hose D, Moreaux J, Klein B . Embryonic stem cell markers expression in cancers. Biochem Biophys Res Commun 2009; 383: 157–162.

    CAS  PubMed  Google Scholar 

  12. Jeter CR, Badeaux M, Choy G, Chandra D, Patrawala L, Liu C et al. Functional evidence that the self-renewal gene NANOG regulates human tumor development. Stem Cells. 2009; 27: 993–1005.

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Segal E, Friedman N, Koller D, Regev A . A module map showing conditional activity of expression modules in cancer. Nat Genet 2004; 36: 1090–1098.

    CAS  PubMed  Google Scholar 

  14. Wong DJ, Liu H, Ridky TW, Cassarino D, Segal E, Chang HY . Module map of stem cell genes guides creation of epithelial cancer stem cells. Cell Stem Cell 2008; 2: 333–344.

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Ben-Porath I, Thomson MW, Carey VJ, Ge R, Bell GW, Regev A et al. An embryonic stem cell-like gene expression signature in poorly differentiated aggressive human tumors. Nat Genet 2008; 40: 499–507.

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Wellner U, Schubert J, Burk UC, Schmalhofer O, Zhu F, Sonntag A et al. The EMT-activator ZEB1 promotes tumorigenicity by repressing stemness-inhibiting microRNAs. Nat Cell Biol 2009; 11: 1487–1495.

    CAS  PubMed  Google Scholar 

  17. Kong D, Banerjee S, Ahmad A, Li Y, Wang Z, Sethi S et al. Epithelial to mesenchymal transition is mechanistically linked with stem cell signatures in prostate cancer cells. PLoS One 2010; 5: e12445.

    PubMed  PubMed Central  Google Scholar 

  18. Morel AP, Lievre M, Thomas C, Hinkal G, Ansieau S, Puisieux A . Generation of breast cancer stem cells through epithelial-mesenchymal transition. PLoS One 2008; 3: e2888.

    PubMed  PubMed Central  Google Scholar 

  19. Mani SA, Guo W, Liao MJ, Eaton EN, Ayyanan A, Zhou AY et al. The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell 2008; 133: 704–715.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Ahmed N, Maines-Bandiera S, Quinn MA, Unger WG, Dedhar S, Auersperg N . Molecular pathways regulating EGF-induced epithelio-mesenchymal transition in human ovarian surface epithelium. Am J Physiol Cell Physiol 2006; 290: C1532–C1542.

    CAS  PubMed  Google Scholar 

  21. Lim J, Thiery JP . Epithelial-mesenchymal transitions: insights from development. Development 2012; 139: 3471–3486.

    CAS  PubMed  Google Scholar 

  22. Borovski T, De Sousa EMF, Vermeulen L, Medema JP . Cancer stem cell niche: the place to be. Cancer Res 2011; 71: 634–639.

    CAS  PubMed  Google Scholar 

  23. Shigdar S, Lin J, Li Y, Yang CJ, Wei M, Zhus Y et al. Cancer stem cell targeting: the next generation of cancer therapy and molecular imaging. Ther Deliv 2012; 3: 227–244.

    CAS  PubMed  Google Scholar 

  24. LaBarge MA . The difficulty of targeting cancer stem cell niches. Clin Cancer Res 2010; 16: 3121–3129.

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Hollier BG, Evans K, Mani SA . The epithelial-to-mesenchymal transition and cancer stem cells: a coalition against cancer therapies. J Mammary Gland Biol Neoplasia 2009; 14: 29–43.

    PubMed  Google Scholar 

  26. Biddle A, Mackenzie IC . Cancer stem cells and EMT in carcinoma. Cancer Metastasis Rev 2012; 31: 285–293.

    Google Scholar 

  27. Bromberg J . Stat proteins and oncogenesis. J Clin Invest 2002; 109: 1139–1142.

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Zushi S, Shinomura Y, Kiyohara T, Miyazaki Y, Kondo S, Sugimachi M et al. STAT3 mediates the survival signal in oncogenic ras-transfected intestinal epithelial cells. Int J Cancer 1998; 78: 326–330.

    CAS  PubMed  Google Scholar 

  29. Sikora A, Grzesiuk E . Heat shock response in gastrointestinal tract. J Physiol Pharmacol 2007; 58: 43–62.

    PubMed  Google Scholar 

  30. Niu G, Wright KL, Huang M, Song L, Haura E, Turkson J et al. Constitutive Stat3 activity up-regulates VEGF expression and tumor angiogenesis. Oncogene 2002; 21: 2000–2008.

    Article  CAS  PubMed  Google Scholar 

  31. Pawlus MR, Wang L, Murakami A, Dai G, Hu CJ . STAT3 or USF2 contributes to HIF target gene specificity. PLoS One 2013; 8: e72358.

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Zhou B, Damrauer JS, Bailey ST, Hadzic T, Jeong Y, Clark K et al. Erythropoietin promotes breast tumorigenesis through tumor-initiating cell self-renewal. J Clin Invest 2014; 124: 553–563.

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Cook AM, Li L, Ho Y, Lin A, Stein A, Forman S et al. Role of altered growth factor receptor-mediated JAK2 signaling in growth and maintenance of human acute myeloid leukemia stem cells. Blood 2014; 123: 2826–2837.

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Sherry MM, Reeves A, Wu JK, Cochran BH . STAT3 is required for proliferation and maintenance of multipotency in glioblastoma stem cells. Stem Cells 2009; 27: 2383–2392.

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Liu RY, Zeng Y, Lei Z, Wang L, Yang H, Liu Z et al. JAK/STAT3 signaling is required for TGF-beta-induced epithelial-mesenchymal transition in lung cancer cells. Int J Oncol 2014; 44: 1643–1651.

