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Origins of Metastasis-Initiating Cells

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Stem Cells and Human Diseases

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Abstract

Current models of primary cancers suggest that tumour formation and growth is due to a rare subpopulation of stem cell-like tumour-initiating cells. These cells have the capability of self-renewal and the ability to form all cell types of the heterogenous tumour. Due to the nature of the metastatic process, where only a small number of primary cells are capable of successfully forming a metastasis, it is suggestive that metastases may also form from a rare tumour-initiating population. Currently, the existence and origin of these putative metastasis-initiating cells is unclear. Here we aim to discuss current evidence for such a metastasis-initiating cell population, and the potential models for the origin of these cells. The therapeutic implications of targeting chemo- and radioresistent primary tumour-initiating cells may also apply to the treatment of metastatic disease.

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Abbreviations

ALDH1:

Aldehyde dehydrogenase 1

BBB:

Blood–brain-barrier

Bmi1:

B-cell-specific Moloney murine leukemia virus insertion site-1

COX2:

Cyclooxygenase 2

CSC:

Cancer stem cell

EGF:

Epidermal growth factor

EMT:

Epithelial-mesenchymal transition

EpCAM:

Epithelial cell adhesion molecule (a.k.a ESA)

ESA:

Epithelial-specific antigen (a.k.a. EpCAM)

FoxM1:

Forkhead box M1

HIF1:

Hypoxia-inducible factor-1

HNSCC:

Head and neck squamous cell carcinoma

HOXB9:

Homeobox B9

HSC:

Hematopoietic stem cell

ID1:

Inhibitor of DNA binding 1

IL11 / IL8:

Interleukin-11 / Interleukin-8

LAC:

Lung adenocarcinoma

LEF1:

Lymphoid enhancer binding factor 1

LWS:

Lung cancer WNT gene set

MIC:

Metastasis-initiating cell

MMP:

Matrix metalloproteinase

MV:

Microvesicle

NOD-SCID:

Non-obese diabetic severe combined immunodeficient

ST6GALNAC5:

α2,6-sialytransferase

TGFβ:

Transforming growth factor β

TIC:

Tumour-initiating cell

TNFα:

Tumour necrosis factor α

VEGF:

Vascular endothelial growth factor

References

  1. Fidler IJ (2001) Seed and soil revisited: contribution of the organ microenvironment to cancer metastasis. Surg Oncol Clin N Am 10(2):257–269, vii–viiii

    PubMed  CAS  Google Scholar 

  2. Croker AK, Allan AL (2008) Cancer stem cells: implications for the progression and treatment of metastatic disease. J Cell Mol Med 12(2):374–390

    Article  PubMed  CAS  Google Scholar 

  3. Luzzi KJ et al (1998) Multistep nature of metastatic inefficiency: dormancy of solitary cells after successful extravasation and limited survival of early micrometastases. Am J Pathol 153(3):865–873

    Article  PubMed  CAS  Google Scholar 

  4. Singh SK et al (2003) Identification of a cancer stem cell in human brain tumors. Cancer Res 63(18):5821–5828

    PubMed  CAS  Google Scholar 

  5. Singh SK et al (2004) Identification of human brain tumour initiating cells. Nature 432(7015):396–401

    Article  PubMed  CAS  Google Scholar 

  6. Mao XG et al (2009) Brain tumor stem-like cells identified by neural stem cell marker CD15. Transl Oncol 2(4):247–257

    PubMed  Google Scholar 

  7. Al-Hajj M et al (2003) Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci USA 100(7):3983–3988

    Article  PubMed  CAS  Google Scholar 

  8. Ginestier C et al (2007) ALDH1 is a marker of normal and malignant human mammary stem cells and a predictor of poor clinical outcome. Cell Stem Cell 1(5):555–567

    Article  PubMed  CAS  Google Scholar 

  9. O’Brien CA et al (2007) A human colon cancer cell capable of initiating tumour growth in immunodeficient mice. Nature 445(7123):106–110

