Adrenocortical Stem and Progenitor Cells: Implications for Cancer

  • Joanne H. Heaton
  • Gary D. Hammer


It is estimated that close to 1.5 million men and women will be diagnosed with cancer and over 500,000 will die of cancer in 2010 ( While scientific discovery has begun to uncover mechanisms of both tumor initiation and tumor maintenance, these discoveries have until recently been slow to be translated into effective treatments that significantly change cancer death statistics.


Cancer Stem Cell Adrenal Cortex Side Population Adrenocortical Carcinoma Adrenocortical Cell 
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  1. 1.
    Dick JE (2003) Breast cancer stem cells revealed. Proc Natl Acad Sci U S A 100(7):3547–3549PubMedCrossRefGoogle Scholar
  2. 2.
    Reya T et al (2001) Stem cells, cancer, and cancer stem cells. Nature 414(6859):105–111PubMedCrossRefGoogle Scholar
  3. 3.
    Dalerba P et al (2007) Cancer stem cells: models and concepts. Annu Rev Med 58:267–284PubMedCrossRefGoogle Scholar
  4. 4.
    Lobo NA et al (2007) The biology of cancer stem cells. Annu Rev Cell Dev Biol 23:675–699PubMedCrossRefGoogle Scholar
  5. 5.
    Shackleton M et al (2009) Heterogeneity in cancer: cancer stem cells versus clonal evolution. Cell 138(5):822–829PubMedCrossRefGoogle Scholar
  6. 6.
    Ailles LE, Weissman IL (2007) Cancer stem cells in solid tumors. Curr Opin Biotechnol 18(5):460–466PubMedCrossRefGoogle Scholar
  7. 7.
    Quintana E et al (2008) Efficient tumour formation by single human melanoma cells. Nature 456(7222):593–598PubMedCrossRefGoogle Scholar
  8. 8.
    Libe R et al (2007) Adrenocortical cancer: pathophysiology and clinical management. Endocr Relat Cancer 14(1):13–28PubMedCrossRefGoogle Scholar
  9. 9.
    Bertherat J, Bertagna X (2009) Pathogenesis of adrenocortical cancer. Best Pract Res Clin Endocrinol Metab 23(2):261–271PubMedCrossRefGoogle Scholar
  10. 10.
    Keegan CE, Hammer GD (2002) Recent insights into organogenesis of the adrenal cortex. Trends Endocrinol Metab 13(5):200–208PubMedCrossRefGoogle Scholar
  11. 11.
    Kim AC, Hammer GD (2007) Adrenocortical cells with stem/progenitor cell properties: recent advances. Mol Cell Endocrinol 265–266:10–16Google Scholar
  12. 12.
    Luo X et al (1994) A cell-specific nuclear receptor is essential for adrenal and gonadal development and sexual differentiation. Cell 77(4):481–490PubMedCrossRefGoogle Scholar
  13. 13.
    Sadovsky Y et al (1995) Mice deficient in the orphan receptor steroidogenic factor 1 lack adrenal glands and gonads but express P450 side-chain-cleavage enzyme in the placenta and have normal embryonic serum levels of corticosteroids. Proc Natl Acad Sci U S A 92(24):10939–10943PubMedCrossRefGoogle Scholar
  14. 14.
    Schnabel CA et al (2003) Pbx1 is essential for adrenal development and urogenital differentiation. Genesis 37(3):123–130PubMedCrossRefGoogle Scholar
  15. 15.
    James RG et al (2006) Odd-skipped related 1 is required for development of the metanephric kidney and regulates formation and differentiation of kidney precursor cells. Development 133(15):2995–3004PubMedCrossRefGoogle Scholar
  16. 16.
    Katoh-Fukui Y et al (2005) Mouse Polycomb M33 is required for splenic vascular and adrenal gland formation through regulating Ad4BP/SF1 expression. Blood 106(5):1612–1620PubMedCrossRefGoogle Scholar
  17. 17.
    Val P et al (2007) Adrenal development is initiated by Cited2 and Wt1 through modulation of Sf-1 dosage. Development 134(12):2349–2358PubMedCrossRefGoogle Scholar
  18. 18.
