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PubMed2002

Towards a new understanding and classification of chondrogenic neoplasias of the skeleton--biochemistry and cell biology of chondrosarcoma and its variants.

Despite substantial knowledge on the clinicopathology of chondrogenic skeletal neoplasms, only limited insights into the biology of the different tumor variants are available. There are virtually no established molecular markers for identification and classification of these neoplasms. In this paper, we present a systematic review of the biochemistry and cell biology of chondrogenic neoplasms of the bone focussing on our own recent investigations. The hallmark of all differentiated chondrogenic tumors is the presence of neoplastic chondrocytic cells responsible for the formation of the characteristic cartilaginous tumor matrix. These cells can show the full differentiation potential of physiologic chondrocytes depending on the tumor entity investigated. The high phenotypic diversity of physiologic chondrocytes explains the previously poorly understood, striking heterogeneity of the neoplastic cells and their surrounding extracellular matrix not only between different but also within chondrogenic tumors. In our studies, tumor classifications, so far based only on histomorphological criteria, were either confirmed or corrected: mesenchymal chondrosarcomas represent the prototypic neoplasm of pre-chondrogenic undifferentiated cells undergoing multifocal chondrocytic differentiation. Enchondromas, osteochondromas, and conventional chondrosarcomas are neoplasms of multi-phenotypically differentiated chondrocytes. Clear cell chondrosarcomas appear to be neoplasms of hypertrophic chondrocytic cells. A peculiar biology is displayed by dedifferentiated chondrosarcomas, which at least in most cases show neither "anaplasia" nor "dedifferentiation", but most likely "transdifferentiation" of part of the neoplastic cells to a cellular phenotype of a different mesenchymal differentiation lineage. Chondroblastomas do not show any chondroblastic differentiation at all. Our studies delineate molecular markers of chondrogenic neoplasms of the skeleton, which have the potential to be the basis of a new biology-orientated classification of skeletal neoplasms. The expression analysis of extracellular matrix genes, in particular of the collagen types, might be able to play herein a leading role in classification and diagnosis, similar to the cytokeratin subtypes or the CDs (cluster of differentiation) for the classification and diagnosis of neoplasms of the epithelia and the lymphatics.

Animals↗
PubMed2004

Immunological and morphogenic basis of gastric mucosa atrophy and metaplasia.

Chronic gastritis with gastric mucosa atrophy, intestinal metaplasia and endocrine cell hyperplasia are alterations with an increased risk for the development of gastric neoplasias. Immunological studies in autoimmune gastritis, in atrophic Helicobacter pylori gastritis and in studies with transgenic mice point to a central role of the parietal cell in the development of gastric mucosa atrophy. Destruction of gastric epithelial cells alone might not be sufficient for the loss of complete gastric glands. Gastric atrophy, endocrine cell hyperplasia and intestinal and pancreatic metaplasia can be regarded as the result of altered morphogenesis within the gastric mucosa. Impaired expression of the gastric morphogenic factor Sonic Hedgehog by parietal cells and increased expression of the transcriptional activators of intestinal and pancreatic differentiation, namely CDX2 and PDX1, seem to be crucial for the development of gastric atrophy and for intestinal, endocrine and pancreatic transdifferentiation processes. Altered expression of these morphogenic factors is partly caused by changes in the gastric milieu. Further studies concerning the normal and pathological morphogenesis of the gastric mucosa and related tissues might give new insight into the pathogenesis of gastric atrophy and metaplasia.

Animals↗
PubMed2001

Insulinoma of the pancreas with insular-ductular differentiation in its liver metastasis--indication of a common stem-cell origin of the exocrine and endocrine components.

We describe an insulinoma of the pancreas in a 56-year-old patient, which showed insular-ductular differentiation in its liver metastasis. Although the primary tumor was uniformly endocrine in nature with insulin production, the metastasis contained two distinct cell types in organoid arrangement. One cell type was insulin-positive and was arranged in islet-like structures; the other was insulin-negative but distinctly pan-cytokeratin and cytokeratin 7 positive and arranged in ducts. In the primary tumor and the metastasis, the tumor cells were surrounded by a desmoplastic stroma. As to the histogenesis of the tumor and its metastasis, we discuss the following possibilities: (1) the tumor cells might derive from a common stem cell that matures into two phenotypically different cell lines, resembling the situation in embryogenesis and (2) one tumor cell type originates from the other by transdifferentiation (metaplasia). We conclude that the parallel occurrence of endocrine and ductal differentiation supports the concept that, under certain conditions, islet cells and ductular cells may also originate from islets and that mixed endocrine/exocrine pancreatic tumors do not necessarily arise from totipotent duct cells but might also have a primary endocrine cell origin.