    Article  PubMed  Google Scholar 

  10. Ricci-Vitiani L et al (2007) Identification and expansion of human colon-cancer-initiating cells. Nature 445(7123):111–115

    Article  PubMed  CAS  Google Scholar 

  11. Huang EH et al (2009) Aldehyde dehydrogenase 1 is a marker for normal and malignant human colonic stem cells (SC) and tracks SC overpopulation during colon tumorigenesis. Cancer Res 69(8):3382–3389

    Article  PubMed  CAS  Google Scholar 

  12. Eramo A et al (2008) Identification and expansion of the tumorigenic lung cancer stem cell population. Cell Death Differ 15(3):504–514

    Article  PubMed  CAS  Google Scholar 

  13. Schatton T et al (2008) Identification of cells initiating human melanomas. Nature 451(7176):345–349

    Article  PubMed  CAS  Google Scholar 

  14. Chen YC et al (2009) Aldehyde dehydrogenase 1 is a putative marker for cancer stem cells in head and neck squamous cancer. Biochem Biophys Res Commun 385(3):307–313

    Article  PubMed  CAS  Google Scholar 

  15. Li C et al (2007) Identification of pancreatic cancer stem cells. Cancer Res 67(3):1030–1037

    Article  PubMed  CAS  Google Scholar 

  16. Clarke MF et al (2006) Cancer stem cells–perspectives on current status and future directions: AACR Workshop on cancer stem cells. Cancer Res 66(19):9339–9344

    Article  PubMed  CAS  Google Scholar 

  17. Ishizawa K et al (2010) Tumor-initiating cells are rare in many human tumors. Cell Stem Cell 7(3):279–282

    Article  PubMed  CAS  Google Scholar 

  18. Quintana E et al (2008) Efficient tumour formation by single human melanoma cells. Nature 456(7222):593–598

    Article  PubMed  CAS  Google Scholar 

  19. Schouten LJ et al (2002) Incidence of brain metastases in a cohort of patients with carcinoma of the breast, colon, kidney, and lung and melanoma. Cancer 94(10):2698–2705

    Article  PubMed  Google Scholar 

  20. Croker AK et al (2009) High aldehyde dehydrogenase and expression of cancer stem cell markers selects for breast cancer cells with enhanced malignant and metastatic ability. J Cell Mol Med 13(8B):2236–2252

    Article  PubMed  Google Scholar 

  21. Charafe-Jauffret E et al (2010) Aldehyde dehydrogenase 1-positive cancer stem cells mediate metastasis and poor clinical outcome in inflammatory breast cancer. Clin Cancer Res 16(1):45–55

    Article  PubMed  CAS  Google Scholar 

  22. Marcato P et al (2011) Aldehyde dehydrogenase activity of breast cancer stem cells is primarily due to isoform ALDH1A3 and its expression is predictive of metastasis. Stem Cells 29(1):32–45

    Article  PubMed  CAS  Google Scholar 

  23. Sheridan C et al (2006) CD44+/CD24- breast cancer cells exhibit enhanced invasive properties: an early step necessary for metastasis. Breast Cancer Res 8(5):R59

    Article  PubMed  Google Scholar 

  24. Liu H et al (2010) Cancer stem cells from human breast tumors are involved in spontaneous metastases in orthotopic mouse models. Proc Natl Acad Sci USA 107(42):18115–18120

    Article  PubMed  CAS  Google Scholar 

  25. Davis SJ et al (2010) Metastatic potential of cancer stem cells in head and neck squamous cell carcinoma. Arch Otolaryngol Head Neck Surg 136(12):1260–1266

    Article  PubMed  Google Scholar 

  26. Abraham BK et al (2005) Prevalence of CD44+/CD24-/low cells in breast cancer may not be associated with clinical outcome but may favor distant metastasis. Clin Cancer Res 11(3):1154–1159

