Cells which express morphological and functional markers originally described in neurons and neural crest-derived endocrine cells are now known to originate from both ectodermal and endodermal progenitors. These cells are organized to secrete peptides, amines, and other regulatory products in response to neurogenic or chemical stimulation. Individual products may function in endocrine, paracrine, neurotransmitter, or neuromodulatory roles. Multiple products are of ten produced by individual cells and stored in the same secretory granules. The hormonal profiles of particular types of neuroendocrine cells can, to varying degrees, be changed by environmental signals during development or in adult life. These changes are caused both by transcriptional and post-transcriptional mechanisms. Hormonal profiles are also altered during the development and progression of neoplasia. Signals which stimulate hormone secretion produce a number of ancillary effects, including activation and induction of enzymes which replenish hormone stores, activation of cellular oncogenes, and stimulation of cell proliferation. The effects of environmental signals on neuroendocrine cells are mediated by intracellular transduction pathways which involve cyclic AMP, phosphatidylinositol, calcium, and receptor protein kinase activity. These effects can be potentiated, inhibited, or qualitatively altered by exogenous agents.
1. Arias-Stella J and Valcarcel J (1976). Chief cell hyperplasia in the human carotid body at high altitudes.Hum. Pathol.7: 361–373.
2.
2. Barasch JM, Tamir H, Nunez EA, and Gershon MD (1987). Serotonin-storing secretory granules from thyroid parafollicular cells.J. Neurosci.7: 4017–4033.
3.
3. Berridge MJ (1987). Inositol trisphosphate and diacylglycerol: Two interacting second messengers.Ann. Rev. Biochem.56: 159–193.
4.
4. Brodeur GM, Seeger RC, Schwab M, Varmus HE, and Bishop JM (1984). Amplification of N-myc in untreated human neuroblastomas correlates with advanced disease stage.Science224: 1121–1124.
5.
5. Bussolati G and Pearse AGE (1967). Immunofluorescent localization of calcitonin in the C-cells of the dog and pig thyroid.J. Endocrinol.37: 205–209.
6.
6. Campbell AK (1983). Intracellular Calcium: Its Universal Role as Regulator.John Wiley & Sons, New York.
8. Carty SE, Johnson RG, and Scarpa A (1987). Electrochemical proton gradients in amine and peptide containing subcellular organelles. In: Cellular and Molecular Biology of Hormone and Neurotransmitter-Containing Secretory Vesicles, RG Johnson (ed). New York Acad. Science, New York.
9.
9. Chantry CJ, Seidler FJ, and Slotkin TA (1982). Nonneurogenic mechanism for reserpine-induced release of catecholamines from the adrenal medulla of neonatal rats: Possible modulation of opiate receptors.Neuroscience7: 673–678.
10.
10. DeLellis RA, Tischler AS, and Wolfe HJ (1984). Multidirectional differentiation in endocrine neoplasms.J. Histochem. Cytochem.32: 899–904.
11.
11. di Sant'Agnese PA and de-Mesy-Jensen KL (1987). Neuroendocrine differentiation in prostatic carcinoma.Hum. Pathol.18: 849–856.
12.
12. Dobner PR, Tischler AS, Lee YC, Bloom SR, and Donahue SR (1988). Lithium dramatically potentiates neurotensin/neuromedin-N gene expression.J. Biol. Chem.263: 13983–13986.
13.
13. Doupe AJ, Landis SC, and Patterson PH (1985). Environmental influences in the development of neural crest derivatives: Glucocorticoids, growth factor and chromaffin cell plasticity.J. Neurosci.5: 2119–2142.
14.
14. Eisenbarth GS, Shimizu K, Bowring MS, and Wells SA (1982). Expression of receptors for tetanus toxin and monoclonal antibody A2B5 by pancreatic islet cells.Proc. Natl. Acad. Sci. USA79: 5066–5070.
15.
15. El Etreby MF and Gunzel P (1974). Sex hormones. Effects on prolactin cells in the rat, dog, monkey, and man. Histomorphological and immunocytochemical studies.Acta Endocrinol. Suppl. 76: 189.
16.
16. Erny R and Wagner JA (1984). Adenosine-dependent activation of tyrosine hydroxylase is defective in adenosine kinase deficient PC12 cells.Proc. Natl. Acad. Sci. USA81: 4974–4978.
17.
