title: Phaeochromocytoma: a catecholamine and oxidative stress disorder.
abstract: The WHO classification of endocrine tumors defines pheochromocytoma as a tumor arising from chromaffin cells in the adrenal medulla - an intra-adrenal paraganglioma. Closely related tumors of extra-adrenal sympathetic and parasympathetic paraganglia are classified as extra-adrenal paragangliomas. Almost all pheochromocytomas and paragangliomas produce catecholamines. The concentrations of catecholamines in pheochromocytoma tissues are enormous, potentially creating a volcano that can erupt at any time. Significant eruptions result in catecholamine storms called "attacks" or "spells". Acute catecholamine crisis can strike unexpectedly, leaving traumatic memories of acute medical disaster that champions any intensive care unit. A very well-defined genotype-biochemical phenotype relationship exists, guiding proper and cost-effective genetic testing of patients with these tumors. Currently, the production of norepinephrine and epinephrine is optimally assessed by the measurement of their O-methylated metabolites, normetanephrine or metanephrine, respectively. Dopamine is a minor component, but some paragangliomas produce only this catecholamine or this together with norepinephrine. Methoxytyramine, the O-methylated metabolite of dopamine, is the best biochemical marker of these tumors. In those patients with equivocal biochemical results, a modified clonidine suppression test coupled with the measurement of plasma normetanephrine has recently been introduced. In addition to differences in catecholamine enzyme expression, the presence of either constitutive or regulated secretory pathways contributes further to the very unique mutation-dependent catecholamine production and release, resulting in various clinical presentations. Oxidative stress results from a significant imbalance between levels of prooxidants, generated during oxidative phosphorylation, and antioxidants. The gradual accumulation of prooxidants due to metabolic oxidative stress results in proto-oncogene activation, tumor suppressor gene inactivation, DNA damage, and genomic instability. Since the mitochondria serves as the main source of prooxidants, any mitochondrial impairment leads to severe oxidative stress, a major outcome of which is tumor development. In terms of cancer pathogenesis, pheochromocytomas and paragangliomas represent tumors where the oxidative phosphorylation defect due to the mutation of succinate dehydrogenase is the cause, not a consequence, of tumor development. Any succinate dehydrogenase pathogenic mutation results in the shift from oxidative phosphorylation to aerobic glycolysis in the cytoplasm (also called anaerobic glycolysis if hypoxia is the main cause of such a shift). This phenomenon, also called the Warburg effect, is well demonstrated by a positive [18F]-fluorodeoxyglycose positron emission tomography scan. Microarray studies, genome-wide association studies, proteomics and protein arrays, metabolomics, transcriptomics, and bioinformatics approaches will remain powerful tools to further uncover the pathogenesis of these tumors and their unique markers, with the ultimate goal to introduce new therapeutic options for those with metastatic or malignant pheochromocytoma and paraganglioma. Soon oxidative stress will be tightly linked to a multistep cancer process in which the mutation of various genes (perhaps in a logistic way) ultimately results in uncontrolled growth, proliferation, and metastatic potential of practically any cell. Targeting the mTORC, IGF-1, HIF and other pathways, topoisomerases, protein degradation by proteosomes, balancing the activity of protein kinases and phosphatases or even synchronizing the cell cycle before any exposure to any kind of therapy will soon become a reality. Facing such a reality today will favor our chances to "beat" this disease tomorrow.
