Historical Vignette Neuroendocrinology 2006;84:69–82 DOI: 10.1159/000096997
Received: August 14, 2006 Accepted: September 1, 2006 Published online: November 9, 2006
Evolution of the Diffuse Neuroendocrine System – Clear Cells and Cloudy Origins Irvin M. Modlin Manish C. Champaneria Jan Bornschein Mark Kidd Gastrointestinal Pathobiology Research Group, Yale University School of Medicine, New Haven, Conn., USA
Abstract As early as the 2nd century, Galen proposed that ‘vital spirits’ in the blood regulated human bodily functions. However, the concept of hormonal activity required a further 18 centuries to develop and relied upon the identification of ‘ductless glands’, Schwann’s cell and the recognition by Bayliss and Starling of chemical messengers. Bernard’s introduction of ‘internal secretion’ and its role in homeostasis laid a physiological basis for the development of endocrinology. Kocher and Addison recognized the consequences of ablation of glands by disease or surgery and identified their necessary role in life. Detailed descriptions of the endocrine cells of the gut and pancreas and their putative function were provided by Heidenhain, Langerhans, Laguesse and Sharpey-Schäfer. Despite the dominant 19th century concept of nervism (Pavlov), in 1902, Starling and Bayliss using Hardy’s term ‘hormonos’ described secretin and in so doing, established the gut as an endocrine organ. Thus, nervism was supplanted by hormonal regulation of function and thereafter numerous bioactive gut peptides and amines were identified. At virtually the same time (1892), Ramón y Cajal of Madrid reported the existence of a group of specialized intestinal cells that he referred to as ‘interstitial cells’. Cajal postulated that they might function as an interface between
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the neural system and the smooth muscles of the gut. Some 22 years later, Keith suggested that their function might be analogous to the electroconductive system of the heart and proposed their role as components of an intestinal pacemaker system. This prescient hypothesis was subsequently confirmed in 1982 by Thuneberg and a decade later Maede identified c-Kit as a critical molecular regulator in the development and function of the interstitial cells of Cajal and further confirmed the commonality of neural and endocrine cells. The additional characterization of the endocrine regulatory system of the GI tract was implemented when Feyrter (1938) using Masson’s staining techniques, identified ‘helle Zellen’ within the pancreatic ductal system and the intestinal epithelium and proposed the concept of a diffuse neuroendocrine system. Pearse subsequently grouped the various cells belonging to that system under the rubric of a unifying APUD series. Currently, the gut neuroendocrine system is viewed as a syncytium of neural and endocrine cells sharing a common cell lineage whose phenotypic regulation is as yet unclear. Their key role in the regulation of gastrointestinal function is, however, indubitable. Copyright © 2006 S. Karger AG, Basel
Introduction
Two major systems are held responsible for the regulation of homeostasis of the human body: the classic endocrine and the neuroendocrine system. Both interact with
Irvin M. Modlin Yale University School of Medicine 333 Cedar Street, PO Box 208062 New Haven, CN 06520-8062 (USA) Tel. +1 203 785 5429, Fax +1 203 737 4067, E-Mail
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Key Words ‘APUD’ Clear cells Feyrter Pearse Neuroendocrine Cajal Carcinoid
tract, clarification is still necessary for characterization and definition of the functional elements and their effectors.
Early Concepts – The Ductless Glands
performed anatomical dissections on animals and gladiators, thus facilitating his appreciation of the anatomic basis for the regulation of bodily function. Fourteen hundred years later, Andreas Vesalius of Padua (1514–1564) (top left) published ‘De humani corporis fabrica libri septem’ (background-frontispiece), a definitive text of anatomy that included an image of the pituitary (center: Vesalius’ depiction of the pituitary), which had first been described by Galen.