17. Forsberg E, Feurstein G, Shohami E, and Pollard HB (1987). Adenosine triphosphate stimulates inositol phospholipid metabolism and prostacyclin formation in adrenal medullary endothelial cells via P2 purinergic receptors.Proc. Natl. Acad. Sci. USA84: 5630–5634.
18.
18. Fujita T, Kanno T, and Kobayshi S (eds) (1988). The Paraneurons.Springer-Verlag, Berlin.
19.
19. Furth J, Dent JN, Burnett WT, and Gadsden EL (1955). The mechanism of induction and the characteristics of pituitary tumors induced by thyroidectomy.J. Clin. Endocrinol. Metab.15: 81–97.
20.
20. Gould VE (1985). The coexpression of distinct classes of intermediate filaments in human neoplasms.Arch. Pathol. Lab. Med.109: 984–985.
21.
21. Gould VE and DeLellis RA (1983). The neuroendocrine cell system: Its tumors, hyperplasias and dysplasias. In: Surgical Pathology, SG Silverberg (ed). John Wiley and Sons, New York, pp. 1487–1501.
22.
22. Gould VE, Lee I, Wiedenmann B, Moll R, Chejfec C, and Franke WW (1986). Synaptophysin: A novel marker for neurons, certain neuroendocrine cells and their neoplasms.Hum. Pathol.17: 979–983.
23.
23. Greenberg ME, Greene LA, and Ziff EB (1985). Nerve growth factor and epidermal growth factor induce. rapid transient changes in proto-oncogene transcription in PC12 cells.J. Biol. Chem.260: 14101–14110.
24.
24. Greenberg ME, Ziff EB, and Greene LA (1986). Stimulation of neuronal acetylcholine receptors induces rapid gene transcription.Science234: 80–83.
25.
25. Greene LA and Tischler AS (1976). Establishment of a noradrenergic clonal line of rat adrenal pheochromocytoma cells which respond to nerve growth factor.Proc. Natl. Acad. Sci. USA73: 2424–2428.
26.
26. Greene LA and Tischler AS (1982). PC12 pheochromocytoma cultures in neurobiological research. In: Advances in Cellular Neurobiology, S Federoff and L Hertz (ed). Academic Press, New York, p. 373.
27.
27. Greenfield S (1984). Acetylcholinesterase may have novel functions in the brain.Trends Neurosci.October: 364–368.
28.
28. Guillemin R, Brazeau P, Bohlen P, Esch F, Ling N, and Wehrenberg WB (1982). Growth hormone-releasing factor from a human pancreatic tumor that caused acromegaly.Science218: 585–587.
29.
29. Håkanson R and Sundler F (1983). The design of the neuroendocrine system: A unifying concept and its consequences.Trends Pharmacol. Sci.4: 41–44.
30.
30. Håkanson R, Ekelund M, and Sundler F (1984). Activation and proliferation of gastric endocrine cells. In: Evolution and Tumor Pathology of the Neuroendocrine System, S Falkner, R Håkanson, and F Sundler (eds). Elsevier Science Publishers, Amsterdam, pp. 371–398.
31.
31. Höfler H, Tischler AS, DeLellis RA, Merck F, and Wolfe HJ (1988). Increased expression of c-fos oncogene mRNA after depolarization of diverse neuroendocrine cell types.Lab. Invest.58: 39A.
32.
32. Holm R, Sobrinho-Simoes M, Nesland JM, Samade C and Johannessen JC (1987). Medullary thyroid carcinoma with thyroglobulin immuno-reactivity. A special entity?Lab. Invest.57: 258–268.
33.
33. Huff KR and Guroff G (1979). Nerve growth factor-induced reduction in epidermal growth factor receptors in PC12 cells: An aspect of cell differentiation.Biochem. Biophys. Res. Commun.89: 175–180.
34.
34. Isaacson P (1981). Crypt cell carcinoma of the appendix (so-called adenocarcinoid).Am. J. Surg. Path.5213: .
35.
35. Johnson RG (ed) (1987). Cellular and Molecular Biology of Hormone and Neurotransmitter-Containing Secretory Vesicles.New York Acad. Science, New York.
36.
36. Jumblatt JE and Tischler AS (1982). Regulation of muscarinic ligand binding sites by nerve growth factor in PC12 pheochromocytoma cells.Nature297152: .
37.
37. Kelly RB (1985). Pathways of protein secretion in eukaryotes.Science230: 25–32.
38.