authors: Program in Reproductive and Adult Endocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health, Bethesda, Maryland 20892, USA. karel@mail.nih.gov
authors: K
authors: K
authors: Pacak
references: Ann Surg. 2006 Jan;243(1):102-7
references: 16371743
references: J La State Med Soc. 1996 Dec;148(12):535-8
references: 8990798
references: J Biol Chem. 1964 Sep;239:2910-7
references: 14216443
references: JAMA. 2002 Mar 20;287(11):1427-34
references: 11903030
references: J Clin Endocrinol Metab. 2005 Apr;90(4):2068-75
references: 15644397
references: N Engl J Med. 1999 Jun 17;340(24):1872-9
references: 10369850
references: Hypertension. 2000 Dec;36(6):1045-52
references: 11116123
references: Hypertension. 1997 May;29(5):1133-9
references: 9149678
references: J Clin Endocrinol Metab. 2004 Jun;89(6):2859-66
references: 15181069
references: Science. 2000 Feb 4;287(5454):848-51
references: 10657297
references: Clin Genet. 2012 Mar;81(3):284-8
references: 21348866
references: Cancer Res. 2005 Apr 15;65(8):3162-70
references: 15833846
references: Clin Sci Mol Med. 1977 Dec;53(6):529-35
references: 22422
references: J Clin Endocrinol Metab. 2010 Jan;95(1):209-14
references: 19897674
references: Nat Rev Urol. 2010 May;7(5):277-85
references: 20448661
references: Eur J Endocrinol. 2008 Mar;158(3):423-9
references: 18299478
references: Cancer Sci. 2007 Aug;98(8):1184-91
references: 17559425
references: Cancer Cell. 2005 Jan;7(1):77-85
references: 15652751
references: J Clin Endocrinol Metab. 2006 Mar;91(3):827-36
references: 16317055
references: Anticancer Res. 2009 Jun;29(6):2127-36
references: 19528473
references: Clin Genet. 2009 Apr;75(4):354-63
references: 19389109
references: JAMA. 2005 Oct 26;294(16):2057-63
references: 16249420
references: Hum Mol Genet. 2010 Aug 1;19(15):3011-20
references: 20484225
references: Pharmacol Rev. 1985 Jun;37(2):165-216
references: 2996038
references: Clin Cancer Res. 2003 Sep 15;9(11):4025-33
references: 14519623
references: Nat Genet. 2000 Nov;26(3):268-70
references: 11062460
references: J Natl Med Assoc. 2003 Nov;95(11):1048-56
references: 14651371
references: Histopathology. 2010 Feb;56(3):405-8
references: 20459544
references: Hum Mol Genet. 2007 Dec 15;16(24):3136-48
references: 17884808
references: N Engl J Med. 1981 Sep 10;305(11):623-6
references: 7266587
references: Am J Med. 1991 Sep 30;91(3C):31S-38S
references: 1928209
references: Ann N Y Acad Sci. 2000;899:349-62
references: 10863552
references: Blood Press. 1995 Jul;4(4):215-7
references: 7496559
references: N Engl J Med. 2002 May 9;346(19):1459-66
references: 12000816
references: N Engl J Med. 1980 Jun 19;302(25):1390-6
references: 6246426
references: Biochem J. 2004 Feb 15;378(Pt 1):17-20
references: 14683524
references: Cancer Res. 2008 Jun 1;68(11):4058-67
references: 18519664
references: Nature. 2000 Nov 9;408(6809):239-47
references: 11089981
references: Biochem Pharmacol. 1975 Mar 15;24(6):651-3
references: 164871
references: Prog Brain Res. 2010;182:343-73
references: 20541673
references: Best Pract Res Clin Endocrinol Metab. 2010 Dec;24(6):957-68
references: 21115164
references: Science. 2009 Aug 28;325(5944):1139-42
references: 19628817
references: Am J Hum Genet. 2004 Jan;74(1):153-9
references: 14685938
references: Pediatr Nephrol. 2009 Jun;24(6):1239-42
references: 19189136
references: Biochim Biophys Acta. 2010 Jun-Jul;1797(6-7):1225-30
references: 20381449
references: J Clin Endocrinol Metab. 1995 Oct;80(10):3009-17
references: 7559889
references: Brain Res Mol Brain Res. 1998 Oct 30;61(1-2):154-61
references: 9795195
references: Am J Physiol. 1948 Jun;153(3):586-600
references: 18882199
references: World J Gastroenterol. 2010 Dec 21;16(47):5925-35
references: 21157968
references: J Clin Endocrinol Metab. 2008 Dec;93(12):4826-32
references: 18840642
references: Hypertension. 1991 Jun;17(6 Pt 1):733-41
references: 2045133
references: Am J Hum Genet. 1972 Sep;24(5):514-32
references: 4340974
references: Fed Proc. 1984 Oct;43(13):2779-84
references: 6383871
references: Ann Intern Med. 2001 Feb 20;134(4):315-29