    CAS  PubMed  Google Scholar 

  36. Rokavec M, Oner MG, Li H, Jackstadt R, Jiang L, Lodygin D et al. IL-6R/STAT3/miR-34a feedback loop promotes EMT-mediated colorectal cancer invasion and metastasis. J Clin Invest 2014; 124: 1853–1867.

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Nusse R, van Ooyen A, Cox D, Fung YK, Varmus H . Mode of proviral activation of a putative mammary oncogene (int-1) on mouse chromosome 15. Nature 1984; 307: 131–136.

    CAS  PubMed  Google Scholar 

  38. Bienz M . beta-Catenin: a pivot between cell adhesion and Wnt signalling. Curr Biol 2005; 15: R64–R67.

    CAS  PubMed  Google Scholar 

  39. Brembeck FH, Schwarz-Romond T, Bakkers J, Wilhelm S, Hammerschmidt M, Birchmeier W . Essential role of BCL9-2 in the switch between beta-catenin's adhesive and transcriptional functions. Genes Dev 2004; 18: 2225–2230.

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Artavanis-Tsakonas S, Rand MD, Lake RJ . Notch signaling: cell fate control and signal integration in development. Science 1999; 284: 770–776.

    CAS  PubMed  Google Scholar 

  41. Farnie G, Clarke RB . Mammary stem cells and breast cancer—role of Notch signalling. Stem Cell Rev 2007; 3: 169–175.

    CAS  PubMed  Google Scholar 

  42. Abel EV, Kim EJ, Wu J, Hynes M, Bednar F, Proctor E et al. The Notch pathway is important in maintaining the cancer stem cell population in pancreatic cancer. PLoS One 2014; 9: e91983.

    PubMed  PubMed Central  Google Scholar 

  43. Abbas T, Dutta A . p21 in cancer: intricate networks and multiple activities. Nat Rev Cancer 2009; 9: 400–414.

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Hassan KA, Wang L, Korkaya H, Chen G, Maillard I, Beer DG et al. Notch pathway activity identifies cells with cancer stem cell-like properties and correlates with worse survival in lung adenocarcinoma. Clin Cancer Res 2013; 19: 1972–1980.

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Ninov N, Borius M, Stainier DY . Different levels of Notch signaling regulate quiescence, renewal and differentiation in pancreatic endocrine progenitors. Development 2012; 139: 1557–1567.

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Thayer SP, di Magliano MP, Heiser PW, Nielsen CM, Roberts DJ, Lauwers GY et al. Hedgehog is an early and late mediator of pancreatic cancer tumorigenesis. Nature 2003; 425: 851–856.

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Liao X, Siu MK, Au CW, Wong ES, Chan HY, Ip PP et al. Aberrant activation of hedgehog signaling pathway in ovarian cancers: effect on prognosis, cell invasion and differentiation. Carcinogenesis 2009; 30: 131–140.

    CAS  PubMed  Google Scholar 

  48. Zhao C, Chen A, Jamieson CH, Fereshteh M, Abrahamsson A, Blum J et al. Hedgehog signalling is essential for maintenance of cancer stem cells in myeloid leukaemia. Nature 2009; 458: 776–779.

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Feldmann G, Dhara S, Fendrich V, Bedja D, Beaty R, Mullendore M et al. Blockade of hedgehog signaling inhibits pancreatic cancer invasion and metastases: a new paradigm for combination therapy in solid cancers. Cancer Res 2007; 67: 2187–2196.

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Song Z, Yue W, Wei B, Wang N, Li T, Guan L et al. Sonic hedgehog pathway is essential for maintenance of cancer stem-like cells in human gastric cancer. PLoS One 2011; 6: e17687.

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Abe Y, Oda-Sato E, Tobiume K, Kawauchi K, Taya Y, Okamoto K et al. Hedgehog signaling overrides p53-mediated tumor suppression by activating Mdm2. Proc Natl Acad Sci USA 2008; 105: 4838–4843.

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Li SH, Fu J, Watkins DN, Srivastava RK, Shankar S . Sulforaphane regulates self-renewal of pancreatic cancer stem cells through the modulation of Sonic hedgehog-GLI pathway. Mol Cell Biochemi 2013; 373: 217–227.

    CAS  Google Scholar 

  53. Lu H, Ouyang W, Huang C . Inflammation, a key event in cancer development. Mol Cancer Res 2006; 4: 221–233.

    PubMed  Google Scholar 

  54. Hirsch HA, Iliopoulos D, Struhl K . Metformin inhibits the inflammatory response associated with cellular transformation and cancer stem cell growth. Proc Natl Acad Sci USA. 2013; 110: 972–977.

    CAS  PubMed  Google Scholar 

  55. Normanno N, De Luca A, Bianco C, Strizzi L, Mancino M, Maiello MR et al. Epidermal growth factor receptor (EGFR) signaling in cancer. Gene 2006; 366: 2–16.

    CAS  PubMed  Google Scholar 

  56. Normanno N, Bianco C, De Luca A, Salomon DS . The role of EGF-related peptides in tumor growth. Front Biosci 2001; 6: D685–D707.

    CAS  PubMed  Google Scholar 

  57. Salomon DS, Brandt R, Ciardiello F, Normanno N . Epidermal growth factor-related peptides and their receptors in human malignancies. Crit Rev Oncol Hematol 1995; 19: 183–232.

    CAS  PubMed  Google Scholar 

  58. Salomon DS, Kim N, Saeki T, Ciardiello F . Transforming growth factor-alpha: an oncodevelopmental growth factor. Cancer Cells 1990; 2: 389–397.

    CAS  PubMed  Google Scholar 

  59. Marmor MD, Yarden Y . Role of protein ubiquitylation in regulating endocytosis of receptor tyrosine kinases. Oncogene 2004; 23: 2057–2070.

    CAS  PubMed  Google Scholar 

  60. Jorissen RN, Walker F, Pouliot N, Garrett TP, Ward CW, Burgess AW . Epidermal growth factor receptor: mechanisms of activation and signalling. Exp Cell Res 2003; 284: 31–53.

