may not fully match that of the cognate stem cells, pluripotent tumor cells with stem cell phenotype and capacity probably contribute signiﬁcantly to the phenotypic heterogeneity seen in solid cancers where the EMT process perhaps is the most extensively studied. Acknowledgements This work was supported by the Swedish Cancer Society, the Children’s Cancer Foundation of Sweden, the Swedish Research Council, the SSF Strategic Center for Translational Cancer Research— CREATE Health, BioCARE, a Strategic Research Program at Lund University, Hans von Kantzows Stiftelse, Gyllenstiernska Krapperup Foundation, Gunnar Nilsson’s Cancer Foundation, Jeanssons Stiftelser, Magnus Bergvalls Stiftelse, The Royal Physiographic Society, and the research funds of Malmö University Hospital. Declaration of interest: The authors report no conﬂicts of interest. The authors alone are responsible for the content and writing of the paper. References 1. Hay ED. The mesenchymal cell, its role in the embryo, and the remarkable signaling mechanisms that create it. Dev Dyn. 2005;233:706–20. 2. Boström A-K, Möller C, Nilsson E, Elfving P, Axelson H, Johansson ME. Sarcomatoid renal cell carcinoma may denote a biological example of epithelial to mesenchymal transition. Hum Pathol. 2011. 3. Cushing H, Wolbach SB. The transformation of a malignant paravertebral sympathicoblastoma into a benign ganglioneur- oma. Am J Pathol. 1927;3(3):203–216. 4. Fredlund E, Ringner M, Maris JM, Påhlman S. High Myc pathway activity and low stage of neuronal differentiation associate with poor outcome in neuroblastoma. Proc Natl Acad Sci USA. 2008;105:14094–9. 5. Påhlman S, Odelstad L, Larsson E, Grotte G, Nilsson K. Phenotypic changes of human neuroblastoma cells in culture induced by 12-O-tetradecanoyl-phorbol-13-acetate. Int J Cancer. 1981;28:583–9. 6. Sidell N. Retinoic acid-induced growth inhibition and mor- phologic differentiation of human neuroblastoma cells in vitro. J Natl Cancer Inst. 1982;68:589–96. 7. Hedborg F, Ohlsson R, Sandstedt B, Grimelius L, Hoehner JC, Påhlman S. IGF2 expression is a marker for paraganglionic/SIF cell differentiation in neuroblastoma. Am J Pathol. 1995;146:833–47. 8. Gestblom C, Hoehner JC, Hedborg F, Sandstedt B, Påhlman S. In vivo spontaneous neuronal to neuroendocrine lineage conversion in a subset of neuroblastomas. Am J Pathol. 1997;150:107–17. 9. Höckel M, Vaupel P. Tumor hypoxia: Deﬁnitions and current clinical, biologic, and molecular aspects. J Natl Cancer Inst. 2001;93:266–76. Differentiation and cancer 223 10. Semenza GL, Roth PH, Fang HM, Wang GL. Transcriptional regulation of genes encoding glycolytic enzymes by hypoxia- inducible factor 1. J Biol Chem. 1994;269:23757–63. 11. Semenza GL. Deﬁning the role of hypoxia-inducible factor 1 in cancer biology and therapeutics. Oncogene. 2010;29: 625–34. 12. Löfstedt T, Fredlund E, Holmquist-Mengelbier L, Pietras A, Ovenberger M, Poellinger L, et al. Hypoxia inducible factor-2alpha in cancer. Cell Cycle. 2007;6:919–26. 13. Jögi A, Persson P, Grynfeld A, Påhlman S, Axelson H. Mod- ulation of basic helix-loop-helix transcription complex forma- tion by Id proteins during neuronal differentiation. J Biol Chem. 2002;277:9118–26. 14. Jögi A, Vallon-Christersson J, Holmquist L, Axelson H, Borg A, Påhlman S. Human neuroblastoma cells exposed to hypoxia: induction of genes associated with growth, survival, and aggressive behavior. Exp Cell Res. 2004;295:469–87. 15. Pietras A, Johnsson AS, Påhlman S. The HIF-2alpha-driven pseudo-hypoxic phenotype in tumor aggressiveness, differen- tiation, and vascularization. Curr Top Microbiol Immunol. 2010;345:1–20. 16. Kaelin WG Jr, Ratcliffe PJ. Oxygen sensing by metazoans: the central role of the HIF hydroxylase pathway. Mol Cell. 2008; 30:393–402. 17. Holmquist-Mengelbier L, Fredlund E, Löfstedt T, Noguera R, Navarro S, Nilsson H, et al. Recruitment of HIF-1 alpha and HIF-2 alpha to common target genes is differentially regulated in neuroblastoma: HIF-2 alpha pro- motes an aggressive phenotype. Cancer Cell. 2006;10:413–23. 18. Pietras A, Gisselsson D, Øra I, Noguera R, Beckman S, Navarro S, et al. High levels of HIF-2alpha highlight an immature neural crest-like neuroblastoma cell cohort located in a perivascular niche. J Pathol. 2008;214:482–8. 19. Noguera R, Fredlund E, Piqueras M, Pietras A, Beckman S, Navarro S, et al. HIF-1alpha and HIF-2alpha are differentially regulated in vivo in neuroblastoma: high HIF-1alpha corre- lates negatively to advanced clinical stage and tumor vascu- larization. Clin Cancer Res. 2009;15:7130–6. 20. Li Z, Bao S, Wu Q, Wang H, Eyler C, Sathornsumetee S, et al. Hypoxia-inducible factors regulate tumorigenic capacity of glioma stem cells. Cancer Cell. 2009;15:501–13. 21. Pietras A, Hansford LM, Johnsson AS, Bridges E, Sjölund J, Gisselsson D, et al. HIF-2alpha maintains an undifferentiated state in neural crest-like human neuroblastoma tumor- initiating cells. Proc Natl Acad Sci USA. 2009;106:16805–10. 22. Brisken C, Duss S. Stem cells and the stem cell niche in the breast: an integrated hormonal and developmental perspec- tive. Stem Cell Rev. 2007;3:147–56. 23. Helczynska K, Kronblad A, Jögi A, Nilsson E, Beckman S, Landberg G, et al. Hypoxia promotes a dedifferentiated phe- notype in ductal breast carcinoma in situ. Cancer Res. 2003; 63:1441–4. 24. Vaapil et al., unpublished paper. 25. Jögi A, Helczynska K, Vaapil M, Johansson E, Beckman S, Larsson C, et al. Hypoxia impairs morphological and func- tional differentiation of immortalized human breast epithelial cells in 3D basement membrane matrix-culture. Abstract #235. AACR Annual Conference. AACR 100th Annual Meeting, Denver, Colorado, April 18-22. 2009. 26. Helczynska K, Larsson AM, Holmquist Mengelbier L, Bridges E, Fredlund E, Borgquist S, et al. Hypoxia-inducible factor-2alpha correlates to distant recurrence and poor out- come in invasive breast cancer. Cancer Res. 2008;68:9212–20. 27. Al-Hajj M, Wicha MS, Benito-Hernandez A, Morrison SJ, Clarke MF. Prospective identiﬁcation of tumorigenic