Skip to main content
Log in

Chromaffin cell biology: inferences from The Cancer Genome Atlas

  • Review
  • Published:
Cell and Tissue Research Aims and scope Submit manuscript

Abstract

Pheochromocytomas and paragangliomas (PCC/PGLs) are rare neuroendocrine tumors that are unusually diverse in metabolic profiles, in classes of molecular alterations and across a large number of altered genes. The Cancer Genome Atlas (TCGA) comprehensively profiled the molecular landscape of PCC/PGLs and identified novel genomic alterations and a new molecular classification of PCC/PGLs. In this review, we discuss the significant clinico-molecular findings of this integrated profiling study. We then review the molecular data of the TCGA cohort centering around known markers of sympathoadrenal cell lineage to better understand chromaffin cell biology. This analysis adds a new layer, that of chromaffin cell type, onto the published molecular classifications and in doing so provides inferences about underlying chromaffin cell biology and diversity.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2

Similar content being viewed by others

References

  • Ayala-Ramirez M, Feng L, Johnson MM, Ejaz S, Habra MA, Rich T, Busaidy N, Cote GJ, Perrier N, Phan A, Patel S, Waguespack S, Jimenez C (2011) Clinical risk factors for malignancy and overall survival in patients with pheochromocytomas and sympathetic paragangliomas: primary tumor size and primary tumor location as prognostic indicators. J Clin Endocrinol Metab 96:717–725

    Article  CAS  PubMed  Google Scholar 

  • Bilek R, Safarik L, Ciprova V, Vlcek P, Lisa L (2008) Chromogranin A, a member of neuroendocrine secretory proteins as a selective marker for laboratory diagnosis of pheochromocytoma. Physiol Res 57(Suppl 1):S171–S179

    CAS  PubMed  Google Scholar 

  • Burnichon N, Vescovo L, Amar L, Libe R, de Reynies A, Venisse A, Jouanno E, Laurendeau I, Parfait B, Bertherat J, Plouin PF, Jeunemaitre X, Favier J, Gimenez-Roqueplo AP (2011) Integrative genomic analysis reveals somatic mutations in pheochromocytoma and paraganglioma. Hum Mol Genet 20:3974–3985

    Article  CAS  PubMed  Google Scholar 

  • Burnichon N, Cascon A, Schiavi F, Morales NP, Comino-Mendez I, Abermil N, Inglada-Perez L, de Cubas AA, Amar L, Barontini M, de Quiros SB, Bertherat J, Bignon YJ, Blok MJ, Bobisse S, Borrego S, Castellano M, Chanson P, Chiara MD, Corssmit EP, Giacche M, de Krijger RR, Ercolino T, Girerd X, Gomez-Garcia EB, Gomez-Grana A, Guilhem I, Hes FJ, Honrado E, Korpershoek E, Lenders JW, Leton R, Mensenkamp AR, Merlo A, Mori L, Murat A, Pierre P, Plouin PF, Prodanov T, Quesada-Charneco M, Qin N, Rapizzi E, Raymond V, Reisch N, Roncador G, Ruiz-Ferrer M, Schillo F, Stegmann AP, Suarez C, Taschin E, Timmers HJ, Tops CM, Urioste M, Beuschlein F, Pacak K, Mannelli M, Dahia PL, Opocher G, Eisenhofer G, Gimenez-Roqueplo AP, Robledo M (2012) MAX mutations cause hereditary and sporadic pheochromocytoma and paraganglioma. Clin Cancer Res 18:2828–2837

    Article  CAS  PubMed  Google Scholar 

  • Castro-Vega LJ, Letouze E, Burnichon N, Buffet A, Disderot PH, Khalifa E, Loriot C, Elarouci N, Morin A, Menara M, Lepoutre-Lussey C, Badoual C, Sibony M, Dousset B, Libe R, Zinzindohoue F, Plouin PF, Bertherat J, Amar L, de Reynies A, Favier J, Gimenez-Roqueplo AP (2015) Multi-omics analysis defines core genomic alterations in pheochromocytomas and paragangliomas. Nat Commun 6:6044

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chan WH, Gonsalvez DG, Young HM, Southard-Smith EM, Cane KN, Anderson CR (2016) Differences in CART expression and cell cycle behavior discriminate sympathetic neuroblast from chromaffin cell lineages in mouse sympathoadrenal cells. Dev Neurobiol 76:137–149