Biomarkers, Tumor↗
PubMed2002

Tonic fibres in axial muscle of cyprinid fish larvae: their definition, possible origins and functional importance.

Teleost fish are known to develop small populations of muscle fibres that are assumed to be tonic in nature although their contractile properties and many other characteristics remain unknown. Here we attempt to resolve some of the ambiguity and confusions surrounding the definition and functional role of tonic fibres in teleosts and provide new information on their ontogeny. We investigate the differentiation of tonic muscle fibres in three species of cyprinid fish using electron microscopy, histochemistry, immunohistochemistry and in situ hybridization. The fine structure of the fibres defined as tonic in the larvae used in this study complies with patterns known from studies in teleost adults. This allows formal definition of tonic fibres in cyprinid larvae. The tonic fibres may be recognized by a variety of features: (1) by their characteristic position along the medial confines of the red muscle insertion at the horizontal septum, (2) their fine structure, including solid clusters of irregularly cleaved myofibrils, thick and wavy Z-lines, and T-tubules at the A-band/I-band transitions, (3) their histochemical features, specifically weak but obvious staining for mATPase after alkaline preincubation, and lack of SDH activity in the more advanced larval stages, (4) their unique immunological properties, being the only fibre type in the myotome that reacts with a serum against chicken tonic myosin (anti- T2). Expression of tonic characters usually begins within a few fibres in the dorsal domain of the superficial red muscle insertion at the horizontal septum and hence involves a high degree of dorso-ventral polarity. The present evidence indicates that tonic fibres arise from separate myogenic stem cells rather than by transdifferentiation from existing red fibres. First appearance of tonic fibres during ontogeny correlates closely with the onset of free swimming and exogeneous feeding. We use this fact to argue that tonic fibres are probably a prerequisite for efficient locomotory control during prey capture, shoaling and predator avoidance.

Animals↗
PubMed1998

Immunoreactivity of the ets-1 transcription factor correlates with areas of epithelial-mesenchymal transition in the developing avian heart.

Cardiac morphogenesis involves substantial remodeling processes that include cell transdifferentiation and migration. The c-ets-1 protooncogene codes for a transcription factor that can transactivate a number of genes involved in developmental processes such as degradation of extracellular matrices and cell migration. We have immunolocated the ets-1 protein in the heart of quail and chick embryos between the Hamburger and Hamilton stages HH16 and HH37. In HH16-17 embryos, the ets-1 transcription factor was only detected in some endocardial cells and in most mesothelial and mesenchymal cells of the proepicardium. Ets-1 immunoreactivity increased markedly in the developing endocardial cushions, myocardium, epicardium and early subepicardial mesenchyme of HH18-19 embryos. By HH20-24 the immunoreactivity was found throughout the heart, with a stronger intensity in the areas of epithelial-mesenchymal transition of the endocardium and epicardium. In embryos between HH26 and HH33, ets-1 immunoreactivity increased in the cushion mesenchyme, atrioventricular endocardium, ventricular epicardium and subepicardial mesenchyme cells, but not in other areas of the heart. The immunoreactivity declined in the innermost part of the endocardial cushions. The subepicardial mesenchyme was particularly immunoreactive in these stages, coinciding with the development of the subepicardial vascular network. In fact, ets-1 colocalized with the quail vascular marker QH1 in the subepicardial mesenchymal cells. Ets-1-negative cells were abundant in the subepicardium and valvuloseptal tissue of the HH37 embryos. The results suggest that ets-1, probably through transactivation of genes such as urokinase-type plasminogen activator and matrix metalloproteinases, might play a crucial role in the differentiation of the cushion and subepicardial mesenchyme, the formation of the intratrabecular sinusoids and the early development of the cardiac vessels.

Animals↗
PubMed2003

Phenotype-dependent synthesis of transferrin receptor in rat alveolar epithelial cell monolayers.

