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

The majority of renal cancers are thought to arise from the proximal tubule epithelium, but little is known about their etiology. In this investigation, we have established an in vitro model to study the transformation of these target cells using rat kidney proximal tubule epithelial cells (RPTE) transformed in defined medium with SV40-viral DNA. Selection by passaging cells onto plastic surfaces yielded a population of cells (SV-RPTE) that expressed keratin and vimentin along with SV40 large-T antigen. The cells were morphologically transformed and lost their differentiated character as determined by several RPTE markers. SV-RPTE cells grew in soft agar in serum-supplemented medium containing insulin, epidermal growth factor, and cholera toxin, but were unable to grow when serum and growth factors were not combined. Acidic and basic fibroblast growth factors (aFGF and bFGF) were unique since they were the only single factor that induced anchorage-independent growth in the presence of serum alone. Transforming growth factor-beta 1 (TGF-beta 1) was a potent inhibitor of anchorage-independent growth, but the inhibition was partially overcome by a combination of growth factors. The growth factor responses of SV-RPTE in monolayer cultures differed from those in soft agar; the cells were more sensitive to growth stimulation by insulin and insulin-like growth factor, neither of which stimulated anchorage-independent growth. SV-RPTE cells in monolayer cultures had also lost the sensitivity to growth inhibition by TGF-beta 1 characteristic of normal RPTE. The RPTE transformation model described here will be very useful for investigating the molecular basis and etiology of renal cancers. Furthermore, the data suggest that maintenance of the transformed phenotype by aFGF and bFGF and loss of negative growth regulation by TGF-beta 1 could play a role in renal carcinogenesis.
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PMID:Altered growth regulation of rat kidney proximal tubule epithelial cells transformed in vitro by SV40 viral DNA: fibroblast growth factors (heparin-binding growth factors) are potent inducers of anchorage-independent growth. 164 62

This study examined the characteristics of keratinocytes from 4-nitroquinoline N-oxide-treated rat oral epithelium that formed well differentiated carcinomas or spindle cell tumours when transplanted s.c. to athymic mice. Small polygonal-type cells in early culture passage gave rise to xenografts that were well differentiated carcinomas with keratin positivity and a differential reactivity with two anti-vimentin antibodies (positive Vim Dako, negative Vim 3B4). Progressive culture of the polygonal cells resulted in cells of a more stellate-like morphology which, when transplanted, formed spindle cell tumours that were keratin negative and vimentin positive (Vim Dako and Vim 3B4). The staining pattern of the xenografts was similar to that of the cultured cell derivatives. By contrast to normal oral keratinocytes which were stimulated by epidermal growth factor (EGF), the parental and xenograft-derived cells were markedly less responsive and at times refractory to EGF. Low affinity EGF receptors characterized normal keratinocytes whilst parental and xenograft-derived cells from well differentiated carcinomas and spindle cell tumours expressed diminished numbers of low and high affinity and high affinity EGF receptors respectively. Normal keratinocytes and parental tumour cells were inhibited by transforming growth factor (TGF-beta) whereas xenograft-derived cell lines from both well differentiated carcinomas and spindle cell tumours were refractory to TGF-beta. TGF-beta receptors were predominantly of high affinity although xenograft-derived cells, particularly from spindle cell tumours, expressed increased numbers of receptors which were of lower affinity. The results indicate that spindle cell tumours are a variant of well differentiated carcinomas and express an aberrant pattern of differentiation. Resistance to EGF-induced stimulation and TGF-beta-induced inhibition appears not to be an integral part of the tumour phenotype but the pattern of EGF and TGF-beta receptor expression closely follows the degree of tumour differentiation.
Carcinogenesis 1991 Mar
PMID:Differentiation of malignant oral rat keratinocytes reflects changes in EGF and TGF-beta receptor expression but not growth factor dependence. 184 51

