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.

  • Original Article
  • Published:

Self-renewal gene tracking to identify tumour-initiating cells associated with metastatic potential

Oncogene volume 31, pages 2438–2449 (2012)Cite this article

Abstract

Tumour-initiating cells (TICs) are rare cancer cells isolated from tumours of different origins including high-grade tumours that sustain neoplasic progression and development of metastatic disease. They harbour deregulated stem cells pathways and exhibit an unchecked ability to self-renew, a property essential for tumour progression. Among the essential factors maintaining embryonic stem (ES) cells properties, OCT-4 (also known as POU5F1) has been detected in tumours of different origins. Although ectopic expression results in dysplasic growth restricted to epithelial tissues, overexpression expands the proportion of immature cells in teratomas. However, OCT-4-expressing cells have not been purified from spontaneously occurring tumours, thus information concerning their properties is rather scant. Here, using p53−/− mice expressing green fluorescent protein and the puromycin resistance gene under the control of the Oct-4 promoter, we show that OCT-4 is expressed in 5% onwards of the undifferentiated tumour cell populations derived from different organs. OCT-4 expression was low as compared with ES cells, but was associated with a ‘stemness’ signature and expression of the chemokine receptor CXCR4. These cells displayed cancer stem cell features, including increased self-renewal and differentiation ability in vitro and in vivo. They not only formed allografts containing immature bone regions but also disseminated into different organs, including lung, liver and bone. Experiments based on RNA interference revealed that Oct-4 expression drives both their engraftment and metastasis formation. This work points out the crucial contribution of Oct-4-expressing TICs in the hierarchical organization of the malignant potential, leading to metastasis formation. Consequently, it provides an appropriate model to develop novel therapies aiming to strike down TICs by targeting self-renewal genes, therefore efficient to reduce tumour growth and metastatic disease.

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
Figure 3
Figure 4
Figure 5

Similar content being viewed by others

References

  • Al-Hajj M, Wicha MS, Benito-Hernandez A, Morrison SJ, Clarke MF . (2003). Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci USA 100: 3983–3988.

    Article  CAS  Google Scholar 

  • Beier D, Hau P, Proescholdt M, Lohmeier A, Wischhusen J, Oefner PJ et al. (2007). CD133(+) and CD133(−) glioblastoma-derived cancer stem cells show differential growth characteristics and molecular profiles. Cancer Res 67: 4010–4015.

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  • Carlisle AJ, Lyttle CA, Carlisle RY, Maris JM . (2009). CXCR4 expression heterogeneity in neuroblastoma cells due to ligand-independent regulation. Mol Cancer 8: 126.

    Article  Google Scholar 

  • Chambers I, Silva J, Colby D, Nichols J, Nijmeijer B, Robertson M et al. (2007). Nanog safeguards pluripotency and mediates germline development. Nature 450: 1230–1234.

    Article  CAS  Google Scholar 

  • Charafe-Jauffret E, Ginestier C, Iovino F, Wicinski J, Cervera N, Finetti P et al. (2009). Breast cancer cell lines contain functional cancer stem cells with metastatic capacity and a distinct molecular signature. Cancer Res 69: 1302–1313.

    Article  CAS  Google Scholar 

  • Charrad RS, Li Y, Delpech B, Balitrand N, Clay D, Jasmin C et al. (1999). Ligation of the CD44 adhesion molecule reverses blockage of differentiation in human acute myeloid leukemia. Nat Med 5: 669–676.

    Article  CAS  Google Scholar 

  • Chiou SH, Wang ML, Chou YT, Chen CJ, Hong CF, Hsieh WJ 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: 10433–10444.

    Article  CAS  Google Scholar 

  • Clement V, Sanchez P, de Tribolet N, Radovanovic I, Ruiz i Altaba A . (2007). HEDGEHOG-GLI1 signaling regulates human glioma growth, cancer stem cell self-renewal, and tumorigenicity. Curr Biol 17: 165–172.

    Article  CAS  Google Scholar 

  • Diehn M, Cho RW, Clarke MF . (2009). Therapeutic implications of the cancer stem cell hypothesis. Semin Radiat Oncol 19: 78–86.

    Article  Google Scholar 

  • Donehower LA, Harvey M, Slagle BL, McArthur MJ, Montgomery Jr CA, Butel JS et al. (1992). Mice deficient for p53 are developmentally normal but susceptible to spontaneous tumours. Nature 356: 215–221.