    CAS  PubMed  Google Scholar 

  61. Arasada RR, Amann JM, Rahman MA, Huppert SS, Carbone DP . EGFR blockade enriches for lung cancer stem-like cells through Notch3-dependent signaling. Cancer Res 2014; 74: 5572–5584.

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Junttila MR, de Sauvage FJ . Influence of tumour micro-environment heterogeneity on therapeutic response. Nature 2013; 501: 346–354.

    CAS  PubMed  Google Scholar 

  63. Grivennikov SI, Greten FR, Karin M . Immunity, inflammation, and cancer. Cell 2010; 140: 883–899.

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Korkaya H, Liu S, Wicha MS . Breast cancer stem cells, cytokine networks, and the tumor microenvironment. J Clin Invest 2011; 121: 3804–3809.

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Raggi C, Invernizzi P, Andersen JB . Impact of microenvironment and stem-like plasticity in cholangiocarcinoma: molecular networks and biological concepts. J Hepatol 2015; 62: 198–207.

    CAS  PubMed  Google Scholar 

  66. Moore KA, Lemischka IR . Stem cells and their niches. Science 2006; 311: 1880–1885.

    CAS  PubMed  Google Scholar 

  67. Margol A, Robison N, Gnanachandran J, Hung LT, Kennedy R, Vali M et al. Tumor associated macrophages in SHH subgroup of medulloblastomas. Clin Cancer Res 2014; 21: 1457–1465.

    PubMed  PubMed Central  Google Scholar 

  68. Noy R, Pollard JW . Tumor-associated macrophages: from mechanisms to therapy. Immunity 2014; 41: 49–61.

    CAS  PubMed  PubMed Central  Google Scholar 

  69. Mantovani A . The yin-yang of tumor-associated neutrophils. Cancer Cell 2009; 16: 173–174.

    CAS  PubMed  Google Scholar 

  70. Mantovani A, Allavena P, Sica A . Tumour-associated macrophages as a prototypic type II polarised phagocyte population: role in tumour progression. Eur J Cancer 2004; 40: 1660–1667.

    CAS  PubMed  Google Scholar 

  71. Mantovani A, Allavena P, Sica A, Balkwill F . Cancer-related inflammation. Nature 2008; 454: 436–444.

    CAS  PubMed  Google Scholar 

  72. Mantovani A, Biswas SK, Galdiero MR, Sica A, Locati M . Macrophage plasticity and polarization in tissue repair and remodelling. J Pathol 2013; 229: 176–185.

    CAS  PubMed  Google Scholar 

  73. Coussens LM, Zitvogel L, Palucka AK . Neutralizing tumor-promoting chronic inflammation: a magic bullet? Science 2013; 339: 286–291.

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Wilson E, Leszczynska K, Poulter NS, Edelmann F, Salisbury VA, Noy PJ et al. RhoJ interacts with the GIT-PIX complex and regulates focal adhesion disassembly. J Cell Sci 2014; 127: 3039–3051.

    CAS  PubMed  PubMed Central  Google Scholar 

  75. Movahedi K, Laoui D, Gysemans C, Baeten M, Stange G, Van den Bossche J et al. Different tumor microenvironments contain functionally distinct subsets of macrophages derived from Ly6C(high) monocytes. Cancer Res 2010; 70: 5728–5739.

    CAS  PubMed  Google Scholar 

  76. Lewis CE, Pollard JW . Distinct role of macrophages in different tumor microenvironments. Cancer Res 2006; 66: 605–612.

    CAS  PubMed  Google Scholar 

  77. Biswas SK, Allavena P, Mantovani A . Tumor-associated macrophages: functional diversity, clinical significance, and open questions. Semin Immunopathol 2013; 35: 585–600.

    CAS  PubMed  Google Scholar 

  78. Richards DM, Hettinger J, Feuerer M . Monocytes and macrophages in cancer: development and functions. Cancer Microenviron 2013; 6: 179–191.

    CAS  PubMed  Google Scholar 

  79. Galdiero MR, Bonavita E, Barajon I, Garlanda C, Mantovani A, Jaillon S . Tumor associated macrophages and neutrophils in cancer. Immunobiology 2013; 218: 1402–1410.

    CAS  PubMed  Google Scholar 

  80. Laoui D, Van Overmeire E, Di Conza G, Aldeni C, Keirsse J, Morias Y et al. Tumor hypoxia does not drive differentiation of tumor-associated macrophages but rather fine-tunes the M2-like macrophage population. Cancer Res 2014; 74: 24–30.

    CAS  PubMed  Google Scholar 

  81. Allavena P, Sica A, Solinas G, Porta C, Mantovani A . The inflammatory micro-environment in tumor progression: the role of tumor-associated macrophages. Crit Rev Oncol Hematol 2008; 66: 1–9.

    PubMed  Google Scholar 

  82. Siveen KS, Kuttan G . Role of macrophages in tumour progression. Immunol Lett 2009; 123: 97–102.

    CAS  PubMed  Google Scholar 

  83. Eljaszewicz A, Wiese M, Helmin-Basa A, Jankowski M, Gackowska L, Kubiszewska I et al. Collaborating with the enemy: function of macrophages in the development of neoplastic disease. Mediators Inflamm 2013; 2013: 831387.

    PubMed  PubMed Central  Google Scholar 

  84. Riether C, Schurch CM, Ochsenbein AF . Regulation of hematopoietic and leukemic stem cells by the immune system. Cell Death Differ 2014; 22: 187–198.

    PubMed  PubMed Central  Google Scholar 

  85. Pollard JW . Trophic macrophages in development and disease. Nat Rev Immunol 2009; 9: 259–270.

    CAS  PubMed  PubMed Central  Google Scholar 

  86. Gyorki DE, Asselin-Labat ML, van Rooijen N, Lindeman GJ, Visvader JE . Resident macrophages influence stem cell activity in the mammary gland. Breast Cancer Res 2009; 11: R62.