    PubMed  CAS  Google Scholar 

  27. Minn AJ et al (2005) Genes that mediate breast cancer metastasis to lung. Nature 436(7050):518–524

    Article  PubMed  CAS  Google Scholar 

  28. Minn AJ et al (2005) Distinct organ-specific metastatic potential of individual breast cancer cells and primary tumors. J Clin Invest 115(1):44–55

    PubMed  CAS  Google Scholar 

  29. Kang Y et al (2003) A multigenic program mediating breast cancer metastasis to bone. Cancer Cell 3(6):537–549

    Article  PubMed  CAS  Google Scholar 

  30. van’t Veer LJ et al (2002) Gene expression profiling predicts clinical outcome of breast cancer. Nature 415(6871):530–536

    Article  Google Scholar 

  31. Bos PD et al (2009) Genes that mediate breast cancer metastasis to the brain. Nature 459(7249):1005–1009

    Article  PubMed  CAS  Google Scholar 

  32. Minn AJ et al (2007) Lung metastasis genes couple breast tumor size and metastatic spread. Proc Natl Acad Sci USA 104(16):6740–6745

    Article  PubMed  CAS  Google Scholar 

  33. Okajima T et al (1999) Molecular cloning of brain-specific GD1alpha synthase (ST6GalNAc V) containing CAG/Glutamine repeats. J Biol Chem 274(43):30557–30562

    Article  PubMed  CAS  Google Scholar 

  34. Nguyen DX et al (2009) WNT/TCF signaling through LEF1 and HOXB9 mediates lung adenocarcinoma metastasis. Cell 138(1):51–62

    Article  PubMed  CAS  Google Scholar 

  35. Hayashida T et al (2010) HOXB9, a gene overexpressed in breast cancer, promotes tumorigenicity and lung metastasis. Proc Natl Acad Sci USA 107(3):1100–1105

    Article  PubMed  CAS  Google Scholar 

  36. Polyak K, Weinberg RA (2009) Transitions between epithelial and mesenchymal states: acquisition of malignant and stem cell traits. Nat Rev Cancer 9(4):265–273

    Article  PubMed  CAS  Google Scholar 

  37. Kalluri R, Weinberg RA (2009) The basics of epithelial-mesenchymal transition. J Clin Invest 119(6):1420–1428

    Article  PubMed  CAS  Google Scholar 

  38. Baum B, Settleman J, Quinlan MP (2008) Transitions between epithelial and mesenchymal states in development and disease. Semin Cell Dev Biol 19(3):294–308

    Article  PubMed  CAS  Google Scholar 

  39. Kang Y, Massague J (2004) Epithelial-mesenchymal transitions: twist in development and metastasis. Cell 118(3):277–279

    Article  PubMed  CAS  Google Scholar 

  40. Yang J, Weinberg RA (2008) Epithelial-mesenchymal transition: at the crossroads of development and tumor metastasis. Dev Cell 14(6):818–829

    Article  PubMed  CAS  Google Scholar 

  41. Thiery JP (2002) Epithelial-mesenchymal transitions in tumour progression. Nat Rev Cancer 2(6):442–454

    Article  PubMed  CAS  Google Scholar 

  42. Turley EA et al (2008) Mechanisms of disease: epithelial-mesenchymal transition–does cellular plasticity fuel neoplastic progression? Nat Clin Pract Oncol 5(5):280–290

    Article  PubMed  CAS  Google Scholar 

  43. Xu J, Lamouille S, Derynck R (2009) TGF-beta-induced epithelial to mesenchymal transition. Cell Res 19(2):156–172

    Article  PubMed  CAS  Google Scholar 

  44. Roussos ET et al (2010) AACR special conference on epithelial-mesenchymal transition and cancer progression and treatment. Cancer Res 70(19):7360–7364

    Article  PubMed  CAS  Google Scholar 

  45. Cano A et al (2000) The transcription factor snail controls epithelial-mesenchymal transitions by repressing E-cadherin expression. Nat Cell Biol 2(2):76–83

    Article  PubMed  CAS  Google Scholar 

  46. Casas E et al (2011) Snail2 is an essential mediator of Twist1-induced epithelial mesenchymal transition and metastasis. Cancer Res 71(1):245–254