38. Krook L, Lutwak L, and McEntee K (1969). Dietary calcium, ultimobranchial tumors and osteoporosis in the bull.Am. J. Clin. Nutr.22: 115–118.
39.
39. Larsson LI (1985). Differential changes in calcitonin, somatostatin and gastrin/cholecystokinin-like immunoreactivities in rat thyroid parafollicular cells during ontogeny.Histochemistry82: 121–130.
40.
40. Lauweryns JM and Van Ranst L (1988). Immunocytochemical localization of aromatic L-amino acid decarboxylase in human, rat and mouse bronchopulmonary and gastrointestinal endocrine cells.J. Histochem. Cytochem.36: 1181–1186.
41.
41. Lauweryns JM and Van Ranst L (1988). Protein gene product 9.5 expression in the lungs of humans and other mammals. Immunocytochemical detection in neuroepithelial bodies, neuroendocrine cells and nerves.Neurosci. Lett.85: 311–316.
42.
42. Le Douarin N (1982). The Neural Crest.Cambridge University Press, Cambridge.
43.
43. Le Douarin N and Teillet MA (1973). The migration of neural crest cells to the wall of the digestive tract in avian embryo.J. Embryol. Exp. Morphol.30: 31–48.
44.
44. Lipinski M, Braham K, Caillud J-M, Carlu C, and Tursz T (1983). HNK-1 antibody detects an antigen expressed on neuroectodermal cells.J. Exp. Med.1581775: .
45.
45. Livett BG, Boksa P, Dean DM, Mizobe F, and Lindenbaum MH (1983). Use of isolated chromaffin cells to study basic release mechanisms.J. Autonom. Nervous Syst.7: 59–86.
46.
46. Lloyd RV, Sisson K, Shapiro B, and Verhofstad AAJ (1986). Histochemical localization of epinephrine, norepinephrine, catecholamine-synthesizing enzymes, and chromogranin in neuroendocrine cells and tumors.Am. J. Pathol.125: 45–54.
47.
47. Mains RE and Patterson PH (1973). Primary cultures of dissociated sympathetic neurons. I. Establishment of long-term growth in culture and studies of differentiated properties.J. Cell Biol.59: 329–345.
48.
48. Maruyama K, Schiavi SC, Huse W, Johnson GL, and Ruley HE (1987). Myc and E1A oncogenes alter the responses of PC12 cells to nerve growth factor and block differentiation.Oncogene1: 361–367.
49.
49. Meldolesi J and Pozzan T (1987). Pathways of Ca++ influx at the plasma membrane: Voltage-, receptor-, and second messenger-operated channels.Exp. Cell Res.171: 271–283.
50.
50. Navone F, Jahn R, DiGioia G, Stukenbrok H, Greengard P, and De Camilli P (1986). Protein p38: An integral membrane protein specific for small vesicles of neurons and neuro-endocrine cells.J. Cell Biol.103: 2511–2527.
51.
51. Neer EG and Clapham DE (1988). Roles of G-protein subunits in transmembrane signalling.Nature333: 129–134.
52.
52. Nesland JM, Memoli VA, Holm R, Gould VE, and Johannessen VE (1985). Breast carcinomas with neuroendocrine differentiation.Ultrastruc. Pathol.8225: .
53.
53. Niki A, Niki H, and Hashioka T (1989). Receptors of paraneurons, with special reference to glucose receptors. Arch. Histol. (in press).
54.
54. Nishizuka Y (1984). Turnover of inositol phospholipids and signal transduction.Science225: 1365–1370.
55.
55. Njus D, Knoth J, and Zallakian M (1981). Proton linked transport in chromaffin granules.Curr. Top. Bioenerg.11: 107–147.
56.
56. Pasmantier R, Danoff A, Fleischer N, and Schubart UK (1986). P19, a hormonally regulated phospho-protein of peptide hormone-producing cells: Secretagogue-induced phosphorylation in AtT-20 mouse pituitary tumor cells and in rat and hamster insulinoma cells.Endocrinology19: 1229–1238.
57.
57. Payne CM, Nagle R, and Borduin V (1984). An ultrastructural cytochemical stain for human neuroendocrine neoplasms.Lab. Invest.51: 350–365.
58.
58. Pearse AGE (1966). Common cytochemical properties of cells producing polypeptide hormones, with particular reference to calcitonin and thyroid C-cells.Vet. Rec.79: 587–590.
59.