their target organs or target tissues via secretion of ubiquitous messenger molecules which can be peptides, amines or steroids. The effects of such messengers have been broadly considered as endocrine, paracrine, neuracrine and autocrine. In most instances secretion is modulated by a variety of interconnected feedback loops which, in some areas (pituitary, the thyroid, adrenal cortex), are relatively well-defined. In other circumstances, particularly the diffuse neuroendocrine system (DNES) of the liver, heart, kidney and epithelium of the gastrointestinal 70
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Fig. 1. Claudius Galen of Pergamon (129–200 CE) (bottom right)
The majority of the glands and tissues that comprise the endocrine system had been identified by the end of the 19th century. Although they were initially described and studied individually, they were subsequently recognized to comprise an interrelated group of ‘ductless glands’ which were regarded as the source of ‘internal secretions’ [1]. Malfunction of elements of the group were recognized as early as 1600 BC by the Chinese who described goiters and used burnt sponge and seaweed for treatment [2]. The Egyptians identified ovaries as a crucial organ for the female reproductive cycle and even performed ovariotomy for the purpose of contraception [3]. Galen (129–200 CE) described the pituitary and proposed that the blood contained ‘vital spirits’ released into circulation by the brain [4], while Andreas Vesalius (1514– 1564) of Padua described the thyroid in 1543 [5] (fig. 1). By the mid-17th century, Thomas Wharton (1614–1673) had already included the thyroid, suprarenals, pancreas, lymphatic and salivary glands, testicles, ovaries, and prostate among the glands of the body in the classic ‘Adenographia sive glandularum totius corporis description’ [6]. The word ‘gland’, which had been used somewhat indiscriminately up until this time, gained a more accurate definition and was used to describe an organ or tissue with secretory function. Ducts were regarded as critical elements of the function of such organs and individuals including J. Wirsung (1589–1643), G. Santorini (1681– 1737), T. Wharton (1614–1673), R. De Graaf (1641–1673) and F. Sylvius (1613–1672) attained considerable recognition for the delineation of such structures [7]. Nevertheless, the functions of the endocrine glands were still unknown and subject of much speculation until 1776, when Albrecht von Haller (1708–1777) described the thyroid, thymus and spleen as glands without ducts (ductless) that poured substances directly into the circulation [8]. During the 18th century, much fruitless effort was devoted to the definition of the different structures of such glands in an attempt to develop an integrated classification system for these organs. The formulation of a cell-based theory by M.J. Schleiden (1804–1881) in 1838 and its extrapolation by Theodore Schwann (1810–1882) laid the basis for the cellular understanding of organ structure and thereafter disease. Sir Edward Sharpey-Schäfer (1850–1935) in
Fig. 2. Two young scientists in the laboratory of Johannes Müller (1801–1858) (top left) of Berlin provided the initial appreciation of the cellular basis of life. In 1838, Matthias Jakob Schleiden (1804–1881) (center) published his hypothesis that plants were composed of single cells (background). In 1839, his colleague Theodor Schwann (1810–1882) (bottom right) applied this concept to animal life-forms and his manuscript, ‘Mikroskopische Untersuchungen über Uebereinstimmung in der Struktur und dem Wachsthum der Thiere und Pflanzen’ (frontispiece, top right) laid the basis for the ‘single cell theory of disease’ and the foundation of cellular pathology. The image (bottom left) is an original drawing by Schwann of cartilage cells.
The Single Cell Theory – Function and Disease
Matthias Jakob Schleiden was born in Hamburg, Germany, in 1804. After a short career as a lawyer in his hometown, he began his medical studies at the University of Göttingen in 1832 before finally focusing on botanical subjects in the laboratory of Johannes Müller (1801–1858) in Berlin. In 1838, Schleiden published Beiträge zur Phytogenesis (Contributions to phytogenesis), in which he stated that the cell and its products formed the basic, structural elements of all plants [10] (fig. 2). Although not a novel observation, this concept had never History of the Diffuse Neuroendocrine System
previously been published. Schleiden discussed his thoughts while dining with his laboratory colleague, Schwann, who thereafter examined whether animal lifeforms were also composed of cells [11]. Working under the guidance of Müller, Schwann [12] had already demonstrated substantial creativity in physiology having in a 2-year period measured muscle contraction, described yeast fermentation and identified pepsin. In 1839, Schwann [13] published his most important scientific work Mikroskopische Untersuchungen über Übereinstimmung in der Struktur und dem Wachstum der Tiere und Pflanzen (Microscopic investigations into the similarities of the structure and growth of animals and plants), which were to become the cornerstone in the evolution of the single cell theory of disease. Within this manuscript, he identified cells as the fundamental particles of not only plants, but also of animals. Presciently, Schwann reported a dual existence of cells as an independent living strucNeuroendocrinology 2006;84:69–82
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1907, subsequently produced a unifying proposal that linked glandular structures together, reconciling the previous murkiness of definition between the divergent glands and their different secretions [9].
Internal Secretions and the Advent of Endocrinology
The broad concept of regulation as represented by the endocrine and neuroendocrine systems originated with Claude Bernard (1813–1878) who initially addressed the issue of homeostasis. In 1850, Bernard, among the first to use the term ‘internal secretion’, enunciated that the liver possessed both an external secretion (sécretion externe) in the form of bile and an internal secretion (sécretion interne) of sugar that directly entered the systemic circulation and that this was a prerequisite of homeostasis [15]. He also considered the adrenals, thyroid, lymphatic glands and spleen as further sources of ‘internal secretion’.