    Zubair M et al (2006) Two-step regulation of Ad4BP/SF-1 gene transcription during fetal adrenal development: initiation by a Hox-Pbx1-Prep1 complex and maintenance via autoregulation by Ad4BP/SF-1. Mol Cell Biol 26(11):4111–4121PubMedCrossRefGoogle Scholar
  19. 19.
    Else T, Hammer GD (2005) Genetic analysis of adrenal absence: agenesis and aplasia. Trends Endocrinol Metab 16(10):458–468PubMedCrossRefGoogle Scholar
  20. 20.
    Beuschlein F et al (2002) Steroidogenic factor-1 is essential for compensatory adrenal growth following unilateral adrenalectomy. Endocrinology 143(8):3122–3135PubMedCrossRefGoogle Scholar
  21. 21.
    Pignatelli D et al (2002) Proliferation of capsular stem cells induced by ACTH in the rat adrenal cortex. Endocr Res 28(4):683–691PubMedCrossRefGoogle Scholar
  22. 22.
    Ford JK, Young RW (1963) Cell proliferation and displacement in the adrenal cortex of young rats injected with tritiated thymidine. Anat Rec 146:125–137PubMedCrossRefGoogle Scholar
  23. 23.
    Zubair M et al (2008) Developmental links between the fetal and adult zones of the adrenal cortex revealed by lineage tracing. Mol Cell Biol 28(23):7030–7040PubMedCrossRefGoogle Scholar
  24. 24.
    Ingham PW, McMahon AP (2001) Hedgehog signaling in animal development: paradigms and principles. Genes Dev 15(23):3059–3087PubMedCrossRefGoogle Scholar
  25. 25.
    Xie K, Abbruzzese JL (2003) Developmental biology informs cancer: the emerging role of the hedgehog signaling pathway in upper gastrointestinal cancers. Cancer Cell 4(4):245–247PubMedCrossRefGoogle Scholar
  26. 26.
    Han YG et al (2008) Hedgehog signaling and primary cilia are required for the formation of adult neural stem cells. Nat Neurosci 11(3):277–284PubMedCrossRefGoogle Scholar
  27. 27.
    Komada M et al (2008) Hedgehog signaling is involved in development of the neocortex. Development 135(16):2717–2727PubMedCrossRefGoogle Scholar
  28. 28.
    King P et al (2009) Shh signaling regulates adrenocortical development and identifies progenitors of steroidogenic lineages. Proc Natl Acad Sci U S A 106(50):21185–21190PubMedCrossRefGoogle Scholar
  29. 29.
    Huang CC et al (2010) Progenitor Cell Expansion and Organ Size of Mouse Adrenal Is Regulated by Sonic Hedgehog. Endocrinology 151(3):1119–1128PubMedCrossRefGoogle Scholar
  30. 30.
    Ching S, Vilain E (2009) Targeted disruption of Sonic Hedgehog in the mouse adrenal leads to adrenocortical hypoplasia. Genesis 47(9):628–637PubMedCrossRefGoogle Scholar
  31. 31.
    Muscatelli F et al (1994) Mutations in the DAX-1 gene give rise to both X-linked adrenal hypoplasia congenita and hypogonadotropic hypogonadism. Nature 372(6507):672–676PubMedCrossRefGoogle Scholar
  32. 32.
    Kim AC et al (2009) In search of adrenocortical stem and progenitor cells. Endocr Rev 30(3):241–263PubMedCrossRefGoogle Scholar
  33. 33.
    Phelan JK, McCabe ER (2001) Mutations in NR0B1 (DAX1) and NR5A1 (SF1) responsible for adrenal hypoplasia congenita. Hum Mutat 18(6):472–487PubMedCrossRefGoogle Scholar
  34. 34.
    Zanaria E et al (1994) An unusual member of the nuclear hormone receptor superfamily responsible for X-linked adrenal hypoplasia congenita. Nature 372(6507):635–641PubMedCrossRefGoogle Scholar
  35. 35.