The iron carrier protein transferrin plays a prominent antioxidant and anti-bacterial role in the lower respiratory tract and is present at elevated concentrations in lung epithelial lining fluid relative to plasma. The level of transferrin receptor synthesis in primary cultures of rat alveolar epithelial cells (AECs) was investigated. Transferrin receptor was found to be synthesized early in AEC cultures with the alveolar type II cell-like phenotype. Cell-surface receptor localization was attenuated upon apparent transdifferentiation to the alveolar type I cell-like phenotype later in culture. Binding of (125)I-labeled transferrin to the receptor indicated that surface and total cellular transferrin receptor levels were decreased in the type I-like cells. Inclusion of keratinocyte growth factor (KGF) in culture media (10 ng/ml) resulted in retention of transferrin receptor localized to the basolateral surface. Transferrin-receptor-specific internalization of (59)Fe-transferrin was also limited to the basolateral surface of KGF-treated monolayers. These data suggest that alveolar type II (but not type I) cells express functional transferrin receptor in adult rat alveolar epithelium.

Animals↗
PubMed2000

Epidermal growth factor, insulin, and estrogen stimulate development of prolactin-secreting cells in cultures of GH3 cells.

Pituitary tumor GH3 cells synthesize and secrete both growth hormone (GH) and prolactin (PRL). Morphological and functional changes of GH3 cells induced by epidermal growth factor (EGF, 10 nM), insulin (300 nM), and estradiol-17beta (E2, 1 nM) were studied. Treatment of cultures of GH3 cells for 6 days with EGF, insulin, or E2 alone, and with EGF plus E2 did not affect the total number of GH3 cells, but a combination of EGF, insulin, and E2 decreased the total number of GH3 cells compared with control treatment. DNA-synthesizing cells were detected by monitoring 5-bromo-2'-deoxyuridine (BrdU) uptake. EGF, E2, or a combination of EGF, insulin, and E2 significantly decreased the proportion of BrdU-labeled cells (21.1+/-1.7%, 21.0+/-1.4%, 18.2+/-1.3%; P<0.05, P<0.05, P<0.01, respectively) compared with control treatment (28.6+/-1.5%), but insulin did not (31.4+/-2.4%). Immunocytochemical analysis of GH3 cells cultured in 5% fetal calf serum-supplemented medium (control) showed that about 70% of all GH3 cells were GH-immunoreactive cells (GH-ir cells), apparently containing only GH, and 14% were mammosomatotrophs (MS cells), containing both GH and PRL, while PRL-immunoreactive cells (PRL-ir cells), containing only PRL, were not detected. No GH or PRL immunoreactivity could be detected in the remaining cells (15%). EGF decreased the proportion of GH-ir cells. The effects of EGF were enhanced by simultaneous exposure to insulin and E2; this decreased the proportion of GH-ir cells to about 20% of the total GH3 cells and significantly increased the proportion of MS cells to 300% of controls. Treatment with EGF plus insulin, EGF plus E2, or a combination of EGF, insulin, and E2 all stimulated the appearance of PRL-ir cells. Exposure to EGF caused a significant decrease in GH mRNA (P<0.01) and a significant increase in PRL mRNA (P<0.05). These observations suggest that EGF is closely involved in differentiation of PRL-ir cells from GH-ir cells via MS cells in GH3 cell cultures. Cytosine arabinoside (10(-7) M), an inhibitor of cell division, did not affect the changes in proportion of the three cell types induced by treatment with a combination of EGF, insulin, and E2. It is therefore probable that the transdifferentiation does not require mitosis of the GH3 cells.

Animals↗
PubMed2006

Phenotype analysis by MUC2, MUC5AC, MUC6, and CD10 expression in Epstein-Barr virus-associated gastric carcinoma.

BACKGROUND: Gastric marker mucins (MUC5AC and MUC6) and intestinal marker molecules (MUC2 and CD10) have been used to determine the cell lineage of epithelial cell of gastric carcinoma (GC). METHODS: To clarify the characteristics of Epstein-Barr virus (EBV)-associated GC, 18 cases were immunohistochemically evaluated along with 56 cases of EBV-negative GC. RESULTS: MUC2 expression was lower in EBV-associated GC: immunostaining grades 0, 1, 2, 3, and 4 were observed in 10, 6, 1, 1, and 0 cases of EBV-associated GC, respectively, and in 18, 11, 15, 6, and 6 cases of EBV-negative GC, respectively (P = 0.013). CD10 positivity (grades 2-4) in EBV-associated GC was 6%, significantly lower than in EBV-negative GC (34%) (P = 0.030). When phenotypes of GC were categorized by the combined positivities of gastric markers (either MUC5AC or MUC6) and intestinal markers (either MUC2 or CD10), EBV-associated GC included primarily null (44%) and gastric (39%) types, but EBV-negative GC comprised null (7%), gastric (30%), intestinal (27%), and mixed (36%) types. The age of patients with gastric types was significantly younger for both EBV-associated GC and EBV-negative GC cases. CONCLUSIONS: Neoplastic epithelial cells of EBV-associated GC did not express MUC2 or CD10, and most of them were categorized as null or gastric types. EBV infection may occur in the epithelial cells of null or gastric phenotypes, which may be devoid of transdifferentiation potential toward intestinal phenotypes.