Cells and Organs
The subject of internal secretion and the consequences of its disturbance (removal of certain glands) had earlier been examined by John Hunter (1728–1793) in London in the late 18th century. Although the general effects of castration had been appreciated much earlier, Hunter in 1786 proposed that an internal secretion from the testes was responsible for the development of secondary sex characteristics [16]. Similarly, in 1855, Thomas Addison (1793–1860) of Guy’s Hospital London provided evidence 72
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that the absence or destruction of a particular endocrine gland caused disease. In his publication, ‘On the constitution and local effects of disease of the supra renal capsules’ [17] Addison described a disease of the adrenal capsules (melasma suprarenale), subsequently eponymously referred to as Addison’s disease, and inaugurated the study of diseases of the ‘ductless glands’ (fig. 3). In 1856, Charles Édouard Brown Séquard (1817–1894) suggested a physiological function for ‘internal secretion’ by concluding that the adrenals secreted a substance distributed in the blood that was essential to life [18]. This thesis was later confirmed by Sharpey-Schäfer, Professor of Physiology at University College London, and George Oliver (1841–1915), a general medical practitioner from Harrowgate, England. Their identification of the ‘pressor principle’ (adrenaline) in the adrenal medulla in 1894 [19], was the first internal secretion to be chemically identified. Theodor Kocher (1841–1917), Professor of Surgery at Bern, surgically confirmed the principle of internal secretion in 1883, when he described the condition of ‘cachexia strumipriva’ that supervened after total extirpation of the thyroid gland [20]. The anatomical structures responsible for ‘internal secretion’ were variously determined by a number of scientists including R.P. Heidenhain (1834–1897), Paul Langerhans (1847–1888) and Nikolai Kulchitsky (1856–1925) as microscopy entered the field of physiology. Heidenhain of Breslau, Prussia, described enterochromaffin cells in the gastric mucosa in 1868, and in 1870 also identified small, granulated, yellow staining cells on the surface of the gastric glands (almost certainly the enterochromaffin-like cell (ECL cell) of contemporary gastric biology) [21]. In 1869, in his medical school thesis [22], Langerhans utilized microscopic studies with novel staining techniques to delineate the anatomy of the pancreas and described the clear cell aggregations of the pancreas without reference to their endocrine function. The function of the latter would subsequently be studied by Gustave Edouard Laguesse (1861–1927), who proposed they be referred to as the ‘islets of Langerhans’ as a memorial to the early tragic demise of Langerhans [23]. In 1897, the Russian Kulchitsky noted similar clear cells in the crypts of Lieberkühn in the intestinal mucosa which today bear his name [24] (fig. 4). Given the state of chemical investigation and the absence of knowledge in regard to chemical messengers, no function was ascribed to any of these cells.
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ture and as a component of every organism and suggested that division was the basis of life (and disease) in unicellular and multicellular organisms. Although these seminal proposals proved fundamental to biology, Schwann incorrectly extrapolated his theory of cell formation based upon earlier erroneous suggestions of Schleiden. The concept that cells were fashioned by crystallization of an amorphous substance recruited from either intracellular or extracellular compartments around the nucleus did not prove to be correct. Nevertheless, this view remained en vogue for almost two decades until its revision by Rudolf Virchow (1821–1902) who in 1855, established the biological doctrine ‘omnis cellula e cellula’ (every living cell is derived from a pre-existing cell) [14]. Despite the incorrect cell formation conjecture, Schwann’s establishment of a cell-based theory for all living organisms facilitated the development of systematic scientific investigations that led to the characterization of the cellular structure of human organs and their functional (endocrine) interaction.
Fig. 3. In 1855, Thomas Addison (1793– 1860) (bottom left) described the consequences of the destruction or extirpation of the adrenal capsules (background-superior). In his major opus ‘On the constitution and local effects of disease of the suprarenal capsules’ (right) he described in detail the clinical and pathological changes associated with adrenal destruction (tuberculous). The original specimen (background) he utilized is of tuberculous adrenal glands.
Fig. 4. Rudolf Peter Heidenhain (1834– 1897) (left) first identified human gastrointestinal tract enterochromaffin cells by describing the yellow stained cells of the gastric glands (bottom left – gastric glands with endocrine cells). A further advance was undertaken by Paul Langerhans (1847–1888) (center) who, while a medical student, first reported pancreatic islets in his 1869 manuscript, ‘Beiträge zur mikroskopischen Anatomie der Bauchspeicheldrüse’ (bottom). Eight years later, Gustave Edouard Laguesse (1861–1927) (right), described the cells in detail (bottom right) and proposed their function. He named the cell aggregations, ‘Islets of Langerhans’ (background histology) in memory of Langerhans who had died prematurely of tuberculosis on the island (islet) of Madeira.
Despite these cellular advances, the physiological climate at the turn of the century was dominated by Ivan Petrovich Pavlov’s (1849–1936) concept of ‘nervism’ as the controlling principle for bodily functions. This was conHistory of the Diffuse Neuroendocrine System
sidered particularly important for the control of the secretion of the glands within the gastrointestinal tract and pancreas [25, 26]. The first evidence that the gut was an endocrine organ was provided by William Bayliss (1860– 1924) and Ernest H. Starling (1866–1927) who reported their discovery of secretin and its humoral regulatory role Neuroendocrinology 2006;84:69–82
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Chemical Messengers and Nervism
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crine system could be regarded as an integrated mechanism that chemically controlled body function in a fashion analogous to neural regulation (nervism), as had been originally proposed by Pavlov.