    Peter M et al (1998) Congenital adrenal hypoplasia: clinical spectrum, experience with hormonal diagnosis, and report on new point mutations of the DAX-1 gene. J Clin Endocrinol Metab 83(8):2666–2674PubMedCrossRefGoogle Scholar
  36. 36.
    Achermann JC et al (2000) Presymptomatic diagnosis of X-linked adrenal hypoplasia congenita by analysis of DAX1. J Pediatr 137(6):878–881PubMedCrossRefGoogle Scholar
  37. 37.
    Babu PS et al (2002) Interaction between Dax-1 and steroidogenic factor-1 in vivo: increased adrenal responsiveness to ACTH in the absence of Dax-1. Endocrinology 143(2):665–673PubMedCrossRefGoogle Scholar
  38. 38.
    Gummow BM et al (2003) Convergence of Wnt signaling and steroidogenic factor-1 (SF-1) on transcription of the rat inhibin alpha gene. J Biol Chem 278(29):26572–26579PubMedCrossRefGoogle Scholar
  39. 39.
    Gummow BM et al (2006) Reciprocal regulation of a glucocorticoid receptor-steroidogenic factor-1 transcription complex on the Dax-1 promoter by glucocorticoids and adrenocorticotropic hormone in the adrenal cortex. Mol Endocrinol 20(11):2711–2723PubMedCrossRefGoogle Scholar
  40. 40.
    Niakan KK et al (2006) Novel role for the orphan nuclear receptor Dax1 in embryogenesis, different from steroidogenesis. Mol Genet Metab 88(3):261–271PubMedCrossRefGoogle Scholar
  41. 41.
    Khalfallah O et al (2009) Dax-1 knockdown in mouse embryonic stem cells induces loss of pluripotency and multilineage differentiation. Stem Cells 27(7):1529–1537PubMedCrossRefGoogle Scholar
  42. 42.
    Logan CY, Nusse R (2004) The Wnt signaling pathway in development and disease. Annu Rev Cell Dev Biol 20:781–810PubMedCrossRefGoogle Scholar
  43. 43.
    Blanpain C et al (2007) Epithelial stem cells: turning over new leaves. Cell 128(3):445–458PubMedCrossRefGoogle Scholar
  44. 44.
    Kim AC et al (2008) Targeted disruption of beta-catenin in Sf1-expressing cells impairs development and maintenance of the adrenal cortex. Development 135(15):2593–2602PubMedCrossRefGoogle Scholar
  45. 45.
    Samani AA et al (2007) The role of the IGF system in cancer growth and metastasis: overview and recent insights. Endocr Rev 28(1):20–47PubMedCrossRefGoogle Scholar
  46. 46.
    Mesiano S et al (1993) Mitogenic action, regulation, and localization of insulin-like growth factors in the human fetal adrenal gland. J Clin Endocrinol Metab 76(4):968–976PubMedCrossRefGoogle Scholar
  47. 47.
    Rainey WE et al (2002) The adrenal genetic puzzle: how do the fetal and adult pieces differ? Endocr Res 28(4):611–622PubMedCrossRefGoogle Scholar
  48. 48.
    Bendall SC et al (2007) IGF and FGF cooperatively establish the regulatory stem cell niche of pluripotent human cells in vitro. Nature 448(7157):1015–1021PubMedCrossRefGoogle Scholar
  49. 49.
    Beuschlein F et al (1994) Clonal composition of human adrenocortical neoplasms. Cancer Res 54(18):4927–4932PubMedGoogle Scholar
  50. 50.
    Gicquel C et al (1994) Clonal analysis of human adrenocortical carcinomas and secreting adenomas. Clin Endocrinol (Oxf) 40(4):465–477CrossRefGoogle Scholar
  51. 51.
    Kikuchi A (2003) Tumor formation by genetic mutations in the components of the Wnt signaling pathway. Cancer Sci 94(3):225–229PubMedCrossRefGoogle Scholar
  52. 52.
    Polakis P (2007) The many ways of Wnt in cancer. Curr Opin Genet Dev 17(1):45–51PubMedCrossRefGoogle Scholar
  53. 53.