Aged↗
PubMed2005

Whether modern cell technologies can break down biological limitations of tissue-specific regeneration of the myocardium.

The paper reviews modern concepts of physiological and reparative regeneration of the myocardium as a highly specific and highly differentiated tissue system. Special attention was given to evaluation of the proliferative potential of cardiomyocytes, in particular, to the existence of a population of resident cardiac stem cells in the myocardium. Modern approaches to replenishment of massive cardiomyocyte loss via transplantation and transdifferentiation of adult and embryonic stem cells are discussed and the possibilities of using cell technologies for induction of tissue-specific regeneration of the myocardium are analyzed.

Animals↗
PubMed2006

Induction of mesenchymal stem cells leads to HSP72 synthesis and higher resistance to oxidative stress.

The phenomenon of neuronal transdifferentiation performed on bone marrow mesenchymal stem cells (MSCs) has been criticized by recent studies indicating that acquired neuron-like morphology of induced MSCs is caused by cellular stress. Therefore, to test this hypothesis we have investigated whether exposure of rat MSCs (rMSCs) to chemical inducer 2 mM beta-mercaptoethanol (BME) for 1-3 h followed by 24 h incubation leads to HSP72 synthesis, thus suggesting higher resistance of rMSCs to oxidative damage. Present data from immunohistochemistry clearly indicate development of time-dependent sub-cellular HSP72 distribution, initially seen in nuclei at 1 h followed by its translocation to surrounding central cytoplasm and processes at 2-3 h after BME stimulation. Western blot (WB) analysis confirmed the expression of HSP72 protein in induced rMSCs at both stimulation periods. Furthermore, preconditioned rMSCs with BME for 1 h expressing HSP72 positivity at 24 h showed higher resistance (78 +/- 10% of survival cells) to oxidative stress caused by 1 mM H(2)O(2) when compared to those preconditioned for 3 h (59 +/- 8% of survival cells) or control-unconditioned rMSCs exposed to the same stressor conditions (56 +/- 6% of survival cells). Thus, the cellular protection was lost if the duration of BME preconditioning was increased as far as possible (3 h) (while still remaining sub-lethal). This suggests that exposure of rMSCs to the optimal concentration of BME (2 mM) during optimal induction period (1 h) mediate their protection and increases resistance to oxidative injury, while over crossing these limits is in-effective. In addition, our findings confirm that cultured rMSCs remain competent to be preconditioned by BME, through a pathway that may increase the antioxidant balance or involve activation of HSP72 protein induced tolerance.

Animals↗
PubMed2001

Proliferation and differentiation of pituitary somatotrophs and mammotrophs during late fetal and postnatal periods.

Proliferation of somatotrophs and mammotrophs in the rat pituitary during late fetal and postnatal periods up to 4 weeks after birth was quantitatively studied with the double immunostaining of bromodeoxyuridine and the hormones produced by them. Somatotrophs were first detected in 18.5-day fetuses and rapidly increased in number throughout the periods studied. The cells labeled with both anti-BrdU and anti-GH were few in number until shortly before birth and then increased conspicuously during the first 10 days after birth. Mammotrophs were detected at gestational day 19.5 but they were few until the second week after birth, when their number began to increase rapidly. The percentage of the number of the cells double-labeled with both anti-BrdU and anti-GH to all somatotrophs was 8.3% at the most. This was about the same as that of corticotrophs during the late fetal period and that of thyrotrophs in the early postnatal period. In contrast, the percentage of double-labeled cells to all mammotrophs was 3.8% as a maximum, which is lower than the values for somatotrophs, corticotrophs, or thyrotrophs, indicating a smaller contribution of mitosis to mammotroph proliferation. It is possible that this smaller contribution is compensated for by transdifferentiation of cells committed to become the somatotroph lineage. However, coexistence of GH and PRL was not observed in the present material.

Animals↗
PubMed1985

Embryologic development of rat adrenal medulla in transplants to the anterior chamber of the eye.