    Article  CAS  PubMed  Google Scholar 

  • Creutz CE, Pazoles CJ, Pollard HB (1978) Identification and purification of an adrenal medullary protein (synexin) that causes calcium-dependent aggregation of isolated chromaffin granules. J Biol Chem 253:2858–2866

    CAS  PubMed  Google Scholar 

  • Dahia PL, Hao K, Rogus J, Colin C, Pujana MA, Ross K, Magoffin D, Aronin N, Cascon A, Hayashida CY, Li C, Toledo SP, Stiles CD (2005) Novel pheochromocytoma susceptibility loci identified by integrative genomics. Cancer Res 65:9651–9658

    Article  CAS  PubMed  Google Scholar 

  • Eisenhofer G, Walther MM, Huynh TT, Li ST, Bornstein SR, Vortmeyer A, Mannelli M, Goldstein DS, Linehan WM, Lenders JW, Pacak K (2001) Pheochromocytomas in von Hippel-Lindau syndrome and multiple endocrine neoplasia type 2 display distinct biochemical and clinical phenotypes. J Clin Endocrinol Metab 86:1999–2008

    Article  CAS  PubMed  Google Scholar 

  • Eisenhofer G, Huynh TT, Pacak K, Brouwers FM, Walther MM, Linehan WM, Munson PJ, Mannelli M, Goldstein DS, Elkahloun AG (2004) Distinct gene expression profiles in norepinephrine- and epinephrine-producing hereditary and sporadic pheochromocytomas: activation of hypoxia-driven angiogenic pathways in von Hippel-Lindau syndrome. Endocr Relat Cancer 11:897–911

    Article  CAS  PubMed  Google Scholar 

  • Fishbein L (2016) Pheochromocytoma and paraganglioma: genetics, diagnosis, and treatment. Hematol Oncol Clin North Am 30:135–150

    Article  PubMed  Google Scholar 

  • Fishbein L, Merrill S, Fraker DL, Cohen DL, Nathanson KL (2013) Inherited mutations in pheochromocytoma and paraganglioma: why all patients should be offered genetic testing. Ann Surg Oncol 20:1444–1450

    Article  PubMed  PubMed Central  Google Scholar 

  • Fishbein L, Khare S, Wubbenhorst B, DeSloover D, D'Andrea K, Merrill S, Cho NW, Greenberg RA, Else T, Montone K, LiVolsi V, Fraker D, Daber R, Cohen DL, Nathanson KL (2015) Whole-exome sequencing identifies somatic ATRX mutations in pheochromocytomas and paragangliomas. Nat Commun 6:6140

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fishbein L, Leshchiner I, Walter V, Danilova L, Robertson AG, Johnson AR, Lichtenberg TM, Murray BA, Ghayee HK, Else T, Ling S, Jefferys SR, de Cubas AA, Wenz B, Korpershoek E, Amelio AL, Makowski L, Rathmell WK, Gimenez-Roqueplo AP, Giordano TJ, Asa SL, Tischler AS, Pacak K, Nathanson KL, Wilkerson MD (2017) Comprehensive molecular characterization of pheochromocytoma and paraganglioma. Cancer Cell 31:181–193

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Furlan, A, Dyachuk, V, Kastriti, ME, Calvo-Enrique, L, Abdo, H, Hadjab, S, Chontorotzea, T, Akkuratova, N, Usoskin, D, Kamenev, D, Petersen, J, Sunadome, K, Memic, F, Marklund, U, Fried, K, Topilko, P, Lallemend, F, Kharchenko, PV, Ernfors, P, Adameyko, I (2017) Multipotent peripheral glial cells generate neuroendocrine cells of the adrenal medulla. Science 357:doi: https://doi.org/10.1126/science.aal3753

  • Huber K, Bruhl B, Guillemot F, Olson EN, Ernsberger U, Unsicker K (2002) Development of chromaffin cells depends on MASH1 function. Development 129:4729–4738

    CAS  PubMed  Google Scholar 

  • Huber K, Kalcheim C, Unsicker K (2009) The development of the chromaffin cell lineage from the neural crest. Auton Neurosci 151:10–16

