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Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

This article outlines the principles of radiobiology that can explain the time of onset, duration, and severity of the complex reactions of the lung to ionizing radiation. These reactions have been assayed biochemically, cell kinetically, physiologically, and pathologically. Clinical and experimental data are used to describe the acute and late reactions of the lung to both external and internal radiation including pneumonitis, fibrosis and carcinogenesis. Acute radiation pneumonitis, which can be fatal, develops in both humans and animals within 6 months of exposure to doses greater than or equal to 8 Gy of low LET radiation. It is divisible into a latent period lasting up to 4 weeks; an exudative phase (3-8 weeks) and with an acute pneumonitic phase between 2 and 6 months. The latter is an inflammatory reaction with intra-alveolar and septal edema accompanied by epithelial and endothelial desquamation. The critical role of type II pneumonocytes is discussed. One favored hypothesis suggests that the primary response of the lung is an increase in microvascular permeability. The plasma proteins overwhelm the lymphatic and other drainage mechanisms and this elicits the secondary response of type II cell hyperplasia. This, in its turn, produces an excess of surfactant that ultimately causes the fall in compliance, abnormal gas exchange values, and even respiratory failure. The inflammatory early reaction may progress to chronic fibrosis. There is much evidence to suggest that pneumonitis is an epithelial reaction and some evidence to suggest that this early damage may not be predictive of late fibrosis. However, despite detailed work on collagen metabolism, the pathogenesis of radiation fibrosis remains unknown. The data on radiation-induced pulmonary cancer, both in man and experimental animals from both external and internal irradiation following the inhalation of both soluble and insoluble alpha and beta emitting radionuclides are reviewed. Emphasis is placed on the data showing that alpha emitters are at least an order of magnitude more hazardous than beta/gamma radiation and on recent data showing that the more homogeneous the irradiation of the lung, the greater is the carcinogenic hazard which contradicts the so-called "hot particle" theory.
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PMID:Radiation effects in the lung. 354 78

Treatment of mouse fibroblast BALB/c 3T6 cells with the tumor promoter 12-O-tetradecanoylphorbol-13-acetate or the antipromoter retinoic acid affects the release of several glycoproteins into the medium. The phorbol ester decreases the secretion of a 180-kd and 160-kd glycoprotein and increases the release of a 38-kd glycoprotein. In contrast, retinoic acid affects these glycoproteins in the opposite way. Moreover, retinoic acid enhances the level of a 55-kd and 60-kd glycoprotein. The 180-kd and 160-kd glycoproteins appear sensitive to collagenase and after pepsin treatment are converted to bands which comigrate with collagen alpha 1 (I) and alpha 2 (I). These glycoproteins are tentatively identified as being pro alpha 1 (I) and pro alpha 2 (I). The 38-kd glycoprotein appears to comigrate with the major excreted protein. Retinoic acid appears to reduce significantly the incorporation of mannose into secreted glycoproteins whereas treatment with the phorbol ester induces an enhancement in mannose incorporation. Our results indicate that both phorbol esters and retinoids alter the release of several glycoproteins from 3T6 mouse fibroblasts. These changes appear to relate to the influence of these compounds on the expression of the transformed phenotype of these cells.
Carcinogenesis 1985 Mar
PMID:Retinoic acid and 12-O-tetradecanoylphorbol-13-acetate alter release of glycoproteins from mouse fibroblast BALB/C 3T6 cells. 391 54

Treatment of the skin with the tumor promoting phorbol ester 12-O-tetradecanoylphorbol-13-acetate leads to a reduction of the collagen content of the dermis of the mouse. The collagen degradation as well as synthesis is affected by the tumor promoter, the effect on degradation being more pronounced at the beginning of the treatment. The collagenolytic activity that can be extracted from the dermis is increased 5- to 6-fold during the first five applications and approximately 2-fold at later times. The uptake of [14C]proline in both total protein and NaCl-soluble collagen is doubled, but the increase of collagen synthesis does not restore a normal collagen content in the dermis, as it is accompanied by an elevated level of collagenolytic activity.
Carcinogenesis 1985 Apr
PMID:Dermal collagen metabolism during tumor promotion with 12-O-tetradecanoylphorbol-13-acetate in mouse skin. 398 56