The morphological development and plasticity of embryonic and postnatal rat adrenal medullary cells were studied in homologous adrenal grafts to the anterior chamber of the eye. The eyes of recipient rats were adrenergically denervated 10 days prior to grafting by extirpation of the superior cervical ganglion in order to increase levels of NGF and NGF-like activities in the iris. Grafts taken at the 15th day of embryonic development (E15), i.e., at the beginning of immigration of medullary progenitor cells into the adrenal cortical anlagen, contained no cortical or mature medullary cells after 2 weeks in oculo. Numerous sympathoblastic cells, however, were located at the anterior surface of the iris. E 16 and E 17 transplants showed abundant mature cortical tissue after 2 weeks. Small groups of medullary cells with the ultrastructural characteristics of mature pheochromoblasts or young chromaffin cells were interspersed among cortical cells without forming a discrete medulla. Neuronal cells were exclusively found outside the cortical cell mass. Sympathoblasts grew at the surface of the iris, while young sympathetic nerve cells, which were invested by Schwann cells and received synaptic axon terminals, were embedded into the stroma of the iris. Grafting of E 21 adrenals yielded very similar results except that, in a few instances, young chromaffin cells were located outside the cortex and sympathetic nerve cells were seen to be in close contact with cortical cells. In transplants of adult medullary cells typical mature adrenaline and noradrenaline cells were clearly distinguishable after 8 weeks even in the absence of cortical cells. The only indication of phenotypical changes in these cells was the formation by some of them, of neuritic processes which could be visualized in glyoxylic acid-treated whole mounts of irises. These results are compatible with the idea that embryonic adrenal medullary cells have the environmentally controlled potential to develop along the neuronal or endocrine line, but could also be interpreted in terms of a selection of a specific subpopulation with predetermined potentialities by a specific microenvironment. Moreover, these results suggest that increasing differentiation of medullary cells is accompanied by progressive restrictions in their genetic program, which eventually prevent full transdifferentiation of mature chromaffin into neuronal cells.

Adrenal Medulla↗
PubMed1987

Immunohistochemical characterization of delta crystallin-containing retina/optic nerve "boundary" cells in the chick embryo.

The term "transdifferentiation" has been used to describe the apparent phenotypic conversion of chick embryo neural retina Müller glial cells into lens-like cells in vitro. This phenotypic conversion is characterized by expression of such lens-specific proteins as delta crystallin and has been viewed as an example of cells transforming from the phenotype of a given tissue to that of another. We have identified a population of neuroglia-like cells in the embryonic chick retina which express high levels of delta crystallin as a function of normal development. The position and morphology of these cells is quite distinctive in that they form a loose meshwork which defines the boundary between the neural retina and the optic nerve head. These "boundary" cells are detectable as early as Day 5 of development through hatching. However, the meshwork structure formed by the cells is only readily observed between Days 8 and 9 of development. Double-immunolabeling procedures comparing delta crystallin staining to that of glial and neuronal markers suggest that these cells are a form of retinal Müller glial cell. The results show that under appropriate microenvironmental conditions, expression of delta crystallin falls into the normal repertoire of retinoblast cells. The results also demonstrate the presence of a cellular boundary defining the junction between the neural retina and the optic nerve, tissues that are ontogenetically and structurally continuous but functionally distinct.

Animals↗
PubMed1989

Basic fibroblast growth factor induces retinal regeneration in vivo.

In the present study, we have investigated the effect of basic fibroblast growth factor (bFGF) on retinal regeneration in the stage 22-24 chick embryo. The neural retina was surgically removed in ovo leaving the retinal pigment epithelium (RPE) intact and then slow-release, plastic implants containing bFGF were inserted into the eye. Light microscopic examination of eyes 7 days later revealed that bFGF induced retinal regeneration in a dose-dependent manner. The absence of the RPE in these eyes and the reversed polarity of the regenerated neural retina is consistent with the hypothesis that this process occurs by transdifferentiation of the RPE. This represents the first time that a known molecule has been shown to induce retinal regeneration in vivo.

Animals↗
PubMed1991

Chronic exposure to an activator of protein kinase C mimics early effects of NGF in chromaffin cells.