    PubMed  PubMed Central  Google Scholar 

  87. London A, Itskovich E, Benhar I, Kalchenko V, Mack M, Jung S et al. Neuroprotection and progenitor cell renewal in the injured adult murine retina requires healing monocyte-derived macrophages. J Exp Med 2011; 208: 23–39.

    CAS  PubMed  PubMed Central  Google Scholar 

  88. Kim J, Hematti P . Mesenchymal stem cell-educated macrophages: a novel type of alternatively activated macrophages. Exp Hemat 2009; 37: 1445–1453.

    CAS  PubMed  Google Scholar 

  89. Asimakopoulos F, Kim J, Denu RA, Hope C, Jensen JL, Ollar SJ et al. Macrophages in multiple myeloma: emerging concepts and therapeutic implications. Leuk Lymphoma 2013; 54: 2112–2121.

    PubMed  PubMed Central  Google Scholar 

  90. Bonnet D, Dick JE . Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nat Med 1997; 3: 730–737.

    CAS  PubMed  Google Scholar 

  91. Lapidot T, Sirard C, Vormoor J, Murdoch B, Hoang T, Caceres-Cortes J et al. A cell initiating human acute myeloid leukaemia after transplantation into SCID mice. Nature 1994; 367: 645–648.

    CAS  PubMed  Google Scholar 

  92. Bradstock KF, Gottlieb DJ . Interaction of acute leukemia cells with the bone marrow microenvironment: implications for control of minimal residual disease. Leuk Lymph 1995; 18: 1–16.

    CAS  Google Scholar 

  93. Ishikawa F, Yoshida S, Saito Y, Hijikata A, Kitamura H, Tanaka S et al. Chemotherapy-resistant human AML stem cells home to and engraft within the bone-marrow endosteal region. Nat Biotechnol 2007; 25: 1315–1321.

    CAS  PubMed  Google Scholar 

  94. Bhatia R, McGlave PB, Dewald GW, Blazar BR, Verfaillie CM . Abnormal function of the bone marrow microenvironment in chronic myelogenous leukemia: role of malignant stromal macrophages. Blood 1995; 85: 3636–3645.

    CAS  PubMed  Google Scholar 

  95. Winkler IG, Sims NA, Pettit AR, Barbier V, Nowlan B, Helwani F et al. Bone marrow macrophages maintain hematopoietic stem cell (HSC) niches and their depletion mobilizes HSCs. Blood 2010; 116: 4815–4828.

    CAS  PubMed  Google Scholar 

  96. Chow A, Lucas D, Hidalgo A, Mendez-Ferrer S, Hashimoto D, Scheiermann C et al. Bone marrow CD169+ macrophages promote the retention of hematopoietic stem and progenitor cells in the mesenchymal stem cell niche. J Exp Med 2011; 208: 261–271.

    CAS  PubMed  PubMed Central  Google Scholar 

  97. Chow A, Huggins M, Ahmed J, Hashimoto D, Lucas D, Kunisaki Y et al. CD169(+) macrophages provide a niche promoting erythropoiesis under homeostasis and stress. Nat Med 2013; 19: 429–436.

    CAS  PubMed  PubMed Central  Google Scholar 

  98. Ludin A, Itkin T, Gur-Cohen S, Mildner A, Shezen E, Golan K et al. Monocytes-macrophages that express alpha-smooth muscle actin preserve primitive hematopoietic cells in the bone marrow. Nat Immunol 2012; 13: 1072–1082.

    CAS  PubMed  Google Scholar 

  99. Jin L, Hope KJ, Zhai Q, Smadja-Joffe F, Dick JE . Targeting of CD44 eradicates human acute myeloid leukemic stem cells. Nat Med 2006; 12: 1167–1174.

    PubMed  Google Scholar 

  100. Tavor S, Petit I, Porozov S, Avigdor A, Dar A, Leider-Trejo L et al. CXCR4 regulates migration and development of human acute myelogenous leukemia stem cells in transplanted NOD/SCID mice. Cancer Res 2004; 64: 2817–2824.

    CAS  PubMed  Google Scholar 

  101. Jaiswal S, Jamieson CH, Pang WW, Park CY, Chao MP, Majeti R et al. CD47 is upregulated on circulating hematopoietic stem cells and leukemia cells to avoid phagocytosis. Cell 2009; 138: 271–285.

    CAS  PubMed  PubMed Central  Google Scholar 

  102. Majeti R, Chao MP, Alizadeh AA, Pang WW, Jaiswal S, Gibbs Jr KD et al. CD47 is an adverse prognostic factor and therapeutic antibody target on human acute myeloid leukemia stem cells. Cell 2009; 138: 286–299.

    CAS  PubMed  PubMed Central  Google Scholar 

  103. Theocharides AP, Jin L, Cheng PY, Prasolava TK, Malko AV, Ho JM et al. Disruption of SIRPalpha signaling in macrophages eliminates human acute myeloid leukemia stem cells in xenografts. J Exp Med 2012; 209: 1883–1899.

    CAS  PubMed  PubMed Central  Google Scholar 

  104. Tseng D, Volkmer JP, Willingham SB, Contreras-Trujillo H, Fathman JW, Fernhoff NB et al. Anti-CD47 antibody-mediated phagocytosis of cancer by macrophages primes an effective antitumor T-cell response. Proc Natl Acad Sci USA. 2013; 110: 11103–11108.

    CAS  PubMed  PubMed Central  Google Scholar 

  105. Liu DQ, Li LM, Guo YL, Bai R, Wang C, Bian Z et al. Signal regulatory protein alpha negatively regulates beta2 integrin-mediated monocyte adhesion, transendothelial migration and phagocytosis. PLoS One 2008; 3: e3291.