    Article  PubMed  CAS  Google Scholar 

  47. Chen C et al (2011) Evidence for epithelial-mesenchymal transition in cancer stem cells of head and neck squamous cell carcinoma. PLoS One 6(1):e16466

    Article  PubMed  CAS  Google Scholar 

  48. Mani SA et al (2008) The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell 133(4):704–715

    Article  PubMed  CAS  Google Scholar 

  49. Yu CC et al (2011) Bmi-1 regulates snail expression and promotes metastasis ability in head and neck aquamous cancer-derived ALDH1 positive cells. J Oncol 2011. doi:10.1155/2011/609259

    Google Scholar 

  50. Lo WL et al (2011) MicroRNA-200c attenuates tumour growth and metastasis of presumptive head and neck squamous cell carcinoma stem cells. J Pathol 223(4):482–495

    Article  PubMed  CAS  Google Scholar 

  51. Bao B et al (2011) Notch-1 induces epithelial-mesenchymal transition consistent with cancer stem cell phenotype in pancreatic cancer cells. Cancer Lett 307(1):26–36

    Article  PubMed  CAS  Google Scholar 

  52. Biddle A et al (2011) Cancer stem cells in squamous cell carcinoma switch between two distinct phenotypes that are preferentially migratory or proliferative. Cancer Res 71(15):5317–5326

    Google Scholar 

  53. Pilarsky C et al (2004) Identification and validation of commonly overexpressed genes in solid tumors by comparison of microarray data. Neoplasia 6(6):744–750

    Article  PubMed  CAS  Google Scholar 

  54. Bao B et al (2011) Over-expression of FoxM1 leads to epithelial-mesenchymal transition and cancer stem cell phenotype in pancreatic cancer cells. J Cell Biochem 112(9):2296–2306

    Article  PubMed  CAS  Google Scholar 

  55. Jiang L, Li J, Song L (2009) Bmi-1, stem cells and cancer. Acta Biochim Biophys Sin (Shanghai) 41(7):527–534

    Article  CAS  Google Scholar 

  56. Park IK, Morrison SJ, Clarke MF (2004) Bmi1, stem cells, and senescence regulation. J Clin Invest 113(2):175–179

    PubMed  CAS  Google Scholar 

  57. Shimono Y et al (2009) Downregulation of miRNA-200c links breast cancer stem cells with normal stem cells. Cell 138(3):592–603

    Article  PubMed  CAS  Google Scholar 

  58. Burk U et al (2008) A reciprocal repression between ZEB1 and members of the miR-200 family promotes EMT and invasion in cancer cells. EMBO Rep 9(6):582–589

    Article  PubMed  CAS  Google Scholar 

  59. Hoenerhoff MJ et al (2009) BMI1 cooperates with H-RAS to induce an aggressive breast cancer phenotype with brain metastases. Oncogene 28(34):3022–3032

    Article  PubMed  CAS  Google Scholar 

  60. Song LB et al (2009) The polycomb group protein Bmi-1 represses the tumor suppressor PTEN and induces epithelial-mesenchymal transition in human nasopharyngeal epithelial cells. J Clin Invest 119(12):3626–3636

    Article  PubMed  CAS  Google Scholar 

  61. Mihic-Probst D et al (2007) Consistent expression of the stem cell renewal factor BMI-1 in primary and metastatic melanoma. Int J Cancer 121(8):1764–1770

    Article  PubMed  CAS  Google Scholar 

  62. Nichols J et al (1998) Formation of pluripotent stem cells in the mammalian embryo depends on the POU transcription factor Oct4. Cell 95(3):379–391

    Article  PubMed  CAS  Google Scholar 

  63. Park IH et al (2008) Reprogramming of human somatic cells to pluripotency with defined factors. Nature 451(7175):141–146

    Article  PubMed  CAS  Google Scholar 

  64. Chambers I et al (2003) Functional expression cloning of Nanog, a pluripotency sustaining factor in embryonic stem cells. Cell 113(5):643–655