Adrenal chromaffin cells respond to nerve growth factor (NGF) in vitro by expressing neuronal characteristics and, over a period of 2 to 4 weeks, transdifferentiating into postmitotic sympathetic neurons. Phorbol myristate acetate (PMA) is a potent activator of protein kinase C (PKC); chronic exposure to PMA mimics the initial actions of NGF by promoting the outgrowth of neurites and increasing the incorporation of [3H] thymidine in primary cultures of adrenal chromaffin cells from young rats. PMA and NGF affect the same populations of cells and even individual neurites. These effects are specific for active phorbol ester and do not result from the release of NGF or FGF in the cultures. As in the case of NGF, the effects are inhibited by glucocorticoids. The PKC inhibitor staurosporine inhibits the effects of PMA, as well as those of NGF, in a dose-dependent manner. These results suggest that a modulation in activity of PKC is important in the neuritogenic and proliferative effects of NGF, at least for an initial period of approximately 1 week.

Animals↗
PubMed1991

Induction of retinal regeneration in vivo by growth factors.

We have previously reported that basic fibroblast growth factor (bFGF) can induce retinal regeneration in the stage 22-24 chicken embryo. The present study was undertaken to identify the cellular source of the regenerate and to determine whether other growth factors also elicit regeneration in this animal model. Polymer implants containing bFGF were inserted into eyes of chicken embryos immediately after extirpation of the neural retina. The retinal pigment epithelium (RPE) was left intact. Evaluation by light microscopy revealed that in bFGF-treated eyes the new neural retina arose by transdifferentiation of the entire RPE layer. Differentiation of the new neural retina occurred in a sequence similar to that of normal development but proceeded in a reverse (vitread) direction. All retinal laminae had differentiated by Day 15. However, the regenerate displayed reversed polarity, with photoreceptors closest to the lens. The RPE, pecten, and optic nerve were absent. Focal areas of degeneration in the retinal regenerate became evident for the first time on Day 10. Retinal regeneration was also observed after treatment with higher doses of acidic fibroblast growth factor, but not with nerve growth factor-beta, transforming growth factor-beta 1, insulin, or insulin-like growth factors I or II. These results raise the possibility that FGFs may play a role in retinal differentiation during development.

Animals↗
PubMed1993

Absence of monoclonal antibody detectable Kaposi sarcoma-specific antigens on lesion-derived cultured cells.

To define the histogenesis and cell origin of Kaposi sarcoma (KS), we cultured KS cells without retrovirally conditioned media from three HIV seropositive AIDS patients and then attempted to raise mouse hybrid monoclonal antibodies (Mabs) specific to these AIDS-KS cells. After both in vivo and in vitro immunization trials, all putative Mabs reacted positively to KS cells but also non-specifically with other human (CH5 and OM) and non-human (RSE-1) control endothelial cell lines. To overcome this crossreactivity, we further "absorbed" previously cloned hybrids and pre-hybrid splenocytes by incubating them with the control endothelial cell lines to eliminate splenocytes and/or hybridomas reactive to normal endothelium. Whereas absorption successfully eliminated immunoreactivity to control endothelium, it also excluded reactivity to KS cells. These findings (lack of specific antigenicity and immunoresponsiveness of KS similar to non-KS control endothelium) suggest that AIDS-KS cells are neither antigenically transformed nor neoplastic, but instead represent dedifferentiated or transdifferentiated endothelium which retains immunogenicity of its original endothelial cell prototype.

Acquired Immunodeficiency Syndrome↗
PubMed1990

Pancreatic hepatocytes in Fischer and Wistar rats induced by repeated injections of cadmium chloride.

The effects of multiple sc injections of cadmium chloride (CdCl2) on the pancreas of two rat strains (Wistar [WF/NCr] and Fischer [F344/NCr]) were studied by histological and immunohistochemical examinations. A high incidence of hepatocytic foci occurred within the pancreata of both strains that was associated with this cadmium exposure. Although pancreatic hepatocytes (PH) were found in both strains, Wistar rats were more susceptible to cadmium-induced PH formation while showing more tolerance to cadmium in general. The highest incidence of PH was 93% in Wistar rats and 50% in Fisher rats. Dose-related increases in incidence of PH occurred at levels of 360-513 mumol Cd/kg. Number of PH foci/rat correlated well with PH incidence. By avidin-biotin immunohistochemistry, PH exhibited rat albumen and a gap junction protein (Connexin32) found in hepatocytes. PH were frequently seen along with pancreatic acinar atrophy (fatty replacement) and interstitial fibrosis. Thus, it appears that cadmium must be considered one of the most efficacious agents for production of PH within the rat pancreas. The ability of cadmium to induce this transdifferentiation is also clearly dose and strain related.

Animals↗