Ramón y Cajal – An Interstitial Event in Gut Regulation
In 1889, Santiago Ramón y Cajal (1852–1934) reported his identification of an interstitial cell type within the muscular layers of the intestinal wall and thereafter in 1893, produced a more detailed description of this hitherto unrecognized cell type [37, 38]. Cajal, the son of a surgeon in Petilla de Aragón, Spain was at an early age more interested in the arts, but his father insisted that he study medicine. Since science was his second passion, this parental decision did not cause difficulty and Cajal’s later work reflected his unique talents in both fields. On graduation in 1873, he declined to enter clinical practice and chose rather to concentrate on the field of microscopic anatomy, where he exhibited remarkable skills in the development of novel staining techniques. In particular, his introduction of the application of silver precipitation to stain nerve cells revolutionized their photomicrography [39]. This technique involved the modification of the silver impregnation technique initially introduced by Camillo Golgi (1843–1926) of Italy in 1873 [40]. In 1906, both he and Golgi were to share the Nobel prize for their contributions to the delineation of central and peripheral neural systems. Two decades after his initial report describing the interstitial cells, Cajal hypothesized that the networks of anastomosing cells represented a new type of neuron, which acted as an interface between the vegetative nervous system and the smooth muscle of the gastrointestinal tract [41]. In 1914, Sir Arthur Keith (1866–1955) became the first to propose the existence of gastrointestinal pacemaker cells similar to the ‘nodal tissue’ he had previously described in the heart [42, 43]. Keith described a group of cells within the muscular layers of the intestine, and appears to have independently identified a cell system identical to that of the interstitial cells described by Cajal [44]. In the following decades, the medical literature was permeated by confusion regarding the origin and classification of the ICC (interstitial cells of Cajal). This reflected the variable interpretation of the different immunohistochemical staining techniques which identified characteristics common to several different cell types ranging from Schwann cells to connective tissue elements [45–48]. In Modlin/Champaneria/Bornschein/Kidd
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in 1902 [27]. Their observations highlighted the importance of the ‘ductless glands’ and provided evidence that ‘nervism’ was not the only mechanism controlling gut secretion. Bayliss and Starling, in a discovery ‘breathtaking in its elegant simplicity’ [28] noted that acid in the gut stimulated secretion of the pancreas when both organs were denervated. They concluded that since acid introduced directly into the circulation failed to cause this response, whereas injection of the jejunal mucosal extract did, that the action of acid on the gut was the effect of a chemical reflex. They proposed the name ‘secretin’ for the hypothetical chemical messenger involved, and suggested a new class of chemical substances that they grouped together under the term ‘hormone’ (derived from hormonos {I arouse to excitement}), initially proposed by W.B. Hardy (1864–1934). Starling in his Croonian Lecture of 1905, presciently noted the potential role of such agents in both secretion and as regulators of growth [29]. The discovery of a ‘chemical messenger’ initiated the development of endocrinology and the subsequent evolution of concepts that included the neuro-humoral regulation of body function as well as the brain-gut axis. As a result, the consideration of nervism as the only regulatory mechanism of the body waned and the advent of endocrinology was initiated. Following the observation of Bayliss and Starling, numerous hormones and their cells of origin were identified and their functions and complex interrelationships explored. Thus, the Leydig cells of the testes, the thyroid and parathyroid glands, and the pituitary were all recognized as components of the endocrine system and investigated [30]. Ernst Laqueur (1880–1947) and colleagues in Amsterdam (Netherlands) isolated testosterone from the testis in 1935 [31], James Bertram Collip (1892–1965) isolated parathormone at Edmonton, Canada, in 1925 [32], and Harvey Cushing (1869–1939) of Boston, presented the first experimental evidence of the link between the anterior pituitary and the reproductive organs thus delineating its role as a major endocrine organ [33]. Thyroxin was isolated from the thyroid by Edward Kendall (1886–1972) of the Mayo Clinic in 1914 [34] and in 1921, Frederick Banting (1891–1941), an orthopedic surgeon and physiologist from Ontario, and his student Charles Best (1899–1978) extracted insulin from the pancreatic islet cells [35]. In 1935, Sir Walter Langdon Brown (1870– 1946) of London, England, described the pituitary as the ‘leader in the endocrine orchestra’ and the endocrine glands were regarded as sharing not only a common mode of action but to be functionally interdependent [36]. Thus, by the 1930s, sufficient evidence had accumulated to realign thought in such a fashion that the endo-