    Article  PubMed  CAS  Google Scholar 

  65. Chiou SH et al (2010) Coexpression of Oct4 and Nanog enhances malignancy in lung adenocarcinoma by inducing cancer stem cell-like properties and epithelial-mesenchymal transdifferentiation. Cancer Res 70(24):10433–10444

    Article  PubMed  CAS  Google Scholar 

  66. Ying M et al (2011) Regulation of glioblastoma stem cells by retinoic acid: role for Notch pathway inhibition. Oncogene 30:3454–3467

    Article  PubMed  CAS  Google Scholar 

  67. Sullivan JP et al (2010) Aldehyde dehydrogenase activity selects for lung adenocarcinoma stem cells dependent on notch signaling. Cancer Res 70(23):9937–9948

    Article  PubMed  CAS  Google Scholar 

  68. Korpal M et al (2008) The miR-200 family inhibits epithelial-mesenchymal transition and cancer cell migration by direct targeting of E-cadherin transcriptional repressors ZEB1 and ZEB2. J Biol Chem 283(22):14910–14914

    Article  PubMed  CAS  Google Scholar 

  69. Park SM et al (2008) The miR-200 family determines the epithelial phenotype of cancer cells by targeting the E-cadherin repressors ZEB1 and ZEB2. Genes Dev 22(7):894–907

    Article  PubMed  CAS  Google Scholar 

  70. Hwang WL et al (2011) SNAIL regulates interleukin-8 expression, stem cell-like activity, and tumorigenicity of human colorectal carcinoma cells. Gastroenterology 141(1):279–291

    Article  PubMed  CAS  Google Scholar 

  71. Yang MH et al (2010) Bmi1 is essential in Twist1-induced epithelial-mesenchymal transition. Nat Cell Biol 12(10):982–992

    Article  PubMed  Google Scholar 

  72. Vesuna F et al (2009) Twist modulates breast cancer stem cells by transcriptional regulation of CD24 expression. Neoplasia 11(12):1318–1328

    PubMed  CAS  Google Scholar 

  73. Fang X et al (2011) Twist2 contributes to breast cancer progression by promoting an epithelial-mesenchymal transition and cancer stem-like cell self-renewal. Oncogene 30(47):4707–4720

    Google Scholar 

  74. Asiedu MK et al (2011) TGF{beta}/TNF{alpha}-mediated epithelial-mesenchymal transition generates breast cancer stem cells with a Claudin-low phenotype. Cancer Res 71(13):4707–4719

    Article  PubMed  CAS  Google Scholar 

  75. McAllister SS et al (2008) Systemic endocrine instigation of indolent tumor growth requires osteopontin. Cell 133(6):994–1005

    Article  PubMed  CAS  Google Scholar 

  76. Elkabets M et al (2011) Human tumors instigate granulin-expressing hematopoietic cells that promote malignancy by activating stromal fibroblasts in mice. J Clin Invest 121(2):784–799

    Article  PubMed  CAS  Google Scholar 

  77. Grange C et al (2011) Microvesicles released from human renal cancer stem cells stimulate angiogenesis and formation of lung pre-metastatic niche. Cancer Res 71(15):5346–5356

    Article  PubMed  CAS  Google Scholar 

  78. Shiozawa Y et al (2011) Human prostate cancer metastases target the hematopoietic stem cell niche to establish footholds in mouse bone marrow. J Clin Invest 121(4):1298–1312

    Article  PubMed  CAS  Google Scholar 

  79. Pommier SJ et al (2010) Characterizing the HER2/neu status and metastatic potential of breast cancer stem/progenitor cells. Ann Surg Oncol 17(2):613–623

    Article  PubMed  Google Scholar 

  80. Seike T et al (2011) Interaction between lung cancer cells and astrocytes via specific inflammatory cytokines in the microenvironment of brain metastasis. Clin Exp Metastasis 28(1):13–25