    PubMed  PubMed Central  Google Scholar 

  106. van Beek EM, Cochrane F, Barclay AN, van den Berg TK . Signal regulatory proteins in the immune system. J Immunol 2005; 175: 7781–7787.

    CAS  PubMed  Google Scholar 

  107. Smith RE, Patel V, Seatter SD, Deehan MR, Brown MH, Brooke GP et al. A novel MyD-1 (SIRP-1alpha) signaling pathway that inhibits LPS-induced TNFalpha production by monocytes. Blood 2003; 102: 2532–2540.

    CAS  PubMed  Google Scholar 

  108. Zhao XW, van Beek EM, Schornagel K, Van der Maaden H, Van Houdt M, Otten MA et al. CD47-signal regulatory protein-alpha (SIRPalpha) interactions form a barrier for antibody-mediated tumor cell destruction. Proc Natl Acad Sci USA 2011; 108: 18342–18347.

    CAS  PubMed  PubMed Central  Google Scholar 

  109. Kaur S, Soto-Pantoja DR, Stein EV, Liu C, Elkahloun AG, Pendrak ML et al. Thrombospondin-1 signaling through CD47 inhibits self-renewal by regulating c-Myc and other stem cell transcription factors. Sci Rep 2013; 3: 1673.

    PubMed  PubMed Central  Google Scholar 

  110. Nie Z, Hu G, Wei G, Cui K, Yamane A, Resch W et al. c-Myc is a universal amplifier of expressed genes in lymphocytes and embryonic stem cells. Cell 2012; 151: 68–79.

    CAS  PubMed  PubMed Central  Google Scholar 

  111. Zhang Y, Sime W, Juhas M, Sjolander A . Crosstalk between colon cancer cells and macrophages via inflammatory mediators and CD47 promotes tumour cell migration. Eur J Cancer 2013; 49: 3320–3334.

    CAS  PubMed  Google Scholar 

  112. Monney L, Sabatos CA, Gaglia JL, Ryu A, Waldner H, Chernova T et al. Th1-specific cell surface protein Tim-3 regulates macrophage activation and severity of an autoimmune disease. Nature 2002; 415: 536–541.

    CAS  PubMed  Google Scholar 

  113. Zhang Y, Ma CJ, Wang JM, Ji XJ, Wu XY, Jia ZS et al. Tim-3 negatively regulates IL-12 expression by monocytes in HCV infection. PLoS One 2011; 6: e19664.

    CAS  PubMed  PubMed Central  Google Scholar 

  114. Kryczek I, Zou L, Rodriguez P, Zhu G, Wei S, Mottram P et al. B7-H4 expression identifies a novel suppressive macrophage population in human ovarian carcinoma. J Exp Med 2006; 203: 871–881.

    CAS  PubMed  PubMed Central  Google Scholar 

  115. Jan M, Chao MP, Cha AC, Alizadeh AA, Gentles AJ, Weissman IL et al. Prospective separation of normal and leukemic stem cells based on differential expression of TIM3, a human acute myeloid leukemia stem cell marker. Proc Natl Acad Sci USA 2011; 108: 5009–5014.

    CAS  PubMed  PubMed Central  Google Scholar 

  116. Kikushige Y, Shima T, Takayanagi S, Urata S, Miyamoto T, Iwasaki H et al. TIM-3 is a promising target to selectively kill acute myeloid leukemia stem cells. Cell Stem Cell 2010; 7: 708–717.

    CAS  PubMed  Google Scholar 

  117. Gao L, Yu S, Zhang X . Hypothesis: Tim-3/Galectin-9, a new pathway for leukemia stem cells survival by promoting expansion of myeloid-derived suppressor cells and differentiating into tumor-associated macrophages. Cell Biochem Biophys 2014; 70: 273–277.

    CAS  PubMed  Google Scholar 

  118. Fourcade J, Sun Z, Benallaoua M, Guillaume P, Luescher IF, Sander C et al. Upregulation of Tim-3 and PD-1 expression is associated with tumor antigen-specific CD8+ T cell dysfunction in melanoma patients. J Exp Med 2010; 207: 2175–2186.

    CAS  PubMed  PubMed Central  Google Scholar 

  119. Gao X, Zhu Y, Li G, Huang H, Zhang G, Wang F et al. TIM-3 expression characterizes regulatory T cells in tumor tissues and is associated with lung cancer progression. PLoS One 2012; 7: e30676.

    CAS  PubMed  PubMed Central  Google Scholar 

  120. Wu J, Liu C, Qian S, Hou H . The expression of Tim-3 in peripheral blood of ovarian cancer. DNA Cell Biol 2013; 32: 648–653.

    CAS  PubMed  Google Scholar 

  121. Shang Y, Li Z, Li H, Xia H, Lin Z . TIM-3 expression in human osteosarcoma: correlation with the expression of epithelial-mesenchymal transition-specific biomarkers. Oncol Lett 2013; 6: 490–494.

    PubMed  PubMed Central  Google Scholar 

  122. Ngiow SF, von Scheidt B, Akiba H, Yagita H, Teng MW, Smyth MJ . Anti-TIM3 antibody promotes T cell IFN-gamma-mediated antitumor immunity and suppresses established tumors. Cancer Res 2011; 71: 3540–3551.

    CAS  PubMed  Google Scholar 

  123. Ezekowitz RA . Local opsonization for apoptosis? Nat Immunol 2002; 3: 510–512.

    CAS  PubMed  Google Scholar 

  124. Hanayama R, Tanaka M, Miwa K, Shinohara A, Iwamatsu A, Nagata S . Identification of a factor that links apoptotic cells to phagocytes. Nature 2002; 417: 182–187.

    CAS  PubMed  Google Scholar 

  125. Jinushi M, Chiba S, Yoshiyama H, Masutomi K, Kinoshita I, Dosaka-Akita H et al. Tumor-associated macrophages regulate tumorigenicity and anticancer drug responses of cancer stem/initiating cells. Proc Natl Acad Sci USA 2011; 108: 12425–12430.