1965, Taxi resolved this uncertainty using electron microscopy to successfully distinguished ICC from neurons, smooth muscle cells, fibroblasts and Schwann cells. He identified this unique group of cells as ‘cellules neuroïdes’ (neuron-like cells) and ICC were thereafter accepted as a unique and separate cell type expressing characteristics synonymous with neural elements [49–51]. In addition to the issues regarding the cell of origin, there was controversy regarding the function of the ICC. In 1937, Tinel [52] subsumed Cajal’s original suggestion that the interstitial cells represented a link between the nervous system and the muscular tissue of the intestine and referred to them as ‘le troisième neurone vegetative’ (the third vegetative neuron). His proposal was subsequently adumbrated upon by Imaizumi and Hama (1969) and Yamamoto (1977), who demonstrated that the ICC transmitted stimuli between the terminal axons and intestinal smooth muscle cells [53, 54]. Edwin E. Daniel (1977) in reviewing the subject, described the ICC as ‘hybrid cells’ located between the circular muscle and the nerves, proposing that they functioned as an interface in both directions [55]. He declared that these cells played a role both as transducers of neural information towards the muscle and as mechanoreceptors, in recognizing the contraction of the muscle. In contradistinction, Ambache [56], in 1947, supported Keith’s proposal that the ICC represented the elements of a diffuse intestinal pacemaker and that their expression of electrical slow waves represented the intrinsic control of intestinal contractions. He further proposed that the syncytial structure of Cajal’s interstitial cells was consistent with the ‘nodal tissue’ originally reported by Keith. The first scientific validation of the interstitial cells of Cajal as the pacemakers of the GI tract was provided by Thuneberg in 1982 who demonstrated that the intrinsic slow wave activity of the gut was abolished after photo-ablation of the ICC-AP [57]. In his studies, he additionally proposed that the ICC system had two and possibly three components. The first, a network adjacent to Auerbach’s plexus (ICC-AP) and the second, an ICC group associated with the deep muscular plexus (ICCDMP), which had been previously alluded to by Daniel [55]. In addition, he supported Stach [58] who had proposed a third group of interstitial cells located between the submucosa and the circular muscles (ICC-SMP). In 1989, Barajas-Lopez et al. [59] definitively identified the ICC as the source of intestinal slow wave activity in the circular muscular layer of the canine colon. Technical progress during the last two decades has resulted in further delineation of ICC function and in 1999,
Lee et al. [60] demonstrated spontaneous voltage oscillations of the ICC using the nystatin perforated patch clamp technique. Contrary to the activity of the smooth muscle cells, these potentials could not be inhibited by hyperpolarization or L-type calcium channel blockers, indicating that the generation of slow wave potentials in the intestine is an intrinsic property of the ICC. A critical observation in the elucidation cornerstone of the ‘NE-ICCSMC units’ [61] was provided by Maeda et al. [62] who noted that the proto-oncogene c-Kit (a receptor tyrosine kinase), was expressed within the smooth muscle layers of the developing intestine of mice. Postnatal blockade of the c-kit expression using a monoclonal antibody strategy led to severe anomalies in the development and function of the gut. Several investigators identified that the ICC expressed c-kit and that c-kit negative mutant mice lacked the ICC-AP/MP (myenteric plexus) and as a consequence lacked pacemaker activity [63, 64]. The recognition that ICC expressed c-Kit further facilitated classification of these cells and Romert using immunohistochemical techniques, defined the differential distribution of cells within the small and large intestine [65]. In 1996, Lecoin et al. [66] using a c-Kit deficient quail-chick chimera demonstrated evidence of a mesenchymal origin of the cells and thereafter, Klüppel et al. [67] proposed the existence of a mesenchymal progenitor cell with c-Kit exhibiting a crucial role in the differentiation of functional interstitial cells. An alternative proposal by Torihashi et al. [68, 69] based upon blockade of c-Kit suggested a common precursor for ICC and longitudinal muscle cells of the intestine. Thus, disappearance of interstitial cells led to ICC myenteric plexus replacement by cells characterized by the ultrastructural features of smooth muscle cells. The complex nature of the ICC system was underlined by the further identification of different types of ICC [70, 71]. As yet, the interface between this predominantly motor (neural) regulatory system of the gut and the secretory (endocrine) regulatory system is unclear. What is, however, apparent is that the governing system is neither neural nor endocrine alone and that it certainly is diffuse as opposed to a focal aggregation (organ) of cells.
History of the Diffuse Neuroendocrine System
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The Concept of the Diffuse Neuroendocrine System
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The origins of the concept of a DNES reflect the interrelationship between nerves, endocrine cells, and the regulation of gut, motor, and secretory activity. In 1905, Paul Schiefferdecker (1849–1931) of Bonn, Germany, described
Fig. 5. In 1914, Pierre Masson (1880–1959)
(right) described a novel silver stain technique to classify endocrine cells (background: Masson stain of intestinal glands). Masson was the first to suggest that the scattered endocrine cells of the gastrointestinal tract were connected so as to constitute a diffuse endocrine organ (left: Masson’s drawings of silver stained cells). In collaboration with Antonin Gosset (1872–1944) (bottom left), he postulated the endocrine origin of intestinal carcinoids and suggested the relation between neural and endocrine lesions in the appendix (top right) thus laying the basis for the concept of neuroendocrine tumors.
