APUD cells and APUD cell tumors.
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APUD Cells↗
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[APUD cells in gastric cancer].
Endocrine cells (APUD cells) of digestive mucosa can be source of neoplasias, usually called "carcinoids". Nevertheless, there are some reports in literature about the presence of APUD cells in carcinomas as a tumor component. However, these tumors seem to have not the biological and clinical behavior of carcinoids. These types of neoplasias have been reported mainly in stomach and colon. In the present work, the frequency of APUD cells was studied in 42 gastric carcinomas. Argyrophil cells were observed in six cases (14.3%) and argentaffin cells in one (2.3%); their histopathological pattern were well differentiated adenocarcinoma (5) and "signet ring cell carcinoma" (1). The APUD cell distribution and number in these neoplasias were quite irregular in each case examined and in different areas of the same case.
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The APUD cell concept.
Embryonic neural crest cells have been traced to the primitive entoderm where they differentiate into a family of hormone-producing cells, APUD cells. The APUD cell concept explains many otherwise seemingly dissociated clinical circumstances involving endocrine glands and hormone production by tumors.
Amines↗
SIF cells as APUD cells: a possible endocrine role.
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Animals↗
[Biogenic amines in endocrine cells producing polypeptide hormones. The APUD-cells (Pearse) (author's transl)].
APUD-cells (A = Amine, P = Pprecursor, U = Uptake, D = Decarboxylation) are endocrine cells with numerous common characteristics: 1. They produce polypeptide hormones of low molecular weight. 2. They possess specific 1-amino acid decarboxylases to synthesize catecholamines and/or 5-hydroxytryptamine from precursors. 3. A part of the APUD-cell family primarily accumulates biogenic amines within their cytoplasm. 4. All APUD-cells are rich in specific secretory granules that are the morphological substrate for most of their common features.--Enzyme histochemically the APUD-cells represent a rather heterogenous population. The capacity to take up biogenic amines from the blood is confined to a smaller numer of APUD-cells. The concept of the APUD-cells representing a peripheral neurosecretory system (Pearse und Polak, 1971) appears to be premature. It is probable that in several APUD-cells the accumulation of biogenic amines only constitutes a phenomenon without any physiological relevance which, notwithstanding, could explain pathological reactions of APUD-cells.
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Investigations of endocrine cells in the gastrointestinal tract and pancreas during the metamorphosis of an anuran (Alytes obstetricans L.): histochemical detection of APUD cells.
Endocrine cells were detected at premetamorphosis, prometamorphosis, climax, and juvenile stages using an amine-inducing fluorescence technique with or without previous L-3,4-dihydroxyphenylalanine (L-DOPA) treatment. At premetamorphosis, serotonin cells exhibited yellow fluorescence in the gut primary epithelium of the L-DOPA untreated animals. In the treated animals, green fluorescent APUD cells could be seen in addition to the serotonin cells. In the pancreas, numerous clusters of fluorescent APUD cells were observed. At prometamorphosis the number of fluorescent cells increased in the intestinal primary epithelium and, close to the basal membrane, numerous small regenerative buds devoid of fluorescent cells appeared. In the pancreas of L-DOPA-treated animals, two types of APUD cells could be distinguished by their different fluorescence intensities. At the climax stage, the stomach developed and APUD cells were detectable in the gastric glandular buds. The degenerated primary intestinal epithelium was progressively removed in the intestinal lumen. At this stage, the regenerative buds of the secondary epithelium exhibited APUD cells. In the disorganized pancreas, the induced fluorescence decreased strongly. At the juvenile stage, cords of APUD cells displayed a cytoplasmic green fluorescence in the pancreas. In the stomach and intestine, serotonin and APUD cells were numerous.
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The endodermal origin of digestive and respiratory tract APUD cells. Histopathologic evidence and a review of the literature.
Twenty-seven small cell carcinomas of the lung and three tumors of the large intestine with combined adenocarcinomatous and small cell and/or anaplastic carcinoid-type histologic features were studied by light and electron microscopy. It was shown that the small cells have morphologic characteristics of APUD cells. Also presented are the histologic features of a carcinoma of the lung with large cell undifferentiated carcinoma, adenocarcinoma, squamous cell carcinoma, and giant cell carcinoma areas in the primary site and in several metastatic foci. Two of the renal metastases showed small cell carcinoma. The combined tumors and the numerous other similar neoplasms described in the literature and reviewed here suggest an endodermal origin for digestive and respiratory tract APUD cells based on the hypothesis that cancer is a clonal proliferation, and mucous and squamous cell differentiation is an endodermal rather than neural crest characteristic. The ultrastructural features of tumors of cells of known neural crest origin, including a medullary carcinoma of the thyroid, three carotid body tumors, a pheochromocytoma, and two cutaneous melanomas were compared with those of other APUD cell tumors including small cell carcinomas of the lung, two bronchial carcinoids, a carcinoid of the appendix, and a carcinoid of the kidney. Cells of the latter group sometimes possessed cytoplasmic tonofibrils, round compact masses of cytoplasmic microfilaments, and ductal lumina. These features were lacking in the former group and may signify a different embryologic origin. The histologic, histopathologic, and embryologic evidence regarding the origin of digestive and respiratory tract APUD cells is reviewed, showing that the former are, and the latter probably are, of endodermal and not neuroectodermal origin.