    Fodde R, Brabletz T (2007) Wnt/beta-catenin signaling in cancer stemness and malignant behavior. Curr Opin Cell Biol 19(2):150–158PubMedCrossRefGoogle Scholar
  54. 54.
    Kinzler KW et al (1991) Identification of FAP locus genes from chromosome 5q21. Science 253(5020):661–665PubMedCrossRefGoogle Scholar
  55. 55.
    Groden J et al (1991) Identification and characterization of the familial adenomatous polyposis coli gene. Cell 66(3):589–600PubMedCrossRefGoogle Scholar
  56. 56.
    Fearnhead NS et al (2001) The ABC of APC. Hum Mol Genet 10(7):721–733PubMedCrossRefGoogle Scholar
  57. 57.
    Naylor EW, Gardner EJ (1981) Adrenal adenomas in a patient with Gardner’s syndrome. Clin Genet 20(1):67–73PubMedCrossRefGoogle Scholar
  58. 58.
    Painter TA, Jagelman DG (1985) Adrenal adenomas and adrenal carcinomas in association with hereditary adenomatosis of the colon and rectum. Cancer 55(9):2001–2004PubMedCrossRefGoogle Scholar
  59. 59.
    Tissier F et al (2005) Mutations of beta-catenin in adrenocortical tumors: activation of the Wnt signaling pathway is a frequent event in both benign and malignant adrenocortical tumors. Cancer Res 65(17):7622–7627PubMedGoogle Scholar
  60. 60.
    Giordano TJ et al (2009) Molecular classification and prognostication of adrenocortical tumors by transcriptome profiling. Clin Cancer Res 15(2):668–676PubMedCrossRefGoogle Scholar
  61. 61.
    Berthon A et al (2010) Constitutive β-catenin activation induces adrenal hyperplasia and promotes adrenal cancer development. Hum Mol Genet 19(8):1561–1576PubMedCrossRefGoogle Scholar
  62. 62.
    Harada N et al (1999) Intestinal polyposis in mice with a dominant stable mutation of the beta-catenin gene. EMBO J 18(21):5931–5942PubMedCrossRefGoogle Scholar
  63. 63.
    Liu J et al (1995) H19 and insulin-like growth factor-II gene expression in adrenal tumors and cultured adrenal cells. J Clin Endocrinol Metab 80(2):492–496PubMedCrossRefGoogle Scholar
  64. 64.
    Giordano TJ et al (2003) Distinct transcriptional profiles of adrenocortical tumors uncovered by DNA microarray analysis. Am J Pathol 162(2):521–531PubMedGoogle Scholar
  65. 65.
    West AN et al (2007) Gene expression profiling of childhood adrenocortical tumors. Cancer Res 67(2):600–608PubMedCrossRefGoogle Scholar
  66. 66.
    Velazquez-Fernandez D et al (2005) Expression profiling of adrenocortical neoplasms suggests a molecular signature of malignancy. Surgery 138(6):1087–1094PubMedCrossRefGoogle Scholar
  67. 67.
    Enklaar T et al (2006) Beckwith-Wiedemann syndrome: multiple molecular mechanisms. Expert Rev Mol Med 8(17):1–19PubMedCrossRefGoogle Scholar
  68. 68.
    Sun FL et al (1997) Transactivation of Igf2 in a mouse model of Beckwith-Wiedemann syndrome. Nature 389(6653):809–815PubMedCrossRefGoogle Scholar
  69. 69.
    Weber MM et al (1999) Postnatal overexpression of insulin-like growth factor II in transgenic mice is associated with adrenocortical hyperplasia and enhanced steroidogenesis. Endocrinology 140(4):1537–1543PubMedCrossRefGoogle Scholar
  70. 70.
    Varrault A et al (2006) Zac1 regulates an imprinted gene network critically involved in the control of embryonic growth. Dev Cell 11(5):711–722PubMedCrossRefGoogle Scholar
  71. 71.
    Barlaskar FM et al (2009) Preclinical targeting of the type I insulin-like growth factor receptor in adrenocortical carcinoma. J Clin Endocrinol Metab 94(1):204–212PubMedCrossRefGoogle Scholar
  72. 72.