    Article  PubMed  CAS  Google Scholar 

  81. Arshad F et al (2010) Blood–brain barrier integrity and breast cancer metastasis to the brain. Pathol Res Int 2011:920509

    Google Scholar 

  82. Abdouh M et al (2009) BMI1 sustains human glioblastoma multiforme stem cell renewal. J Neurosci 29(28):8884–8896

    Article  PubMed  CAS  Google Scholar 

  83. Michael LE et al (2008) Bmi1 is required for Hedgehog pathway-driven medulloblastoma expansion. Neoplasia 10(12):1343–1349, 5p following 1349

    PubMed  Google Scholar 

  84. Dean M, Fojo T, Bates S (2005) Tumour stem cells and drug resistance. Nat Rev Cancer 5(4):275–284

    Article  PubMed  CAS  Google Scholar 

  85. Shervington A, Lu C (2008) Expression of multidrug resistance genes in normal and cancer stem cells. Cancer Invest 26(5):535–542

    Article  PubMed  CAS  Google Scholar 

  86. Korur S et al (2009) GSK3beta regulates differentiation and growth arrest in glioblastoma. PLoS One 4(10):e7443

    Article  PubMed  Google Scholar 

  87. Li Y et al (2010) Sulforaphane, a dietary component of broccoli/broccoli sprouts, inhibits breast cancer stem cells. Clin Cancer Res 16(9):2580–2590

    Article  PubMed  CAS  Google Scholar 

  88. Srivastava RK et al (2011) Sulforaphane synergizes with quercetin to inhibit self-renewal capacity of pancreatic cancer stem cells. Front Biosci (Elite Ed) 3:515–528

    Article  Google Scholar 

  89. Mimeault M, Batra SK (2010) New promising drug targets in cancer- and metastasis-initiating cells. Drug Discov Today 15(9–10):354–364

    Article  PubMed  CAS  Google Scholar 

  90. Rubin JB et al (2003) A small-molecule antagonist of CXCR4 inhibits intracranial growth of primary brain tumors. Proc Natl Acad Sci USA 100(23):13513–13518

    Article  PubMed  CAS  Google Scholar 

  91. Terasaki M et al (2011) CXCL12/CXCR4 signaling in malignant brain tumors: a potential pharmacological therapeutic target. Brain Tumor Pathol 28(2):89–97

    Article  PubMed  CAS  Google Scholar 

  92. Dewan MZ et al (2006) Stromal cell-derived factor-1 and CXCR4 receptor interaction in tumor growth and metastasis of breast cancer. Biomed Pharmacother 60(6):273–276

    Article  PubMed  CAS  Google Scholar 

  93. Liang Z et al (2004) Inhibition of breast cancer metastasis by selective synthetic polypeptide against CXCR4. Cancer Res 64(12):4302–4308

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. McMaster Stem Cell and Cancer Research Institute, 1280 Main Street West, Hamilton, ON, L8S 4K1, Canada

    Sara M. Nolte

  2. McMaster Children’s Hospital, 1200 Main Street West., Room 4E5, Hamilton, ON, L8N 3Z5, Canada

    Sheila K. Singh

  3. Department of Surgery, McMaster Stem Cell and Cancer Research Institute, Hamilton, ON, Canada

    Sheila K. Singh

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  1. Sara M. Nolte
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Correspondence to Sheila K. Singh .

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Editors and Affiliations

  1. , Pharmacology and Toxicology, University of Kansas Medical Center, Rainbow Blvd 3901, Kansas City, 66160, Kansas, USA

    Rakesh Srivastava

  2. , Pathology and Laboratory Medicine, University of Kansas Medical Center, Rainbow Blvd 3901, Kansas City, 66160, Kansas, USA

    Sharmila Shankar

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Nolte, S.M., Singh, S.K. (2012). Origins of Metastasis-Initiating Cells. In: Srivastava, R., Shankar, S. (eds) Stem Cells and Human Diseases. Springer, Dordrecht. https://doi.org/10.1007/978-94-007-2801-1_11

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