Changes of cell morphology and the state of differentiation are known to play important roles in embryogenesis as well as in carcinogenesis. Examples of particularly profound changes are the conversions of epithelial to mesenchymal cells; i.e., the dissociation of some or all polygonal, polar epithelial cells and their transformation into elongate, fibroblastoid cells of high motility. As an in vitro model system for such changes in cell morphology, we have used cell cultures of the rat bladder carcinoma-derived cell line NBT-II which, on exposure to inducing medium containing a commercial serum substitute (Ultroser G), show an extensive change in their organization (epithelial-mesenchymal transition): the junctions between the epithelial cells are split, the epithelial cell organization is lost, and the resulting individual cells become motile and assume a spindle-like fibroblastoid appearance. Using immunofluorescence microscopy and biochemical protein characterization techniques, we show that this change is accompanied by a redistribution of desmosomal plaque proteins (desmoplakins, desmoglein, plakoglobin) and by a reorganization of the cytokeratin and the actin-fodrin filament systems. Moreover, intermediate-sized filaments of the vimentin type are formed in the fibroblastoid cells. We demonstrate that the modulation of desmosomal proteins, specifically an increase in soluble desmoplakins, is a relatively early event in cell dissociation and in epithelial-mesenchymal transition. In this process, a latent period of 5 h upon addition of inducing medium precedes the removal of these desmosomal components from the plasma membrane. The transition, which is reversible, is dependent on continued protein synthesis and phosphorylation but not on the presence of the inducing medium beyond the initial 2-h period. We discuss the value of this experimental system as a physiologically relevant approach for studying the regulation of the assembly and disassembly of desmosomes and other intercellular adhesion structures, and as a model of the conversion of cells from one state of differentiation into another.
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PMID:Rearrangements of desmosomal and cytoskeletal proteins during the transition from epithelial to fibroblastoid organization in cultured rat bladder carcinoma cells. 267 20

In order to obtain more information on the in vitro transformation of human cells, a human fetal tracheal epithelial cell line (FHET16/5) was exposed for a long time to diethylnitrosamine (DEN). In 20 passages, this cell line (diploid, male) maintained strong immunohistochemical reactivity for carcino-embryonic antigen and wool merokeratin; it was negative for vimentin. The cells contained PAS-positive mucous substances and ultrastructurally were found to have desmosome-like attachments. Treatment of the cells was with 0.3% dimethyl sulphoxide (DMSO), or DMSO with 150, 450, 1000 or 2000 micrograms/ml of DEN. It was started at the ninth passage and continued for six passages over 9 weeks for the control (DMSO) and the three lowest control doses of DEN, and for three passages over 9 weeks for the 2000 micrograms/ml DEN group. Cells grown for 13 days after the end of treatment were plated in soft agar and injected subcutaneously in nude mice. The frequency of anchorage-independent colonies grown in soft agar was directly related to DEN dose. Colony-forming efficiency, as an expression of toxic effect, was also dose dependent. Autoradiographically detected unscheduled DNA synthesis indicated an association between anchorage-independent transformation and DNA alterations induced by DEN. Cells injected into nude mice did not produce tumours during a 6-month period, but invasiveness was observed when cells from the 2000 micrograms/ml DEN group were transplanted on the dermis of cultured chick embryo skin. The results indicate that DEN causes anchorage-independent transformation accompanied by unscheduled DNA synthesis in a fetal human tracheal epithelial cell line.
Carcinogenesis 1985 Aug
PMID:Growth inhibition and transformation of a human fetal tracheal epithelial cell line by long-term exposure to diethylnitrosamine. 401 81

Two rat ascites hepatoma lines, AH130, originating from a azodye-induced liver carcinoma, and AH130F(N), spontaneously derived from the AH130 line during serial i.p. transplantation were analyzed for their intermediate filament protein expression by one and two-dimensional gel electrophoresis, in vitro translation of their mRNAs and immunolocalization using antisera against distinct subunits and compared with intermediate filament expression of normal hepatocytes. Normal rat hepatocytes synthesize mainly two keratin subunits at 55 and 47 kDa. The AH130 hepatoma line maintains the expression of these proteins, however, in addition also synthesizes a 40-kDa keratin subunit and large amounts of vimentin. In contrast, the AH130F(N) hepatoma line has lost the ability to express keratin subunits; its intermediate-sized filament compound is apparently built up only by vimentin. Even by means of the sensitive immunoblotting technique using antisera against the normal hepatocyte keratin subunits, no keratin synthesis can be demonstrated in this line. The marked differences in the metastatic capacity of the two hepatoma lines make them promising tools to investigate a possible involvement of intermediate-sized filament expression in the process of tumor spreading.
Carcinogenesis 1984 Oct
PMID:Differential expression of intermediate filament proteins in two rat ascites hepatoma lines of common origin. 620 51