    CAS  PubMed  PubMed Central  Google Scholar 

  126. Brissette MJ, Lepage S, Lamonde AS, Sirois I, Groleau J, Laurin LP et al. MFG-E8 released by apoptotic endothelial cells triggers anti-inflammatory macrophage reprogramming. PLoS One 2012; 7: e36368.

    CAS  PubMed  PubMed Central  Google Scholar 

  127. Segall JE, Tyerech S, Boselli L, Masseling S, Helft J, Chan A et al. EGF stimulates lamellipod extension in metastatic mammary adenocarcinoma cells by an actin-dependent mechanism. Clin Exp Metastasis 1996; 14: 61–72.

    CAS  PubMed  Google Scholar 

  128. Lu Z, Ghosh S, Wang Z, Hunter T . Downregulation of caveolin-1 function by EGF leads to the loss of E-cadherin, increased transcriptional activity of beta-catenin, and enhanced tumor cell invasion. Cancer Cell 2003; 4: 499–515.

    CAS  PubMed  Google Scholar 

  129. O'Sullivan C, Lewis CE, Harris AL, McGee JO . Secretion of epidermal growth factor by macrophages associated with breast carcinoma. Lancet 1993; 342: 148–149.

    CAS  PubMed  Google Scholar 

  130. Peoples GE, Blotnick S, Takahashi K, Freeman MR, Klagsbrun M, Eberlein TJ . T lymphocytes that infiltrate tumors and atherosclerotic plaques produce heparin-binding epidermal growth factor-like growth factor and basic fibroblast growth factor: a potential pathologic role. Proc Natl Acad Sci USA 1995; 92: 6547–6551.

    CAS  PubMed  PubMed Central  Google Scholar 

  131. Goswami S, Sahai E, Wyckoff JB, Cammer M, Cox D, Pixley FJ et al. Macrophages promote the invasion of breast carcinoma cells via a colony-stimulating factor-1/epidermal growth factor paracrine loop. Cancer Res 2005; 65: 5278–5283.

    CAS  PubMed  Google Scholar 

  132. Sapi E, Kacinski BM . The role of CSF-1 in normal and neoplastic breast physiology. Proc Soc Exp Biol Med 1999; 220: 1–8.

    CAS  PubMed  Google Scholar 

  133. Yang J, Liao D, Chen C, Liu Y, Chuang TH, Xiang R et al. Tumor-associated macrophages regulate murine breast cancer stem cells through a novel paracrine EGFR/Stat3/Sox-2 signaling pathway. Stem Cells 2013; 31: 248–258.

    CAS  PubMed  Google Scholar 

  134. Lu H, Clauser KR, Tam WL, Frose J, Ye X, Eaton EN et al. A breast cancer stem cell niche supported by juxtacrine signalling from monocytes and macrophages. Nat Cell Biol 2014; 16: 1105–1117.

    CAS  PubMed  PubMed Central  Google Scholar 

  135. Mitchem JB, Brennan DJ, Knolhoff BL, Belt BA, Zhu Y, Sanford DE et al. Targeting tumor-infiltrating macrophages decreases tumor-initiating cells, relieves immunosuppression, and improves chemotherapeutic responses. Cancer Res 2013; 73: 1128–1141.

    CAS  PubMed  Google Scholar 

  136. Weizman N, Krelin Y, Shabtay-Orbach A, Amit M, Binenbaum Y, Wong RJ et al. Macrophages mediate gemcitabine resistance of pancreatic adenocarcinoma by upregulating cytidine deaminase. Oncogene 2013; 33: 3812–3819.

    PubMed  Google Scholar 

  137. Zhou W, Ke SQ, Huang Z, Flavahan W, Fang X, Paul J et al. Periostin secreted by glioblastoma stem cells recruits M2 tumour-associated macrophages and promotes malignant growth. Nat Cell Biol 2015; 17: 170–182.

    CAS  PubMed  PubMed Central  Google Scholar 

  138. Wan S, Zhao E, Kryczek I, Vatan L, Sadovskaya A, Ludema G et al. Tumor-associated macrophages produce interleukin 6 and signal via STAT3 to promote expansion of human hepatocellular carcinoma stem cells. Gastroenterology 2014; 147: 1393–1404.

    CAS  PubMed  Google Scholar 

  139. Sica A, Mantovani A . Macrophage plasticity and polarization: in vivo veritas. J Clin Invest 2012; 122: 787–795.

    CAS  PubMed  PubMed Central  Google Scholar 

  140. He KF, Zhang L, Huang CF, Ma SR, Wang YF, Wang WM et al. CD163+ tumor-associated macrophages correlated with poor prognosis and cancer stem cells in oral squamous cell carcinoma. BioMed Res Int 2014; 2014: 838632.

    PubMed  PubMed Central  Google Scholar 

  141. Fan QM, Jing YY, Yu GF, Kou XR, Ye F, Gao L et al. Tumor-associated macrophages promote cancer stem cell-like properties via transforming growth factor-beta1-induced epithelial-mesenchymal transition in hepatocellular carcinoma. Cancer Lett 2014; 352: 160–168.

    CAS  PubMed  Google Scholar 

  142. Yamashina T, Baghdadi M, Yoneda A, Kinoshita I, Suzu S, Dosaka-Akita H et al. Cancer stem-like cells derived from chemoresistant tumors have a unique capacity to prime tumorigenic myeloid cells. Cancer Res 2014; 74: 2698–2709.

    CAS  PubMed  Google Scholar 

  143. Chaturvedi P, Gilkes DM, Takano N, Semenza GL . Hypoxia-inducible factor-dependent signaling between triple-negative breast cancer cells and mesenchymal stem cells promotes macrophage recruitment. Proc Natl Acad Sci USA 2014; 111: E2120–E2129.