    Haluska P et al (2009) Safety, tolerability, and pharmacokinetics of the anti-IGF-1R monoclonal antibody figitumumab in patients with refractory adrenocortical carcinoma. Cancer Chemother Pharmacol 65(4):765–773PubMedCrossRefGoogle Scholar
  73. 73.
    Lu J et al (1998) Capsulin: a novel bHLH transcription factor expressed in epicardial progenitors and mesenchyme of visceral organs. Mech Dev 73(1):23–32PubMedCrossRefGoogle Scholar
  74. 74.
    Quaggin SE et al (1998) Pod-1, a mesoderm-specific basic-helix-loop-helix protein expressed in mesenchymal and glomerular epithelial cells in the developing kidney. Mech Dev 71(1–2):37–48PubMedCrossRefGoogle Scholar
  75. 75.
    Cui S et al (2004) Disrupted gonadogenesis and male-to-female sex reversal in Pod1 knockout mice. Development 131(16):4095–4105PubMedCrossRefGoogle Scholar
  76. 76.
    Tamura M et al (2001) Pod-1/Capsulin shows a sex- and stage-dependent expression pattern in the mouse gonad development and represses expression of Ad4BP/SF-1. Mech Dev 102(1–2):135–144PubMedCrossRefGoogle Scholar
  77. 77.
    Doghman M et al (2007) Increased steroidogenic factor-1 dosage triggers adrenocortical cell proliferation and cancer. Mol Endocrinol 21(12):2968–2987PubMedCrossRefGoogle Scholar
  78. 78.
    Keegan CE et al (2005) Urogenital and caudal dysgenesis in adrenocortical dysplasia (acd) mice is caused by a splicing mutation in a novel telomeric regulator. Hum Mol Genet 14(1):113–123PubMedCrossRefGoogle Scholar
  79. 79.
    Bianchi A, Shore D (2008) How telomerase reaches its end: mechanism of telomerase regulation by the telomeric complex. Mol Cell 31(2):153–165PubMedCrossRefGoogle Scholar
  80. 80.
    Deng Y et al (2008) Telomere dysfunction and tumour suppression: the senescence connection. Nat Rev Cancer 8(6):450–458PubMedCrossRefGoogle Scholar
  81. 81.
    Ljungman M (2000) Dial 9-1-1 for p53: mechanisms of p53 activation by cellular stress. Neoplasia 2(3):208–225PubMedCrossRefGoogle Scholar
  82. 82.
    Else T (2009) Telomeres and telomerase in adrenocortical tissue maintenance, carcinogenesis, and aging. J Mol Endocrinol 43(4):131–141PubMedCrossRefGoogle Scholar
  83. 83.
    Dick JE (2008) Stem cell concepts renew cancer research. Blood 112(13):4793–4807PubMedCrossRefGoogle Scholar
  84. 84.
    Goodell MA et al (1996) Isolation and functional properties of murine hematopoietic stem cells that are replicating in vivo. J Exp Med 183(4):1797–1806PubMedCrossRefGoogle Scholar
  85. 85.
    Lichtenauer UD, Beuschlein F (2009) The tumor stem cell concept-implications for endocrine tumors? Mol Cell Endocrinol 300(1–2):158–163PubMedCrossRefGoogle Scholar
  86. 86.
    Hirschmann-Jax C et al (2004) A distinct “side population” of cells with high drug efflux capacity in human tumor cells. Proc Natl Acad Sci U S A 101(39):14228–14233PubMedCrossRefGoogle Scholar
  87. 87.
    Lichtenauer UD et al (2008) Side population does not define stem cell-like cancer cells in the adrenocortical carcinoma cell line NCI h295R. Endocrinology 149(3):1314–1322PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  1. 1.Department of lnternal Medicine, Division of Metabolism, Endocrinology & DiabetesUniversity of Michigan Medical SchoolAnn ArborUSA
  2. 2.Endocrine Oncology Program - Comprehensive Cancer Center, Department of Internal Medicine - Division of Metabolism, Endocrinology & Diabetes, Department of Molecular & Integrative Physiology, Department of Cell & Developmental BiologyUniversity of MichiganAnn ArborUSA

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