The present study was concerned with oral reparative and inflammatory reactions, benign epithelial proliferations and malignant lesions including their prestages. Following investigations of normal oral mucosa, biopsy and surgical specimens of diseased human oral mucosa were studied with light and electron microscopical methods. In addition, experimental models of oral wound healing and carcinogenesis were developed. Combining morphological (immunofluorescence, immunocytochemistry, electron microscopy) and biochemical (SDS polyacrylamide gel electrophoresis) techniques differentiation and function of epithelial and non-epithelial cells of the oral mucosa were investigated. Clinical pathology. 725 oral lesions were collected from the files of the Dermatological Clinic of the University of Hamburg. Among these lesions epithelial hyperplasias and neoplasias represented the most frequent alterations of the oral mucosa. The incidence of premalignant lesions (3.7%) was consistent with the percentages reported in the literature. On frozen or glutaraldehyde-fixed tissue samples the value of immunohistological and ultrastructural methods was examined with particular respect to the distinction of reactive inflammatory processes from true premalignant and malignant lesions and with special reference to the differential diagnosis of epithelial and non-epithelial tumours. Examples were given for immunological characterization of inflammatory lesions and for histogenetical typing of neoplasias. Normal oral mucosa. Biochemical and morphological investigations of keratin filaments showed that basal and suprabasal epithelia contain different keratin polypeptides related to the degree of cell differentiation. These cytoskeletal modifications were seen to be associated with cell membrane differentiations which was demonstrated by different lectin affinities to basal and suprabasal compartments of epithelium. At the epithelial-mesenchymal interfaces macromolecular substances appeared (e.g. fibronectin) which are produced by basal epithelia (e.g. laminin) and connective tissue cells leading to the formation of the basement membrane zone. Immune competent cells were seen to be regular components of normal oral mucosa. Within the epithelium Langerhans cells and T lymphocytes of the suppressor/cytotoxic phenotype were shown to be the predominant inflammatory cells. B lymphocytes, T lymphocytes of the suppressor/cytotoxic and helper/inducer phenotypes and typical macrophages represented cellular elements of the connective tissue. All these non-epithelial cells were found to contain vimentin filaments.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:[Immunopathology of the oral mucosa. Oral immune system--inflammatory reactions--tumor-"marker"--virus identification]. 632 69

[35S]Methionine labelled polypeptides from mouse CLID, hamster ovary cells (CHO, and 7 derived somatic cell hybrids which have segregated CHO chromosomes, were analysed by means of high resolution two-dimensional gel electrophoresis under conditions in which the position of 600 polypeptides could be reproducibly assessed. As judged from the two-dimensional gel electrophoretic patterns (isoelectric focussing (IEF) and non-equilibrium pH gradient electrophoresis (NEPHGE)) gene expression in all the hybrids resembled the mouse CLID parent and with only one exception they all expressed different numbers and intensities of CHO specific polypeptides. Even though some of the hybrids expressed as much as 50% of the total number of CHO specific polypeptides that could be clearly differentiated from those of the mouse parent we failed to find a direct correlation between the expression of any given CHO polypeptide and the morphological or tumorigenic properties of the hybrids. Most CHO specific polypeptides, however, were expressed at lower levels in the hybrids as compared to the parent CHO cells, a fact that may be due to the chromosomal constitution of the hybrids, regulation or both. Similarly, the quantitation of the major cytoskeletal polypeptides present in the hybrids, such as alpha-and beta-tubulin, vimentin, total actin and 3 polypeptides (IEF 12, 24 and 31) present in intermediate filament enriched cytoskeletons, indicate that changes in the relative proportion of any of these proteins is not sufficient to account for the morphology, actin microfilament pattern or tumorigenicity of the hybrids. Co-expression of cytoskeletal proteins in the hybrids could only be demonstrated in the case of the related mouse IEF 24 and hamster IEF 7 polypeptides. In all other cases the cytoskeletal polypeptides co-migrated and presented similar one-dimensional peptide maps. Some principles are emerging concerning the possibility of using somatic cell hybridization in combination with two-dimensional gel electrophoresis to locate genes coding for particular polypeptides on a given chromosome.
Carcinogenesis 1981
PMID:Gene expression in murine hybrids exhibiting different morphologies and tumorigenic properties. 728 83