Selenium is an essential dietary trace element which has anticancer properties. Among its effects in rats, selenium has been shown to inhibit the development of carcinogen-induced mammary tumors by interfering with the postinitiation, promotion phase of carcinogenesis. We studied the effects of selenium on the growth of rat mammary tumor cells in primary culture. Our objective was to determine whether selenium had any direct influence on cell growth which might explain its influence on tumor development. Rat mammary tumors were induced by N-nitrosomethylurea. Tumor epithelium was prepared by collagenase dispersion and the cells were separated by Ficoll gradient centrifugation. The tumor epithelium was grown in primary culture using a defined serum-free medium. The addition of low concentrations of sodium selenite, less than 1.0 micrograms/ml, stimulated tumor cell proliferation. Protein synthesis and the production of type IV collagen increased within the first hour of exposure, prior to any measurable increase in DNA synthesis. Concentrations of selenite greater than 1.0 micrograms/ml inhibited cell proliferation, the synthesis of protein, and the replication of DNA in a dose-related manner. These studies demonstrated that selenium has the potential to influence the postinitiation phase of rat mammary tumorigenesis by directly altering the growth of tumor cells, possibly through the regulation of protein synthesis.
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PMID:Influence of selenium on the growth of N-nitrosomethylurea-induced mammary tumor cells in culture. 403 31

Rat pancreatic cells were dissociated using a combined enzyme and EDTA method, grown on a plastic surface and then overlayed with collagen gel. Our studies have shown that exocrine pancreatic cells grown in this way have the ability to rearrange themselves into a three-dimensional organoid structure in which well defined epithelial lumina have been identified by ultrastructural and light microscopic examination. This in vitro system has advantages in examining the cytodifferentiation of pancreatic cells and may be exploited in studying pancreatic carcinogenesis.
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PMID:Three-dimensional culture of rat exocrine pancreatic cells using collagen gels. 406 60

The main pathological effects attributed to asbestos are carcinogenesis and fibrogenesis. Statistical studies have shown that asbestos workers may expect a higher morbidity not only from cancer of the lung and mesothelioma but also from cancer at other sites. Carcinomas have been reported in animals following the injection of asbestos, but the production of carcinomas by inhaled asbestos is less easy to demonstrate; most examples of experimental carcinogenesis with asbestos have been produced in rats. Rats and man react differently to asbestos in that rats do not produce asbestos bodies. The fibrosis that follows inhalation of asbestos has been frequently described, but studies with specific pathogen free animals have shown that, like the fibrosis that may follow the inhalation of silica dust, gross fibrosis involving the production of abnormal amount of collagen probably requires the intervention of infection as well as asbestos. Because of the difficulties encountered in the direct investigation of carcinogenesis and fibrogenesis resulting from the inhalation of asbestos, attention has been directed to the mechanisms by which the lung is able to protect itself against these fibrous dusts. While non-fibrous dusts and short fibers can be ingested by macrophages and removed via the bronchus, the long fibers that may also reach the alveolar regions may not be removed by this mechanism. The probability that a fiber may reach the alveoli depends largely on the fiber diameter and only to a small extent on the fiber length, so that, for example, fibers 100 mum long may reach the alveoli of a guinea pig. These long fibers may become coated with a ferroprotein derived from hemoglobin to form an asbestos body and, after morphological changes, the asbestos body may be broken up, the fragments ingested by macrophages and dissolved. The lung is thus cleared of asbestos. In the guinea pig lung, consolidated areas from which the asbestos has disappeared shows signs of return to normal. THIS CLEARANCE MECHANISM IS INHIBITED BY OTHER FACTORS: quartz dust may almost completely inhibit asbestos body formation; tobacco smoke has a considerable effect, and even very heavy loads of carbon may act similarly. The normal lung appears able to efficiently eliminate small loads of both nonfibrous and fibrous dust, including the carcinogenic asbestos fibers. The capacity is not unlimited, however, and when the load is heavy there is a much greater probability that fibers will not be detoxicated. In addition, other factors such as silica dust and tobacco smoke may remove the protective mechanism in the lungs.
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PMID:Small animals in the study of pathological effects of asbestos. 437 72

Mineral particles are customarily inhaled as mixtures, though one component may predominate and determine the response. Although the lesions often possess a characteristic structure, according to the main type of particle deposited, morphology affords little indication of pathogenesis. Being a major element in the evolution of dust lesions, macrophage behavior has been examined extensively in vitro after treatment with mineral particles, attention being directed to membrane and biochemical changes; however, no clear lead to the origin of the lesions has emerged. Pulmonary fibrosis, as one of the ultimate consequences of dust accumulation, required a direct in vitro approach in which the products of the macrophage-particle interaction were utilized to provoke collagen formation by fibroblasts in a two-phase system. By this means, silica and asbestos stimulated connective tissue formation and application of the technique to coal dusts appears promising. Coal workers may develop a peculiar type of emphysema in relation to lesions whose fibrous content is comparatively small. Type II alveolar epithelium is also stimulated by inhaled particles and lipid accumulation follows. Alveolar lipidosis interferes with the fibrotic response by preventing contact between macrophage and particles. This phenomenon may account in part for anomalies, apparent in coal workers, between epidemiological findings and dust composition. Carcinogenesis is a well-recognized feature of asbestos exposure, but, as with fibrosis, risk prediction on the basis of in vitro tests of cytotoxicity is premature and may not be valid.
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PMID:Pulmonary toxicology of silica, coal and asbestos. 632 72