    CAS  PubMed  PubMed Central  Google Scholar 

  144. DeNardo DG, Brennan DJ, Rexhepaj E, Ruffell B, Shiao SL, Madden SF et al. Leukocyte complexity predicts breast cancer survival and functionally regulates response to chemotherapy. Cancer Discov 2011; 1: 54–67.

    CAS  PubMed  PubMed Central  Google Scholar 

  145. Buiting AM, Van Rooijen N . Liposome mediated depletion of macrophages: an approach for fundamental studies. J Drug Target 1994; 2: 357–362.

    CAS  PubMed  Google Scholar 

  146. Germano G, Frapolli R, Simone M, Tavecchio M, Erba E, Pesce S et al. Antitumor and anti-inflammatory effects of trabectedin on human myxoid liposarcoma cells. Cancer Res 2010; 70: 2235–2244.

    CAS  PubMed  Google Scholar 

  147. Yang L, DeBusk LM, Fukuda K, Fingleton B, Green-Jarvis B, Shyr Y et al. Expansion of myeloid immune suppressor Gr+CD11b+ cells in tumor-bearing host directly promotes tumor angiogenesis. Cancer Cell 2004; 6: 409–421.

    CAS  PubMed  Google Scholar 

  148. Kusmartsev S, Nagaraj S, Gabrilovich DI . Tumor-associated CD8+ T cell tolerance induced by bone marrow-derived immature myeloid cells. J Immunol 2005; 175: 4583–4592.

    CAS  PubMed  Google Scholar 

  149. Kusmartsev S, Gabrilovich DI . STAT1 signaling regulates tumor-associated macrophage-mediated T cell deletion. J Immunol 2005; 174: 4880–4891.

    CAS  PubMed  Google Scholar 

  150. Ries CH, Cannarile MA, Hoves S, Benz J, Wartha K, Runza V et al. Targeting tumor-associated macrophages with anti-CSF-1R antibody reveals a strategy for cancer therapy. Cancer Cell 2014; 25: 846–859.

    CAS  PubMed  Google Scholar 

  151. Sarkar S, Doring A, Zemp FJ, Silva C, Lun X, Wang X et al. Therapeutic activation of macrophages and microglia to suppress brain tumor-initiating cells. Nat Neurosci 2014; 17: 46–55.

    CAS  PubMed  Google Scholar 

  152. Samanani S, Mishra M, Silva C, Verhaeghe B, Wang J, Tong J et al. Screening for inhibitors of microglia to reduce neuroinflammation. CNS Neurol Disord Drug Targets 2013; 12: 741–749.

    CAS  PubMed  Google Scholar 

  153. Hiramatsu H, Nishikomori R, Heike T, Ito M, Kobayashi K, Katamura K et al. Complete reconstitution of human lymphocytes from cord blood CD34+ cells using the NOD/SCID/gammacnull mice model. Blood 2003; 102: 873–880.

    CAS  PubMed  Google Scholar 

  154. Takagi S, Saito Y, Hijikata A, Tanaka S, Watanabe T, Hasegawa T et al. Membrane-bound human SCF/KL promotes in vivo human hematopoietic engraftment and myeloid differentiation. Blood 2012; 119: 2768–2777.

    CAS  PubMed  PubMed Central  Google Scholar 

  155. Su S, Liu Q, Chen J, Chen F, He C, Huang D et al. A positive feedback loop between mesenchymal-like cancer cells and macrophages is essential to breast cancer metastasis. Cancer Cell 2014; 25: 605–620.

    PubMed  Google Scholar 

  156. Hermann PC, Huber SL, Herrler T, Aicher A, Ellwart JW, Guba M et al. Distinct populations of cancer stem cells determine tumor growth and metastatic activity in human pancreatic cancer. Cell Stem Cell 2007; 1: 313–323.

    CAS  PubMed  Google Scholar 

  157. am Esch JS 2nd, Knoefel WT, Klein M, Ghodsizad A, Fuerst G, Poll LW et al. Portal application of autologous CD133+ bone marrow cells to the liver: a novel concept to support hepatic regeneration. Stem Cells 2005; 23: 463–470.

    PubMed  Google Scholar 

  158. Ginestier C, Hur MH, Charafe-Jauffret E, Monville F, Dutcher J, Brown M et al. ALDH1 is a marker of normal and malignant human mammary stem cells and a predictor of poor clinical outcome. Cell Stem Cell 2007; 1: 555–567.

    CAS  PubMed  PubMed Central  Google Scholar 

  159. Carpentino JE, Hynes MJ, Appelman HD, Zheng T, Steindler DA, Scott EW et al. Aldehyde dehydrogenase-expressing colon stem cells contribute to tumorigenesis in the transition from colitis to cancer. Cancer Res 2009; 69: 8208–8215.

    CAS  PubMed  PubMed Central  Google Scholar 

  160. Li X, Lewis MT, Huang J, Gutierrez C, Osborne CK, Wu MF et al. Intrinsic resistance of tumorigenic breast cancer cells to chemotherapy. J Natl Cancer Inst 2008; 100: 672–679.

    CAS  PubMed  Google Scholar 

  161. Raggi C, Factor VM, Seo D, Holczbauer A, Gillen MC, Marquardt JU et al. Epigenetic reprogramming modulates malignant properties of human liver cancer. Hepatology 2014; 59: 2251–2262.

    CAS  PubMed  Google Scholar 

  162. Marquardt JU, Raggi C, Andersen JB, Seo D, Avital I, Geller D et al. Human hepatic cancer stem cells are characterized by common stemness traits and diverse oncogenic pathways. Hepatology 2011; 54: 1031–1042.