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[Apud cells in endometrial cancer].
55 endometrial carcinomas containing apud cells are studied. Correlation between the endocrine-metabolic disturbances and mitotic index, on the one hand, and number of apud cells and their product on the other, is revealed. If the percentage of apud cells is above 20 of all parenchymal cells, low mitotic index in the tumour, marked production of serotonin, calcitonin and other hormones and high incidence of endocrine disturbances together with a relatively favourable prognosis are observed. Low number of apud cells associated with high mitotic index and high incidence of unfavourable outcomes while the hormone production and endocrine disturbances were rare or absent.
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The Merkel cell--a member of the APUD cell system. Fluorescence and electron microscopic contribution to the neurotransmitter function of the Merkel cell granules.
Merkel cells of sinus hair follicles of nude mice were investigated by fluorescence and electron microscopy following pretreatment with amine precursors (L-Dopa, L-5-Hydroxytryptophan) and monoaminoxidase-inhibitors (Marsilid, Harmaline). Neither in control animals nor in pretreated animals any evidence for an involvement of Merkel cells in monoamine metabolism could be found. Therefore, the hypothesis that Merkel cells might share the most constant cytochemical characteristics of the cells of the APUD series, i.e., to take up amine precursors, should definitely be left. Following Harmaline treatment, however, Merkel cells were found fluorescent; cytophotometric analysis of the fluorescence emission spectra of formaldehyde-treated tissue ascertained that this fluorescence was due merely to a specific Harmaline fluorescence. The significance of Harmaline uptake in Merkel cells, most probably in the Merkel cell granules, is discussed.
5-Hydroxytryptophan↗
Ontogeny of small-granule APUD cells in hamster lung: a morphological study.
Development of small-granule APUD cells and cell clusters was studied in 13-day to 15-day fetal hamster lungs by periodic acid-Schiff (PAS)-lead hematoxylin staining, monoamine fluorescence, and transmission electron microscopy. We examined 11-day and 12-day fetal, early postnatal, and adult animals only by PAS-lead hematoxylin. Precursors of small-granule cells first appear as PAS-negative clear cells in proximal airways of 13-day lung, occurring singly or in clusters of 2-25 cells and standing out among their undifferentiated, glycogen-laden, PAS-positive neighbors. By 14 days, developing small-granule cell clusters are prominent in main and lobar bronchi, extending 2-3 airway generations into the periphery. Clear-cell clusters, similar to those seen in 13-day lung, appear in peripheral airways and reach within one generation of developing terminal sacs. By 15 days, a few small, small-granule cell clusters are located at bronchioloalveolar junctions. Comparatively mature clusters occur in proximal airways; they are characterized by specific formaldehyde-induced monoamine fluorescence demonstrable after exposure in vitro to 5-hydroxytryptophan. In early postnatal stages, PAS-positive granules are resolvable toward the base of some endocrine cells. Ultrastructurally, pulmonary APUD cells contain numerous membrane-limited granules (180-nm diameter) of varying electron density. In 13-day lung, granules sparsely populate the cytoplasm of clear cells, but as the cells mature, the granule population increases and becomes concentrated in the basal cytoplasm. Fetal development of small-granule cells is therefore compressed into the last 4 days before birth. Most clusters appearing in neonatal lungs are not yet fully mature, and not all subtypes of this population are present until some time later.
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The Merkel cell system and a comparison between it and the neurosecretory or APUD cell system.
The Merkel cell, a neural crest migrant to the skin, possesses a characteristic intranuclear rodlet, cytoplasmic membrane-bound granules, and horn projections and is usually associated with nerve terminations. It is also associated with all types of known organizations of sensory nerve endings in the skin and possesses characteristic enzyme reactions in relation to the ending. The Merkel cell is found in the skin and the oral mucous membranes, and similar cells are observed in the taste buds and pulmonary tissue. A comparison between the Merkel cell and the APUD cell system of polypeptide hormone and amine-producing cells reveals many structural and chemical similarities.