59. Pearse AGE (1977). The diffuse neuroendocrine system and the APUD concept: Related endocrine peptides in brain, intestine, pituitary, placenta, and anuran cutaneous glands.Med. Biol.55: 115–125.
60.
60. Perlman RL, Sheard BE, Tischler AS, and Kwan PWL (1982). Monensin depletes PC12 pheochromocytoma cells of catecholamines and of chromaffin-type granules.Neurosci. Lett.29177: .
61.
61. Polak JM, Pearse AGE, LeLievre C, Fontaine J, and Le Douarin NM (1974). Immunocytochemical confirmation of the neural crest origin of avian calcitonin-producing cells.Histochemistry40: 209–214.
62.
62. Pruss RM and Shepard EA (1987). Cytochrome b561 can be detected in many neuroendocrine tissues using a specific monoclonal antibody.Neuroscience22: 149–157.
63.
63. Rasmussen H (1986). The calcium messenger system.New Engl. J. Med.314: 1094–1101, 1164–1170.
64.
64. Rosen OM (1987). After insulin binds.Science237: 1452–1458.
65.
65. Rosenfeld MG, Mermod JJ, and Amara SG (1983). Production of a novel neuropeptide encoded by the calcitonin gene via tissue specific RNA processing.Nature304: 129–135.
66.
66. Rosenheck K and Lelkes PI (1987). Stimulus-Secretion Coupling in Chromaffin Cells, Vols. 1 & 2. CRC Press Inc., Boca Raton, Florida.
67.
67. Ruff MR and Pert CB (1984). Small cell carcinoma of the lung: Macrophage specific antigens suggest hematopoietic stem cell origin.Science225: 1034–1036.
68.
68. Schmechel D (1985). Gamma subunit of the glycolytic enzyme enolase: Non-specific or neuron-specific?Lab. Invest.52: 239–242.
69.
69. Schmechel D, Marangos PJ, and Brightman M (1978). Neuron-specific enolase is a molecular marker for peripheral and central neuroendocrine cells.Nature17: 834–836.
70.
70. Scully RE, Aguirre P, and DeLellis RA (1984). Argyrophilia, serotonin and peptide hormones in the female genital tract and its tumors.Int. J. Gynec. Path.351: .
71.
71. Seeger RC, Danon YL, Rayner SA, and Hoover F (1982). Definition of thy-1 on human neuroblastoma, glioma, sarcoma, and teratoma cells with a monoclonal antibody.J. Immunol.128: 983–989.
72.
72. Sietzen M, Schober M, Fischer-Colbrie R, Scherman D, Sperk G, and Winkler H (1987). Rat adrenal medulla. Levels of chromogranins, enkephalins, dopamine beta-hydroxylase and the amine transporter are changed by nervous activity and hypophysectomy.Neuroscience22: 131–139.
73.
73. Smith DM and Haggit RC (1984). The prevalence and prognostic significance of argyrophil cells in colorectal carcinomas.Am. J. Surg. Pathol.8: 123–129.
74.
74. Sonnenfeld KH and Ishii DN (1982). Nerve growth factor effects and receptors in cultured human neuroblastoma cell lines.J. Neurosci. Res.8: 375–391.
75.
75. Spiegal AM, Gierschick P, Levine MA, and Downs RN (1985). Clinical implications of guanine nucleotide-binding proteins as receptor-effector couplers.N. Engl. J. Med.312: 26–33.
76.
76. Teitleman G, Joh TH, and Reiss DD (1981). Transformation of catecholaminergic precursors into glucagon (A) cells in mouse embryonic pancreas.Proc. Natl. Acad. Sci. USA78: 5225–5229.
77.
77. Tischler AS (1983). Gut peptide production by tumor cell lines in culture.Scand. J. Gastroenterol. Suppl. 82, 18: 33–43.
78.
78. Tischler AS, DeLellis RA, Biales B, Nunnemacher G, Carabba V, and Wolfe HJ (1980). Nerve growth factor-induced neurite outgrowth from normal human chromaffin cells.Lab. Invest.43: 398–409.
79.
79. Tischler AS, Dichter M, Biales B, DeLellis RA, and Wolfe HJ (1976). Neural properties of cultured human endocrine tumors of proposed neural crest origin.Science192902: .
80.
80. Tischler AS, Dichter M, Biales B, and Greene LA (1977). Neuroendocrine neoplasms and their cells of origin.N. Engl. J. Med.296: 919–925.
81.