    Article  CAS  PubMed  Google Scholar 

  • Kimura N, Takayanagi R, Takizawa N, Itagaki E, Katabami T, Kakoi N, Rakugi H, Ikeda Y, Tanabe A, Nigawara T, Ito S, Kimura I, Naruse M (2014) Pathological grading for predicting metastasis in phaeochromocytoma and paraganglioma. Endocr Relat Cancer 21:405–414

    Article  PubMed  Google Scholar 

  • Kumakura K, Karoum F, Guidotti A, Costa E (1980) Modulation of nicotinic receptors by opiate receptor agonists in cultured adrenal chromaffin cells. Nature 283:489–492

    Article  CAS  PubMed  Google Scholar 

  • Langley K, Grant NJ (1999) Molecular markers of sympathoadrenal cells. Cell Tissue Res 298:185–206

    Article  CAS  PubMed  Google Scholar 

  • Letouze E, Martinelli C, Loriot C, Burnichon N, Abermil N, Ottolenghi C, Janin M, Menara M, Nguyen AT, Benit P, Buffet A, Marcaillou C, Bertherat J, Amar L, Rustin P, De Reynies A, Gimenez-Roqueplo AP, Favier J (2013) SDH mutations establish a hypermethylator phenotype in paraganglioma. Cancer Cell 23:739–752

    Article  CAS  PubMed  Google Scholar 

  • Mannelli M, Maggi M, DeFeo ML, Boscaro M, Opocher G, Mantero F, Baldi E, Giusti G (1986) Opioid modulation of normal and pathological human chromaffin tissue. J Clin Endocrinol Metab 62:577–582

    Article  CAS  PubMed  Google Scholar 

  • Phillips JK, Goodchild AK, Dubey R, Sesiashvili E, Takeda M, Chalmers J, Pilowsky PM, Lipski J (2001) Differential expression of catecholamine biosynthetic enzymes in the rat ventrolateral medulla. J Comp Neurol 432:20–34

    Article  CAS  PubMed  Google Scholar 

  • TCGA (2014) The cancer genome atlas: charting a new course for cancer prevention, diagnosis and treatment. National Cancer Institute and National Human Genome Research Institute NIH Publication No. 14-8009

  • Thompson LD (2002) Pheochromocytoma of the Adrenal gland Scaled Score (PASS) to separate benign from malignant neoplasms: a clinicopathologic and immunophenotypic study of 100 cases. Am J Surg Pathol 26:551–566

    Article  PubMed  Google Scholar 

  • Tian H, Hammer RE, Matsumoto AM, Russell DW, McKnight SL (1998) The hypoxia-responsive transcription factor EPAS1 is essential for catecholamine homeostasis and protection against heart failure during embryonic development. Genes Dev 12:3320–3324

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tillinger A, Sollas A, Serova LI, Kvetnansky R, Sabban EL (2010) Vesicular monoamine transporters (VMATs) in adrenal chromaffin cells: stress-triggered induction of VMAT2 and expression in epinephrine synthesizing cells. Cell Mol Neurobiol 30:1459–1465

    Article  CAS  PubMed  Google Scholar 

  • Unsicker K, Huber K, Schober A, Kalcheim C (2013) Resolved and open issues in chromaffin cell development. Mech Dev 130:324–329

    Article  CAS  PubMed  Google Scholar 

  • Welander J, Andreasson A, Brauckhoff M, Backdahl M, Larsson C, Gimm O, Soderkvist P (2014) Frequent EPAS1/HIF2alpha exons 9 and 12 mutations in non-familial pheochromocytoma. Endocr Relat Cancer 21:495–504

    Article  CAS  PubMed  Google Scholar 

  • Witchel SF (2017) Congenital adrenal hyperplasia. J Pediatr Adolesc Gynecol. https://doi.org/10.1016/j.jpag.2017.04.001

Download references

Funding

LF is supported by the American Cancer Society Mentored Research Scholar Grant MRSG-15-063-01-TBG.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Matthew D. Wilkerson.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Disclaimer

The views expressed in this article are those of the authors and do not reflect the official policy of the Department of Defense or U.S. Government.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Fishbein, L., Wilkerson, M.D. Chromaffin cell biology: inferences from The Cancer Genome Atlas. Cell Tissue Res 372, 339–346 (2018). https://doi.org/10.1007/s00441-018-2795-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00441-018-2795-0

Keywords

Navigation