references: 11182843
references: Hypertens Res. 2004 Mar;27(3):193-202
references: 15080378
references: Mol Aspects Med. 2010 Feb;31(1):1-20
references: 19698742
references: Am J Med. 1967 Mar;42(3):469-75
references: 6018863
references: Endocr Rev. 1994 Jun;15(3):356-68
references: 8076587
references: Best Pract Res Clin Endocrinol Metab. 2010 Dec;24(6):943-56
references: 21115163
references: Pharmacol Rev. 2011 Mar;63(1):182-217
references: 21303898
references: Chang Gung Med J. 2005 Jan;28(1):44-50
references: 15804148
references: Am J Med. 1988 Mar;84(3 Pt 1):419-24
references: 3348244
references: J Physiol. 1949 Jun 15;108(4):525-9
references: 16991883
references: Ann Clin Biochem. 2002 Nov;39(Pt 6):557-66
references: 12564837
references: Nat Rev Cancer. 2005 Nov;5(11):857-66
references: 16327764
references: Endocr Relat Cancer. 2010 Dec 21;18(1):97-111
references: 21051559
references: J Clin Endocrinol Metab. 2007 Mar;92(3):779-86
references: 17200167
references: Mol Cell Biol. 2008 Jan;28(2):718-31
references: 17967865
references: Metabolomics. 2010 Jun;6(2):229-237
references: 20445757
references: AMA Arch Intern Med. 1950 Dec;86(6):823-36
references: 14777197
references: J Bioenerg Biomembr. 2007 Feb;39(1):1-12
references: 17404823
references: J Med Genet. 2007 Sep;44(9):586-7
references: 17557926
references: J Hypertens. 1994 May;12(5):609-15
references: 7930562
references: Mitochondrion. 2006 Dec;6(6):305-14
references: 17113362
references: Endocr Rev. 2003 Aug;24(4):539-53
references: 12920154
references: Circ Res. 1987 Jul;61(1):86-98
references: 3038368
references: J Pathol. 1971 Aug;104(4):231-8
references: 5135659
references: Rev Endocr Metab Disord. 2001 Oct;2(4):385-93
references: 11725725
references: J Intern Med. 2005 Jul;258(1):55-66
references: 15953133
references: Endocrinol Metab Clin North Am. 2006 Dec;35(4):699-724, viii
references: 17127142
references: Pathol Microbiol (Basel). 1973;39(3):292-7
references: 4578025
references: J Pharmacol Exp Ther. 1980 Aug;214(2):275-81
references: 6104724
references: Ann Surg. 1951 Dec;134(6):929-33
references: 14895119
references: J Clin Invest. 1964 Jan;43:94-102
references: 14105236
references: J Clin Oncol. 2005 Dec 1;23(34):8812-8
references: 16314641
references: Hum Mol Genet. 1992 Apr;1(1):7-10
references: 1301144
references: Proc Natl Acad Sci U S A. 1999 Mar 16;96(6):2811-6
references: 10077593
references: Ann N Y Acad Sci. 2006 Aug;1073:332-47
references: 17102103
references: Urology. 1999 Apr;53(4):679-83
references: 10197840
references: N Engl J Med. 1982 Jul 1;307(1):18-29
references: 6123082
references: Clin Cancer Res. 2010 Aug 15;16(16):4148-54
references: 20592014
references: Science. 1958 Sep 12;128(3324):593-4
references: 13580222
references: J Neurochem. 1996 Apr;66(4):1565-73
references: 8627312
references: Ann Intern Med. 1979 Sep;91(3):450-8
references: 38720
references: Science. 2010 Dec 3;330(6009):1340-4
references: 21127244
references: Tokai J Exp Clin Med. 1988 Jun;13(2):71-8
references: 3074524
references: J Clin Endocrinol Metab. 1997 Nov;82(11):3864-71
references: 9360553
references: Oncogene. 2006 Aug 7;25(34):4675-82
references: 16892081
references: Nutr Metab (Lond). 2010 Jan 27;7:7
references: 20181022
references: Biochim Biophys Acta. 1957 Aug;25(2):422-3
references: 13471587
references: Cancer Res. 2002 Nov 15;62(22):6674-81
references: 12438266
references: Clin Chem. 1994 Feb;40(2):250-6
references: 7906208
references: J Clin Oncol. 2007 Jun 1;25(16):2262-9
references: 17538171
references: PLoS One. 2009 Sep 18;4(9):e7094
references: 19763184
references: J Auton Nerv Syst. 1994 Dec 1;50(1):93-107
references: 7844319
references: Science. 1957 Aug 30;126(3270):400-1
references: 13467217
references: Endocr Relat Cancer. 2011 Jan 13;18(1):143-57
references: 21098082
references: J Clin Endocrinol Metab. 2010 Feb;95(2):481-2
references: 20133468
references: Ugeskr Laeger. 1951 Aug 9;113(32):1068
references: 14867019
references: Cell Tissue Res. 1976 Sep 14;172(2):281-8
references: 991214
references: Eur J Endocrinol. 2005 Oct;153(4):551-63