    Article  CAS  Google Scholar 

  • Felsher DW . (2004). Reversibility of oncogene-induced cancer. Curr Opin Genet Dev 14: 37–42.

    Article  CAS  Google Scholar 

  • Gassmann P, Haier J, Schluter K, Domikowsky B, Wendel C, Wiesner U et al. (2009). CXCR4 regulates the early extravasation of metastatic tumor cells in vivo. Neoplasia 11: 651–661.

    Article  CAS  Google Scholar 

  • Gidekel S, Pizov G, Bergman Y, Pikarsky E . (2003). Oct-3/4 is a dose-dependent oncogenic fate determinant. Cancer Cell 4: 361–370.

    Article  CAS  Google Scholar 

  • Harris MA, Yang H, Low BE, Mukherje J, Guha A, Bronson RT et al. (2008). Cancer stem cells are enriched in the side population cells in a mouse model of glioma. Cancer Res 68: 10051–10059.

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  • Hochedlinger K, Plath K . (2009). Epigenetic reprogramming and induced pluripotency. Development 136: 509–523.

    Article  CAS  Google Scholar 

  • Hochedlinger K, Yamada Y, Beard C, Jaenisch R . (2005). Ectopic expression of Oct-4 blocks progenitor-cell differentiation and causes dysplasia in epithelial tissues. Cell 121: 465–477.

    Article  CAS  Google Scholar 

  • Huang CY, Lee CY, Chen MY, Yang WH, Chen YH, Chang CH et al. (2009). Stromal cell-derived factor-1/CXCR4 enhanced motility of human osteosarcoma cells involves MEK1/2, ERK and NF-kappaB-dependent pathways. J Cell Physiol 221: 204–212.

    Article  CAS  Google Scholar 

  • Hutchin ME, Kariapper MS, Grachtchouk M, Wang A, Wei L, Cummings D et al. (2005). Sustained Hedgehog signaling is required for basal cell carcinoma proliferation and survival: conditional skin tumorigenesis recapitulates the hair growth cycle. Genes Dev 19: 214–223.

    Article  CAS  Google Scholar 

  • Kaufman DS . (2006). Challenges in the treatment of bladder cancer. Ann Oncol 17 (Suppl 5): v106–v112.

    Article  Google Scholar 

  • Kucia M, Ratajczak J, Ratajczak MZ . (2005). Bone marrow as a source of circulating CXCR4+ tissue-committed stem cells. Biol Cell 97: 133–146.

    Article  CAS  Google Scholar 

  • Lee J, Kim JY, Kang IY, Kim HK, Han YM, Kim J . (2007). The EWS-Oct-4 fusion gene encodes a transforming gene. Biochem J 406: 519–526.

    Article  CAS  Google Scholar 

  • Lengner CJ, Camargo FD, Hochedlinger K, Welstead GG, Zaidi S, Gokhale S et al. (2007). Oct4 expression is not required for mouse somatic stem cell self-renewal. Cell Stem Cell 1: 403–415.

    Article  CAS  Google Scholar 

  • Levings PP, McGarry SV, Currie TP, Nickerson DM, McClellan S, Ghivizzani SC et al. (2009). Expression of an exogenous human Oct-4 promoter identifies tumor-initiating cells in osteosarcoma. Cancer Res 69: 5648–5655.

    Article  CAS  Google Scholar 

  • le Viseur C, Hotfilder M, Bomken S, Wilson K, Rottgers S, Schrauder A et al. (2008). In childhood acute lymphoblastic leukemia, blasts at different stages of immunophenotypic maturation have stem cell properties. Cancer Cell 14: 47–58.

    Article  CAS  Google Scholar 

  • Li C, Heidt DG, Dalerba P, Burant CF, Zhang L, Adsay V et al. (2007). Identification of pancreatic cancer stem cells. Cancer Res 67: 1030–1037.

    Article  CAS  Google Scholar 

  • Marangoni E, Lecomte N, Durand L, de Pinieux G, Decaudin D, Chomienne C et al. (2009). CD44 targeting reduces tumour growth and prevents post-chemotherapy relapse of human breast cancers xenografts. Br J Cancer 100: 918–922.