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and central nervous system regulation became a recognized part of hormonal regulation. The ‘helle Zellen’ of the gastrointestinal tract, which comprised the cornerstone of the DNES concept developed by Friedrich Feyrter (1895–1973), were first observed by A. Nicolas in lizards in 1891 [77] and rediscovered in 1905 by J.E. Schmidt [78] and further described in 1906 by Carmèlo Ciaccio (1877–1956) [79, 80]. Ciaccio is best remembered for his introduction of the term ‘enterochromaffin’ to depict the staining of the ‘helle Zellen’ with chromium salts. It, however, remained for Pierre Masson (1880–1959) in 1914, to suggest that the endocrine cells of the gut formed a diffuse endocrine organ and corresponded to the enterochromaffin cells described by Ciaccio [80]. In his manuscript, La glande endocrine de l’intestin chez l’homme [81] (The endocrine glands of the gut in man) and his collaboration with Antonin Gosset (1872–1944) in Les tumeurs endocrines de l’appendice [82] (Endocrine tumors of the appendix), Masson proposed that these cells could be aggregated into a single functional unit. In addition, based on their affinity for silver stain, he classified them as the cell of origin of carcinoid tumors, thereby implicating the latter as an endocrine neoplasm (fig. 5). Later in 1928, he described the enterochromaffin cells to be of neural origin and their secretion of ‘substances’ as responsible for the carcinoid syndrome [83]. Similarly, Modlin/Champaneria/Bornschein/Kidd
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the secretion of endocrine substances by neurons as a means of communication between a neuron and an effector cell in a muscle or a gland [72]. His observations were based on his own reflections and ideas initially propounded by Robert Tigerstedt (1853–1923) (‘automatic’ irritation by metabolic products) [73]. Further support for this concept was provided in 1914 by Walter Cannon (1871–1945), Professor of Physiology at Harvard University, who used adrenaline to demonstrate that the adrenal medulla functioned not only as an endocrine gland but also as part of the autonomic nervous system in what is now termed ‘the flight or fight’ survival response [74]. His experiments on chemical neurotransmission and search for ‘sympathins’ bore some resemblance to those carried out by the Nobel laureate Otto Loewi (1873– 1961). The original idea of chemical transmission in the autonomic nervous system was conceived by Thomas Elliott (1877–1961), who despairingly wrote, ‘I have tried in vain to discover an active principle in the muscle plates of striped muscles’ [75]. In 1921, Loewi, a pharmacologist at Graz, Austria, established the chemical nature of nerve transmission by proving the theory of chemical intermediaries in nervous stimulation and by the 1930s, the secretory cells of the hypothalamus could be demonstrated to exert a neuro-hormonal regulation of the anterior pituitary [76]. Thus, feedback mechanisms were identified
Fig. 6. Friedrich Feyrter (1895–1973) (bot-
tom right) utilized Masson’s staining methods to identify the detailed architecture of the ductal system of the pancreas. He specifically drew attention to a group of cells he identified as ‘helle Zellen’ (bottom left: light microscopic image; top right: drawing of a clear cell by Feyrter). Feyrter noted that these clear cells were present throughout the duct epithelium and within the mucoid glands and postulated that they formed by budding and branching within the ductal system (center). His seminal proposals were assimilated into the concept of a diffuse endocrine organ in the gut and published in 1938 as ‘Über diffuse endocrine epitheliale Organe’ (top left).