The clonal growth and serial propagation of rat esophageal epithelial cells in low serum-containing medium has been achieved without feeder layers or conditioned medium. To date, a total of four lines have been developed and maintained for as many as 40 passages in culture. Growth of the cells was possible only after modifying the culture medium (PFMR-4) by reducing the calcium concentration from 1 to 0.1 mM, and by adding low levels of dialyzed fetal bovine serum and seven growth factors; i.e. epidermal growth factor, hydrocortisone, ethanolamine, phosphoethanolamine, insulin, transferrin, and cholera toxin. Cell lines have been developed from both explant outgrowths and enzyme dissociated esophagi. The epithelial nature of the cells was confirmed by electron microscopy and immunological methods. Clonal growth studies revealed that optimal cell growth occurred in medium containing 2.4% dialyzed fetal bovine serum and 0.1 mM calcium. Calcium levels of 0.3 mM or higher caused the cells to stratify and undergo terminal differentiation. Coating the culture dishes with collagen, or a combination of collagen, fibronectin, and bovine serum albumin, increased both the cell growth rate and the colony forming efficiency. The successful long term culture of rat esophageal epithelial cells permits their use as models in studies concerned with esophageal differentiation and carcinogenesis.
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PMID:Clonal growth and serial propagation of rat esophageal epithelial cells. 634 45

Following the introduction of colon-specific carcinogens, the mode of formation and evolution of colon cancer has been investigated in experimental animals. These carcinogens are cytotoxic to epithelial cells in colonic crypts and induce a series of non-specific acute and chronic changes including cryptal hyperplasia when administered repeatedly. During such processes, a number of neoplastically transformed cells may appear in many crypts. Only when they occur at the base of or form an outpocketing pouch in a crypt, do they appear to succeed in repopulating the given crypt to form a dysplastic crypt, from which an early neoplastic lesion develops usually in the upper part of the mucosa. The neoplastic lesion thus formed grows by various mechanisms, depending on its intrinsic properties of unceasing proliferative activity of neoplastic cells and interaction with the microenvironment: (a) by elongation and tortuosity of neoplastic glands, (b) by evagination of the glandular epithelial lining, with the formation of septa to dichotomise the glands to increase the number of neoplastic glands or with formation of incomplete septa or villi to expand the surface area of the neoplasm, and (c) by invagination and outpocketing pouch formation of neoplastic glands when accompanied with the changes in the basement membrane. In doing so, it may progress in various directions to form a polypoid or discoid lesion. Concomitant with growth, the neoplastic cells may undergo a series of cytological alterations and penetrate through their basement membrane in some areas to manifest early malignant behaviour. With downward progression, the neoplasm penetrates the muscularis mucosae and invades the submucosa, muscularis externa and serosa. Such an invasive process is often associated with the rearrangement of fibroblasts, marked changes in the production of collagen and proteoglycans of the extracellular matrix and lysis of the existing structures of the colonic wall. On morphological grounds, colonic carcinogenesis is a multiple process and is associated with successive breakdown of the host defence barriers. From the studies on experimental colonic tumourigenesis, adenomas and adenocarcinomas appear to share a common aetiological factor, or factors, and they are different end-stages in the evolution of neoplastically transformed cells. At any stage of evolution, however, benign neoplasms may develop dysplastic foci within neoplasms and evolve into a malignant form.
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PMID:Histogenesis of colon cancer in experimental animals. 639 31

Stereological point-counting methods were used to determine the volumetric alterations in collagen from the lamina propria immediately beneath the epithelial-connective tissue junction in hamster check-pouch mucosa treated with the chemical carcinogen DMBA. In addition, a non-neoplastic inflammatory control was evaluated in which a delayed hypersensitivity reaction was induced by the contact-sensitising agent DNCB. DMBA-treated tissues were assigned to histopathologically defined hyperplasia, dysplasia and carcinoma stages. The volume densities of collagen present in unit volume of extracellular lamina propria were found to decrease progressively and significantly in DMBA-treated tissues when compared with values obtained from normal untreated mucosa. Values from the inflammatory control were comparable with those from the dysplasia stage of carcinogenesis. The mechanisms responsible for these decreases in collagen volume density are unknown, but contributory factors might include collagen destruction by enzymes originating in either the epithelium or the cells of the inflammatory infiltrate, dilution of collagen produced by inflammatory oedema or alterations in the synthetic capabilities of fibroblasts.
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PMID:Ultrastructural morphometry of collagen from lamina propria during experimental oral carcinogenesis and chronic inflammation. 642 50


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