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[APUD cells in basal cell proliferative tissue of the prostate].
Basal cell hyperplasia involving intensive APUD cell proliferation should be distinguished among dyshormonal hyperplastic processes of the prostate. This form of hyperplasia can be considered a separate unit for its potential in the promotion of prostatic apudoma onset.
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APUD cells, apudomas and the neural crest.
The most characteristic feature of the APUD cell series is the ability to take up and decarboxylate amine precursors. Other features, regarded as characteristic by Pearse, are the secretion of polypeptide hormones and their origin from the neural crest. An increasing number of APUD cells is being shown to elaborate polypeptide hormones. It is acknowledged that some members are derived from the neural crest, but there is a good reason to believe that others are not, and no good reason to believe that yet others are so derived. It is therefore suggested that the common factor sought in the genesis of the APUD cell, and perhaps other tumours, may be the biochemical, rather than the embryological, relationship of the progenitor cell types.
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[Apud cells and apudomas of the prostate, breast and uterus].
Morphofunctional features of apud cells in the prostatic, mammalian and uterine parenchyma have been studied inadequately and their further comprehensive study is needed. It will help to estimate fully enough those pathologic changes in which apud cells are involved. Dyshormonal hyperplastic processes and, especially, tumours, are of greatest importance among them. It is essential to consider not only morphologic, but functional peculiarities of tumour tissue, that will enable one to study the biological activity, long-term results of reproductive organ apudoma treatment, as well as to solve the problem of their histogenesis sources.
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APUD cells in normal and hyperplastic prostates.
Argyrophilia and argentaffinity, as basic properties of APUD cells, were investigated in 50 normal and hyperplastic prostates, which included both autopsy and surgical specimens from patients of various ages. Normal prostates (including glands from 3 foetuses) had 62% of argyrophil-positive granules in the glandular epithelia, while only 44% of the hyperplastic glands were positive. Argentaffin-positive cells were found in 12% of the surgical hyperplastic cases. Both argyrophil and argentaffin cells were distributed in zones, often in lobule-like shapes, lying along the basal membrane. On the basis of these findings, there is a discussion on the possible roles played by the so-called APUD cells in hyperplastic and neoplastic growths of the prostate, such as carcinoid tumours (apudomas) or endocrine-associated syndromes in the course of prostatic cancer.
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[Functional morphology of breast APUD cells in dysplasia and neoplastic processes].
Histochemical and immunohistochemical methods were used to examine 29 malignant tumors (18 lobular and 11 invasive carcinomas) and 34 fibroadenomas of the mammary gland (MG). APUD cells containing serotonin, melatonin, and beta-endorphine were shown to be present in the duct epithelium of the normal MG and its pericanalicular fibroadenoma. APUD cells were detected in 21 of the 29 malignant tumours of MG. Hormonal differences of APUD cells were found in poorly and well differentiated carcinomas: the former contained serotonin, melatonin, and beta-endorphine (inhibitors of proliferation), the latter--insulin and adrenocorticotropic hormone (stimulators of cell division). Such differences in the endocrine function of MG malignant tumors are likely to be significant in the clinical course and determination of prognosis for carcinomas of various differentiation.
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[Study of the APUD cells of the gastric mucosa].
The results of an histochemical and microscopic study of the APUD cells carried on gastric biopsies are reported. Endocrine cell hyperplasia, microscopically detected, was particularly evident in atrophic gastritis (type A chronic gastritis) and adenomas. The presence of the APUD cells confirmed by electronmicroscopy, which revealed granules of 200 NM with a central nucleus and a membrane-separating electron-lucent ring, gives a further contribution to the hypothesis of a possible association between endocrine cell hyperplasia and intestinal metaplasia.
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[Morphofunctional characteristics of the APUD-cell and lymphocyte reactions in the lungs of children with acute pneumonia].
The lungs of 40 children who had died at the age of 1 month to 3 years were studied using special immunohistochemical and morphometric methods. Destructive lung processes were registered more frequently in children below one year of age with acute pneumonia having a similar viral-bacterial etiology. The content of apud-cells with an argyrophilic reaction, amine-containing APUD-cells and lymphocytes with cyclic nucleotides was significantly decreased and indices of the lymphocyte functional activity lowered comparing to the older age group. An essential role of the physiological immaturity of the biogenic amine synthesis by apud-cells is attributed in the acute pneumonia pathogenesis in children of early age. This aggravates immune deficiency and the development of the destructive forms of inflammation.
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