Feyrter, ‘helle Zellen’ and the Peripheral Endocrine System
In 1938, the Austrian pathologist Feyrter published Über diffuse endocrine epitheliale Organe in which he summated the findings of a decade of investigation of the endocrine system of the pancreas and the enterochromaffin cells of the gastrointestinal tract [88]. In this manuscript, he established a new concept in the field of endocrinology, by proclaiming the existence of a DNES as opposed to the previously accepted dogma of ductless (endocrine) glands and endocrine ‘organs’. Feyrter described in detail the existence of ‘helle Zellen’, present in clusters throughout the duct epithelium and the ‘mucoid’ ductal glands of the pancreas, that deHistory of the Diffuse Neuroendocrine System
veloped by endophytism, budding and branching. In the light of this discovery and further analysis of the structure of the pancreas using Masson’s simplified silver staining technique, Feyrter envisaged a ‘new’ cellular depiction of the pancreas and described it as having four major characteristics: (1) three cell lineages in the pancreatic ductal tree, each distinct, comprised of the exocrine duct epithelium, the exocrine mucoid duct gland, and endocrine clear cells appearing in clusters or individually which did not stain; (2) two endocrine cell types, the Islets of Langerhans and the clear cells, which classified the pancreas as a diffuse endocrine organ; (3) clusters of clear cells that played a role in disease due to their ‘tuberous’ hyperplasia and ‘adenomatosis’, and advanced development of branching and budding, and (4) regeneration of endocrine tissue of the pancreas at the site of the clear cells (fig. 6). In the conclusion of his manuscript, Feyrter suggested that the human endocrine system not only consisted of compact epithelial organs (that released hormones into the lymph and blood), but also consisted of scattered endocrine cells that were present either individually or in groups. These cells were evident not only within the ductal system of the pancreas, but also in ‘columnar epithelial mucous membranes’ throughout the whole body, i.e. inner and the outer surface epithelia, and their syncytium formed ‘diffuse endocrine epithelial organs’ [89]. Feyrter provided examples of the latter and correlated his findings in the pancreas with the intestinal epithelial ‘yellow cells’ of Schmidt [78]. Although the latter cells showed similar characteristics to the clear cells of the Neuroendocrinology 2006;84:69–82
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Erös [84–86] and Kahlau [87], using animal experimental studies, also opined that clear endocrine cells possessed endocrine function and produced hormone-like substances. Thus, as the result of overlapping chemical, histological and physiological studies endocrinology of the gastrointestinal tract became a focus of considerable attention and advanced relatively rapidly. Indeed, the initial observation of Bernard followed by those of Brown-Séquard, Bayliss and Starling in concert with the evolution of staining techniques presented a compelling reassessment of the concept of organ regulation. This ‘gestalt’ provided the foundation for Feyrter’s initial development of his concept of a DNES.
The APUD System
After Feyrter’s 1938 proposal of a diffuse epithelial endocrine organ, numerous suggestions were made as to the nature and origin of the clear cells. In 1939, Sunder-Plassmann (b. 1905) suggested that the clear cells originated from the neural crest [95], and in 1940, Altmann [96] (b. 1916) hypothesized in his manuscript, ‘Die parafollikuläre Zelle der Schilddrüse und ihre Beziehungen zu der Gelben Zelle des Darmes’ (The parafollicular cell of the thyroid 78
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and its relations with the yellow cell of the intestine) that some of the cells might be ‘chemosensors’ derived from the neuroectoderm. This concept was supported by Pagés [97] in his MD thesis (1955) at the University of Montpellier, entitled ‘Essai sur le systéme des cellules claires de Feyrter’ (Essay on the system of clear cells of Feyrter). In 1966, Pearse [98, 99] (1916–2003), a histochemist from London finally provided a classification system that unified the variety of diffusely scattered endocrine cells by introducing the term ‘APUD’. This acronym (amine precursor uptake and decarboxylation) recognized the main common biochemical characteristics for all these cells and enabled Pearse to propose a unifying hypothesis (some of his friends and colleagues also referred to it as Anthony Pearse’s Ultimate Dogma!). More than 40 cells, including Feyrter’s clear cells, were not only capable of amine processing and production of polypeptide hormones but also shared several cytochemical and ultrastructural features that allowed them to be grouped into one entity. These cells were not only sited within the DNES, but also within classic endocrine glands, for example the thyroid, and in neuroepithelial tissue such as the hypothalamus. Pearse [100] also proposed the somewhat fanciful notion that all cells of the APUD series were derived from the neural crest: the epi- or ectoblast. These cells were not only coordinated with each other in respect to the production of peptides and amines with hormonal activity (as well as paracrine hormones and neurotransmitters) but were also coupled with the autonomic and somatic nervous system as a super-ordinate controller [101]. This putative interconnection formed the basis for the concept that such cells represented the endocrine division of the nervous system whose task was to modulate the effects of the faster acting autonomic and somatic divisions [100] (fig. 7). In 1969, the Hungarian endocrinologists Ilona Szijj (b. 1938) and Kálmán Kovács (b. 1926) introduced the neologism ‘Apudoma’ in describing the lesion of a patient with an ACTH-producing medullary carcinoma of the thyroid [102]. Thereafter, the term rapidly achieved cult status and was variably used to embrace all forms of hyperplasia and neoplasia derived from cells of the APUD series, comprising benign hyperplasia as well as carcinoids and carcinomas. These were then further categorized as either orthoendocrine, i.e. secreting the normal peptides of the cells, para-endocrine, secreting amines, hormones and peptides that were not regularly produced by these cells, or multiple (poly) hormone secreting when associated with multiple endocrine adenopathy (MEA) [103]. Modlin/Champaneria/Bornschein/Kidd
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pancreas in regard to their localization and formation within the mucosa, Feyrter noted that Schmidt’s intestinal ‘yellow cells’ only developed by endophytism when induced by ‘inflammation’ or ‘bourgeonnement’ (budding), a term that had originally been used by Masson [81]. Feyrter suggested that the process of ‘bourgeonnement’ provided the mechanism that led to the development of carcinoids within the gastrointestinal tract. The similarities of Feyrter’s ‘helle Zellen’ and Schmidt’s yellow cells, as well as the fact that carcinoids derived from these cell types occurred with variable prevalence throughout the intestine, suggested to Feyrter that there were different types of ‘yellow cells’ with different functions and localizations within the gastrointestinal epithelium. It is noteworthy that more than half a century of further investigation was necessary to finally elucidate the cells from which carcinoids of the stomach (ECL-enterochromaffin-like cells) and the intestine (EC-enterochromaffin cells) originated and the agents that contributed to their tumorigenesis [90–93]. In addition, Feyrter suggested, in allusion to the structure of Meissner’s and Auerbach’s plexus, that the scattered endocrine cells were also connected within a neural network through the wall of the gastrointestinal tract. Supporting this theory were Masson’s pathological findings describing the ‘appendicite neurogene’, drawing attention to the neural aggregations associated with appendicitis [94]. Feyrter compared the diffuse endocrine system to neuroendothelial tissue found within the anatomic association of the inner zone of the adrenal cortex and the adrenal medulla and proposed that the DNES developed by ‘chemotactical migration’ of nervous tissue to specific sites of the body. As enunciated by Feyrter, the linked concept of a peripheral endocrine system, gastrointestinal carcinoids and clear endocrine cells was by far the most comprehensive and integrated neuroendocrine-related hypothesis combining morphology, function, and pathology that arose during the first half of the twentieth century.