references: 16189177
references: Arch Pathol Lab Med. 1976 Dec;100(12):636-9
references: 187143
references: Rev Endocr Metab Disord. 2003 May;4(2):121-8
references: 12766539
references: J Med Genet. 2002 Mar;39(3):178-83
references: 11897817
references: Rev Endocr Metab Disord. 2001 Aug;2(3):297-311
references: 11708294
references: Carcinogenesis. 2007 Apr;28(4):785-91
references: 17127713
references: J Clin Endocrinol Metab. 2009 Aug;94(8):2952-7
references: 19491224
references: Trends Endocrinol Metab. 2003 Dec;14(10):453-9
references: 14643060
references: Life Sci. 1996;59(19):1659-65
references: 8913331
references: Biochim Biophys Acta. 2011 Jun;1807(6):543-51
references: 21035425
references: Res Commun Chem Pathol Pharmacol. 1981 Dec;34(3):389-98
references: 7323441
references: Virchows Arch A Pathol Anat Histopathol. 1992;421(1):25-32
references: 1353277
references: Clin Sci (Lond). 1980 Dec;59 Suppl 6:225s-228s
references: 6108815
references: J Biol Chem. 1966 May 25;241(10):2301-5
references: 4287854
references: Endocr Relat Cancer. 2009 Mar;16(1):291-9
references: 19075037
references: Am Heart J. 1976 Apr;91(4):527-34
references: 769520
references: PLoS Genet. 2005 Jul;1(1):72-80
references: 16103922
references: Endocrinol Metab Clin North Am. 1993 Jun;22(2):329-41
references: 8325290
references: Clin Chem. 2011 Mar;57(3):411-20
references: 21262951
references: Pediatrics. 2006 Sep;118(3):1109-17
references: 16951005
references: Cancer Biol Ther. 2011 Apr 15;11(8):701-7
references: 21311212
references: J Urol. 1988 Dec;140(6):1348-51
references: 2903937
references: JAMA. 2004 Aug 25;292(8):943-51
references: 15328326
references: Lancet. 2005 Aug 20-26;366(9486):665-75
references: 16112304
references: Nat Rev Cancer. 2003 Mar;3(3):193-202
references: 12612654
references: Am J Physiol. 1995 Apr;268(4 Pt 1):G641-9
references: 7733289
references: Eur J Endocrinol. 2006 Mar;154(3):409-17
references: 16498054
references: J Clin Endocrinol Metab. 2007 Nov;92(11):4069-79
references: 17989126
references: Ann Intern Med. 1986 Dec;105(6):887-8
references: 3096183
references: J Hypertens. 2001 Jun;19(6):1029-35
references: 11403350
references: J Clin Endocrinol Metab. 1998 Jun;83(6):2175-85
references: 9626157
references: J Clin Endocrinol Metab. 2006 Nov;91(11):4505-9
references: 16912137
references: J Clin Endocrinol Metab. 2006 Nov;91(11):4593-8
references: 16954163
references: J Natl Cancer Inst. 2001 Apr 18;93(8):648-9
references: 11309443
references: Arch Intern Med. 2000 Oct 23;160(19):2957-63
references: 11041903
references: Surgery. 1986 Dec;100(6):1154-62
references: 3787474
references: Am J Med. 1970 May;48(5):654-60
references: 5425242
references: J Clin Endocrinol Metab. 2010 Mar;95(3):1274-8
references: 19915015
references: J Natl Cancer Inst. 2008 Sep 3;100(17):1260-2
references: 18728283
references: Clin Chim Acta. 1972 Jul;39(2):417-24
references: 4402930
references: J Clin Endocrinol Metab. 1986 Jul;63(1):238-42
references: 3711261
references: J Clin Endocrinol Metab. 2003 Jun;88(6):2656-66
references: 12788870
references: J Endocrinol Invest. 1992 Oct;15(9):631-42
references: 1479146
references: J Clin Hypertens (Greenwich). 2002 Jan-Feb;4(1):62-72
references: 11821644
references: J Recept Signal Transduct Res. 2010 Oct;30(5):347-54
references: 20684667
references: Am J Physiol Endocrinol Metab. 2008 Nov;295(5):E1223-33
references: 18854424
references: Cancer Cell. 2005 Aug;8(2):155-67
references: 16098468
references: Nature. 1998 Aug 13;394(6694):694-7
references: 9716135
references: Anasthesiol Intensivmed Notfallmed Schmerzther. 1995 Oct;30(6):341-9
references: 8541435
references: J Clin Endocrinol Metab. 2010 Jan;95(1):238-45
references: 19897672
references: Scand J Clin Lab Invest. 1952;4(4):263-5
references: 13048603
references: Am J Med. 1948 Dec;5(6):792-806
references: 18100389
references: J Urol. 2004 Oct;172(4 Pt 1):1409-10
references: 15371856
references: Science. 1956 Feb 24;123(3191):309-14
references: 13298683
references: Hum Mol Genet. 2005 Nov 1;14(21):3263-9
references: 16195397