    Article  CAS  Google Scholar 

  • Masui S, Nakatake Y, Toyooka Y, Shimosato D, Yagi R, Takahashi K et al. (2007). Pluripotency governed by Sox2 via regulation of Oct3/4 expression in mouse embryonic stem cells. Nat Cell Biol 9: 625–635.

    Article  CAS  Google Scholar 

  • Monteiro J, Fodde R . (2010). Cancer stemness and metastasis: therapeutic consequences and perspectives. Eur J Cancer 46: 1198–1203.

    Article  CAS  Google Scholar 

  • Muller A, Homey B, Soto H, Ge N, Catron D, Buchanan ME et al. (2001). Involvement of chemokine receptors in breast cancer metastasis. Nature 410: 50–56.

    Article  CAS  Google Scholar 

  • Nguyen DX, Bos PD, Massague J . (2009). Metastasis: from dissemination to organ-specific colonization. Nat Rev Cancer 9: 274–284.

    Article  CAS  Google Scholar 

  • Nichols J, Zevnik B, Anastassiadis K, Niwa H, Klewe-Nebenius D, Chambers I et al. (1998). Formation of pluripotent stem cells in the mammalian embryo depends on the POU transcription factor Oct4. Cell 95: 379–391.

    Article  CAS  Google Scholar 

  • Niwa H, Miyazaki J, Smith AG . (2000). Quantitative expression of Oct-3/4 defines differentiation, dedifferentiation or self-renewal of ES cells. Nat Genet 24: 372–376.

    Article  CAS  Google Scholar 

  • O'Brien CA, Kreso A, Dick JE . (2009). Cancer stem cells in solid tumors: an overview. Semin Radiat Oncol 19: 71–77.

    Article  Google Scholar 

  • O'Brien CA, Pollett A, Gallinger S, Dick JE . (2007). A human colon cancer cell capable of initiating tumour growth in immunodeficient mice. Nature 445: 106–110.

    Article  CAS  Google Scholar 

  • Prince ME, Sivanandan R, Kaczorowski A, Wolf GT, Kaplan MJ, Dalerba P et al. (2007). Identification of a subpopulation of cells with cancer stem cell properties in head and neck squamous cell carcinoma. Proc Natl Acad Sci USA 104: 973–978.

    Article  CAS  Google Scholar 

  • Rajagopalan V, El Kamar FG, Thayaparan R, Grossbard ML . (2005). Bone marrow metastases from glioblastoma multiforme—a case report and review of the literature. J Neurooncol 72: 157–161.

    Article  Google Scholar 

  • Ricci-Vitiani L, Lombardi DG, Pilozzi E, Biffoni M, Todaro M, Peschle C et al. (2007). Identification and expansion of human colon-cancer-initiating cells. Nature 445: 111–115.

    Article  CAS  Google Scholar 

  • Rodriguez AM, Pisani D, Dechesne CA, Turc-Carel C, Kurzenne JY, Wdziekonski B et al. (2005). Transplantation of a multipotent cell population from human adipose tissue induces dystrophin expression in the immunocompetent mdx mouse. J Exp Med 201: 1397–1405.

    Article  CAS  Google Scholar 

  • Ruiz i Altaba A, Brand AH . (2009). Entity versus property: tracking the nature, genesis and role of stem cells in cancer. Conference on Stem cells and cancer. EMBO Rep 10: 832–836.

    Article  CAS  Google Scholar 

  • Santagata S, Ligon KL, Hornick JL . (2007). Embryonic stem cell transcription factor signatures in the diagnosis of primary and metastatic germ cell tumors. Am J Surg Pathol 31: 836–845.

    Article  Google Scholar 

  • Shachaf CM, Kopelman AM, Arvanitis C, Karlsson A, Beer S, Mandl S et al. (2004). MYC inactivation uncovers pluripotent differentiation and tumour dormancy in hepatocellular cancer. Nature 431: 1112–1117.

    Article  CAS  Google Scholar 

  • Shackleton M, Quintana E, Fearon ER, Morrison SJ . (2009). Heterogeneity in cancer: cancer stem cells versus clonal evolution. Cell 138: 822–829.

    Article  CAS  Google Scholar 

  • Shipitsin M, Campbell LL, Argani P, Weremowicz S, Bloushtain-Qimron N, Yao J et al. (2007). Molecular definition of breast tumor heterogeneity. Cancer Cell 11: 259–273.