81. Tischler AS and Greene LA (1975). Nerve growth factor-induced process formation by cultured rat pheochromocytoma cells.Nature258: 341–342.
82.
82. Tischler AS, Lee YC, Perlman RL, Costopoulos D, and Bloom SR (1985). Production of “ectopic” vasoactive intestinal peptide like immunoreactivity in normal human chromaffin cell cultures.Life Sci.37: 1881–1886.
83.
83. Tischler AS, Lee YC, Perlman RL, Costopoulos D, Slayton VW, and Bloom SR (1984). Production of “ectopic” vasoactive intestinal peptide-like and neurotensin-like immunoreactivity in human pheochromocytoma cell cultures.J. Neurosci.4: 1398–1404.
84.
84. Tischler AS, Mobtaker H, Mann K, Nunnemacher G, Dayal Y, DeLellis RA, Adelman L, and Wolfe HJ (1986). Monoclonal antibody Leu-1 (NHK-1) recognizes a constituent of neuroendocrine granule matrix which differs from myelin-associated glycoprotein.J. Histochem. Cytochem.34: 1212–1216.
85.
85. Tischler AS, Perlman RL, Jumblatt JE, Costopoulos D, and Horwitz R (1986). Vasoactive intestinal peptide activates tyrosine hydroxylase in cultures of normal and neoplastic chromaffin cells. In: Neural and Endocrine Peptides and Receptors, T Moody (ed). Plenum, New York.
86.
86. Tischler AS, Perlman RL, Nunnemacher G, Morse GM, DeLellis RA, Wolfe HJ, and Sheard BE (1982). Long-term effects of dexamethasone and nerve growth on adrenal medullary cells cultured from young adult. rats.Cell Tissue Res.249: 525–542.
87.
87. Tischler AS, Ruzicka LA, Donahue SR, and DeLellis RA (1989). Chromaffin cell proliferation in the adult rat adrenal medulla. Intl. J. Devel. Neurosci. (in press).
88.
88. Tougard C, Picart R, Morin A, and Tixier-Vidal A (1983). Effect of monensin on secretory pathway in GH3 prolactin cells. A cytochemical study.J. Histochem. Cytochem.31: 745–754.
89.
89. Trojanowski JQ, (1988). Immunohistochemistry of neurofilament proteins. In: Advances in Immunohistochemistry, RA DeLellis (ed). Raven Press, New York, pp. 237–360.
90.
90. Tsusumi Y, Osamura Y, Watanabe K, and Yanaihara N (1983). Immunohistochemical studies on gastrin releasing peptide and adenocorticotropic hormone-containing cells in the human lung.Lab. Invest.48: 623–632.
91.
91. Unsicker K, Krisch B, Otten U, and Thoenen H (1978). Nerve growth factor-induced fiber outgrowth from isolated rat adrenal chromaffin cells: Impairment by glucocorticoids.Proc. Natl. Acad. Sci. USA75: 3498–3502.
92.
92. Verhofstad AAJ and Jonsson G (1983). Immunohistochemical and neurochemical evidence for the presence of serotonin in the adrenal medulla of the rat.Neuroscience10: 1443–1453.
93.
93. Van Rooijen LAA and Agranoff BW (1985). Inhibition of polyphosphoinositide phosphodiesterase by aminoglycoside antibiotics.Neurochem. Res.10: 1019–1024.
94.
94. Walsh KB and Kass RS (1988). Regulation of a heart potassium channel by protein kinase A and C.Science242: 67–69.
95.
95. Whitman M, Fleishman L, Chahwalah SB, Cantley L, and Rosoff P (1986). Phosphoinositides, mitogenesis and oncogenesis. In: Phosphoinositides and Receptor Mechanisms.Alan Liss, New York, pp. 197–219.
96.
96. Weiler R, Fischer-Colbrie R, Schmid KW, Feichtinger H, Bussolati G, Grimelius L, Krisch K, Kerl H, O'Connor D, and Winkler H (1988). Immunological studies on the occurrence and properties of chromogranin A and B and secretogranin II in endocrine tumors.Am. J. Surg. Pathol.12: 877–884.
97.
97. Winkler H, Apps DK, and Fischer-Colbrie R (1986). The molecular function of adrenal chromaffin granules: Established facts and unresolved topics.Neuroscience18: 261–290.
98.
98. Winkler H (1976). The composition of adrenal chromaffin granules: An assessment of controversial results.Neuroscience4: 65–80.