Fig. 7. A.G.E. Pearse (1916–2003) (left)
proposed that all cells (center) of the DNES shared common characteristics (amine precursor uptake and decarboxylation) (right) and could be classified using the term APUD. He considered that this unifying hypothesis (background) could be applied to the diffuse endocrine system. Although his proposal was initially acclaimed, current information suggests that the scope may be overly broad and the theory requires some modification.
Feyrter’s initial discovery thus triggered the phase in endocrinology that classified neuroendocrine cells as a cohesive group through the concept of the DNES concept or the APUD model. As the fields of gastroenterological endocrinology, peptide endocrinology, and neuroendocrinology became increasingly interconnected, the original concepts were expanded and revised due to results from improved staining techniques, the advancement of molecular biology methodologies and the identification of neuropeptides and cell markers [104–106]. It remains a matter of debate whether the cells of the APUD series are of ectodermal or entodermal origin. Pearse, who first suggested that they were all derived from the neural crest tried to provide evidence for his hypothesis by investigations on chick embryos [107]. Although these studies clearly supported an ectodermal genesis, he admitted, that it still could not be unequivocally determined that the endocrine polypeptide producing cells of the gastrointestinal tract, including the pancreas, were neuro-crest descendants. Although he modified his original theory by introducing the term ‘neuroendocrine-programmed epiblast’, he eventually postulated that while the functional characteristics of neuroendocrine cells argued for the neuroectodermal hypothesis, morphologically, an endodermal development was indicated. For Pearse, however, the origin of the cells was not a pivotal question; he was more History of the Diffuse Neuroendocrine System
concerned with identifying whether the cells had phenotypic plasticity or were already of predetermined function [108]. Amongst others, Ann Andrew stated that the postulate that a neuroendocrine-programmed epiblast was the common source of gut endocrine and other APUD/neuroendocrine cells was ‘untenable’ given the investigations of several groups dealing with that subject [109]. Although still lacking a definite proof for the endodermal theory, her findings argued against the neural crest as the origin [110–112]. The current view of the DNES includes neurons and endocrine cells sharing a common phenotypic program characterized by the expression of markers such as neuropeptides, chromogranins, neuropeptide processing enzymes SPC2 and SPC3 (subtilase-like pro-protein convertases) or dense core secretory granules [101]. It is now recognized that neuroendocrine characteristics can be observed in various cells types, not just normal and neoplastic cells of common embryological origin, due to the cellular plasticity associated with genetic switches as observed in DNA chip experiments [101, 113]. These phenotypic alterations can be triggered by malignant, traumatic or inflammatory processes [114–117], which suggests a robust interaction between the immune – and the neuroendocrine system and has led to the proposition that the term be once again modified or expanded to ‘neuroendocrine-immunology’ [118]. Thus, despite a century of progress, there is still controversy as how best to integrate the scattered endocrine cells of the gastroinNeuroendocrinology 2006;84:69–82
79
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DNES – An Unclear Origin
testinal epithelium into the framework of a regulatory system that embraces both discrete organs, disseminated cells, cellular aggregates and the nervous system [101, 113]. It is likely that even the current 21st century concept of the neuroendocrine system is incomplete/inadequate and will require ongoing revision as the interface between it and the immune-modulatory system becomes more apparent. Feyrter may have only succeeded in opening the neuron endocrine equivalent of Pandora’s Box. Like her, however, he has left only hope behind – that we
will soon comprehend the integration of neural, endocrine and immune regulation as a coherent, modulatory system implicit in gut and systemic homeostasis.
Acknowledgements This work was supported in part by NIH R01-CA-097050 and the Bruggeman Medical Foundation.
References
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