    CAS  PubMed  Google Scholar 

  163. Medema JP . Cancer stem cells: the challenges ahead. Nat Cell Biol 2013; 15: 338–344.

    CAS  PubMed  Google Scholar 

  164. Baguley BC . Multiple drug resistance mechanisms in cancer. Mol Biotechnol 2010; 46: 308–316.

    CAS  PubMed  Google Scholar 

  165. Zhou S, Schuetz JD, Bunting KD, Colapietro AM, Sampath J, Morris JJ et al. The ABC transporter Bcrp1/ABCG2 is expressed in a wide variety of stem cells and is a molecular determinant of the side-population phenotype. Nat Med 2001; 7: 1028–1034.

    CAS  PubMed  Google Scholar 

  166. Singh SK, Hawkins C, Clarke ID, Squire JA, Bayani J, Hide T et al. Identification of human brain tumour initiating cells. Nature 2004; 432: 396–401.

    CAS  PubMed  Google Scholar 

  167. Ponti D, Costa A, Zaffaroni N, Pratesi G, Petrangolini G, Coradini D et al. Isolation and in vitro propagation of tumorigenic breast cancer cells with stem/progenitor cell properties. Cancer Res 2005; 65: 5506–5511.

    CAS  PubMed  Google Scholar 

  168. Li T, Su Y, Mei Y, Leng Q, Leng B, Liu Z et al. ALDH1A1 is a marker for malignant prostate stem cells and predictor of prostate cancer patients' outcome. Lab Invest 2010; 90: 234–244.

    CAS  PubMed  Google Scholar 

  169. Chen J, Li Y, Yu TS, McKay RM, Burns DK, Kernie SG et al. A restricted cell population propagates glioblastoma growth after chemotherapy. Nature 2012; 488: 522–526.

    CAS  PubMed  PubMed Central  Google Scholar 

  170. Schepers AG, Snippert HJ, Stange DE, van den Born M, van Es JH, van de Wetering M et al. Lineage tracing reveals Lgr5+ stem cell activity in mouse intestinal adenomas. Science 2012; 337: 730–735.

    CAS  PubMed  Google Scholar 

  171. Driessens G, Beck B, Caauwe A, Simons BD, Blanpain C . Defining the mode of tumour growth by clonal analysis. Nature 2012; 488: 527–530.

    CAS  PubMed  PubMed Central  Google Scholar 

  172. Wynn TA, Chawla A, Pollard JW . Macrophage biology in development, homeostasis and disease. Nature 2013; 496: 445–455.

    CAS  PubMed  PubMed Central  Google Scholar 

  173. Korkaya H, Wicha MS . Inflammation and autophagy conspire to promote tumor growth. Cell Cycle 2011; 10: 2623–2624.

    CAS  PubMed  Google Scholar 

  174. Porta C, Rimoldi M, Raes G, Brys L, Ghezzi P, Di Liberto D et al. Tolerance and M2 (alternative) macrophage polarization are related processes orchestrated by p50 nuclear factor kappaB. Proc Natl Acad Sci USA 2009; 106: 14978–14983.

    CAS  PubMed  PubMed Central  Google Scholar 

  175. Porta C, Larghi P, Rimoldi M, Totaro MG, Allavena P, Mantovani A et al. Cellular and molecular pathways linking inflammation and cancer. Immunobiology 2009; 214: 761–777.

    CAS  PubMed  Google Scholar 

  176. Murray PJ, Allen JE, Biswas SK, Fisher EA, Gilroy DW, Goerdt S et al. Macrophage activation and polarization: nomenclature and experimental guidelines. Immunity 2014; 41: 14–20.

    CAS  PubMed  PubMed Central  Google Scholar 

  177. Locati M, Mantovani A, Sica A . Macrophage activation and polarization as an adaptive component of innate immunity. Adv Immunol 2013; 120: 163–184.

    CAS  PubMed  Google Scholar 

  178. Li L, Ng DS, Mah W, Almeida FF, Rahmat SA, Rao VK et al. A unique role for p53 in the regulation of M2 macrophage polarization. Cell Death Differ 2014.

  179. Korkaya H, Liu S, Wicha MS . Regulation of cancer stem cells by cytokine networks: attacking cancer's inflammatory roots. Clin Cancer Res 2011; 17: 6125–6129.

    CAS  PubMed  PubMed Central  Google Scholar 

  180. Liu S, Ginestier C, Ou SJ, Clouthier SG, Patel SH, Monville F et al. Breast cancer stem cells are regulated by mesenchymal stem cells through cytokine networks. Cancer Res 2011; 71: 614–624.

    CAS  PubMed  PubMed Central  Google Scholar 

  181. Mosser DM, Edwards JP . Exploring the full spectrum of macrophage activation. Nat Rev Immunol 2008; 8: 958–969.

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

CR, HSM, MC, AS and PI were supported by the Italian Foundation of Cancer Research (AIRC) and Fondazione U Veronesi.

Author Contributions

All authors contributed to this review, and reviewed the final manuscript.

Author information

Author notes

  1. C Raggi and H S Mousa: These two authors contributed equally to this work.

Authors and Affiliations

  1. Liver Unit and Center for Autoimmune Liver Diseases, Humanitas Clinical and Research Center, Milan, Italy

    C Raggi, H S Mousa, M Correnti & P Invernizzi

  2. Laboratory of Molecular Immunology, Humanitas Clinical and Research Center, Milan, Italy

    A Sica

  3. Department of Pharmaceutical Sciences, University of Piemonte Orientale ‘Amedeo Avogadro’, Novara, Italy

    A Sica

Authors
  1. C Raggi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. H S Mousa
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. M Correnti
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. A Sica
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. P Invernizzi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to C Raggi.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Raggi, C., Mousa, H., Correnti, M. et al. Cancer stem cells and tumor-associated macrophages: a roadmap for multitargeting strategies. Oncogene 35, 671–682 (2016). https://doi.org/10.1038/onc.2015.132

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/onc.2015.132

This article is cited by

Search

Advanced search

Quick links