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  • Somervaille TC, Matheny CJ, Spencer GJ, Iwasaki M, Rinn JL, Witten DM et al. (2009). Hierarchical maintenance of MLL myeloid leukemia stem cells employs a transcriptional program shared with embryonic rather than adult stem cells. Cell Stem Cell 4: 129–140.

    Article  CAS  Google Scholar 

  • Wang J, Wang H, Li Z, Wu Q, Lathia JD, McLendon RE et al. (2008). c-Myc is required for maintenance of glioma cancer stem cells. PLoS One 3: e3769.

    Article  Google Scholar 

  • Ying QL, Nichols J, Evans EP, Smith AG . (2002). Changing potency by spontaneous fusion. Nature 416: 545–548.

    Article  CAS  Google Scholar 

  • Zeelenberg IS, Ruuls-Van Stalle L, Roos E . (2001). Retention of CXCR4 in the endoplasmic reticulum blocks dissemination of a T cell hybridoma. J Clin Invest 108: 269–277.

    Article  CAS  Google Scholar 

  • Zeineddine D, Papadimou E, Chebli K, Gineste M, Liu J, Grey C et al. (2006). Oct-3/4 dose dependently regulates specification of embryonic stem cells toward a cardiac lineage and early heart development. Dev Cell 11: 535–546.

    Article  CAS  Google Scholar 

  • Zhang Y, Ma B, Fan Q . (2009). Mechanisms of breast cancer bone metastasis. Cancer Lett 292: 1–7.

    Article  Google Scholar 

Download references

Acknowledgements

We are grateful to Professor Austin Smith and Dr Jenny Nichols for generously providing Oct-4-GiP mice and for useful comments. The contributions of Drs Ez-Zoubir Amri and Gilles Pages for in vivo imaging analyses are appreciated. We thank our colleagues, Dr Katrina Podsypanina and Dr Alain Aurias, for helpful suggestions and discussions. We are indebted to Drs Pascal Peraldi, Nathalie Mazure, Jean-François Peyron, Marie-Christine De Vernejoul and Minoo Rassoulzadegan for a careful reading of this manuscript, and to Drs Amanda Patel and Eric Lingueglia for valuable help in editing this manuscript. We acknowledge expert technical assistance of Katia Havet with histology; Agnes Loubat with flow cytometry; Mansour Djedaini with in vivo imaging; Thibault Fabas and Annie-Claude Peyron with genetic analysis; and Franck Paput, Cendrine Dubaud and Jacky Paput with animal care. Our lab receives financial support from Association pour la Recherche contre le Cancer and Institut National du Cancer (grant numbers: CT 30008187 and PL-96-007). We thank Conseil Général des Alpes-Maritimes for financial support for the animal imaging equipment (SkyScan).

Author information

Author notes

  1. C Y Darini

    Present address: 7Current address: IRCM, 110 Avenue des Pins Ouest, Montreal, Canada H2W 1R7.,

Authors and Affiliations

  1. CNRS, Institute of Biology Development and Cancer, Nice, France

    C Y Darini, D F Pisani, F Pedeutour, C Dani & A Ladoux

  2. University of Nice-Sophia Antipolis, Institute of Biology Development and Cancer, Nice, France

    C Y Darini, D F Pisani, F Pedeutour, C Dani & A Ladoux

  3. Inserm ERI 21/EA 4319 and Human Biobank, Faculty of Medicine and Pasteur Hospital, CHU of Nice, University of Nice-Sophia Antipolis, Nice, France

    P Hofman

  4. Faculty of Medicine, Nice University Hospital, University of Nice-Sophia Antipolis, Nice, France

    F Pedeutour

  5. Haematology laboratory, CHU of Nice, Cimiez Hospital, Nice, France

    I Sudaka

  6. INSERM UMRS 940, Paris Diderot University, Saint-Louis Hospital, Paris, France

    C Chomienne

Authors
  1. C Y Darini
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. D F Pisani
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. P Hofman
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. F Pedeutour
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. I Sudaka
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. C Chomienne
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. C Dani
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. A Ladoux
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to A Ladoux.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Supplementary Information accompanies the paper on the Oncogene website

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Darini, C., Pisani, D., Hofman, P. et al. Self-renewal gene tracking to identify tumour-initiating cells associated with metastatic potential. Oncogene 31, 2438–2449 (2012). https://doi.org/10.1038/onc.2011.421

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/onc.2011.421

Keywords

This article is cited by

Search

Advanced search

Quick links