In search of biomarkers that predict of human prostate cancer progression, we hypothesized that these markers must be expressed in prostatic epithelial cells during multi-step prostate carcinogenesis. Since both genetic and epigenetic factors have been implicated in human prostate cancer development, two osseous-metastatic experimental models were developed in our laboratory, one based on gene transfection and the other on stromal-epithelial interaction studies. In the genetic model, PC-3 cells transfected with point-mutated c-erbB-2/neu oncogene subsequently acquired the potential to metastasize from the prostate to soft tissues and the skeleton. In the epigenetic model, sublines derived from the parental androgen-dependent LNCaP cell line metastasized from the primary tumor to the lymph node and bone. Cells with known lineage relationships were cloned from both the primary and the metastatic tumors and were characterized extensively using cellular, biochemical, immunohistochemical, and molecular techniques. Relevant stage-specific biomarkers associated with prostate cancer progression in these two models were defined and used to evaluate human prostate tissues obtained from the clinic. In this communication, we focused our discussion on the potential importance of c-erbB-2/neu oncogene, vimentin, hepatocyte growth factor/scatter factor and its receptor, c-met oncogene, tumor angiogenesis and neuroendocrine factors as biomarkers for human prostate cancer progression.
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PMID:Biomarkers associated with prostate cancer progression. 752 53

Macroscopic stomach tumors induced in Sprague-Dawley rats during two chronic bioassays with the acetanilide herbicide butachlor at a dietary concentration of 3000 ppm, were evaluated histologically and immunohistochemically in order to determine their identity and pathogenesis. The tumors, which occurred primarily in female rats, were a heterogeneous series, including a few consisting wholly or partly of classic solid or anaplastic epithelium, but with the majority containing diffusely distributed primitive neoplastic cells. The latter had either the general appearance of undifferentiated epithelium or presented a more "mesenchyme-like" pattern where the cells were epithelioid, blastema-like, neuroendocrine-like or sarcoma-like with fascicular disposition. Gastric glandular profiles were also present, usually located near the periphery of the tumors, but in some cases extending into the diffuse tumor tissue. Most of the tumors displayed variable immunohistochemical reactivity for cytokeratin, vimentin and neuron-specific enolase but were negative for muscle-specific actin or desmin except in the stromal tracts. Detailed examination of all available gastric tissue revealed the presence of additional microscopic neoplasms and precursor hyperplastic lesions. All of these were typical gastric neuroendocrine cell lesions (gastric carcinoids) originating in the fundic mucosa but occasionally invading submucosally, and consisting of epithelial cells in organized clusters, rosettes or primitive tubules. The enterochromaffin-like (ECL) nature of these microscopic neoplasms and precursor lesions was substantiated by strong immunohistochemical reactivity for cytokeratin, neuron-specific enolase and chromogranin A, and a negative reaction for vimentin. One microscopic tumor showed a transition from differentiated neuroendocrine type in the fundic mucosa to a dispersed "mesenchyme-like" pattern in the submucosal extension. An additional finding in the butachlor-treated male and female rats was atrophy of the fundic mucosa involving, in particular, reduction in the numbers of parietal cells. This effect was dose-related, being most severe in the high-dose (3000 ppm) females. On the basis of their morphological characteristics, coupled with the continuity evident in the microscopic lesions, it is concluded that the macroscopic stomach tumors associated with the dietary administration of butachlor are poorly differentiated gastric carcinoids, in some cases admixed with a non-neuroendocrine epithelial element. Fundic ECL and stem cells are known to be under the trophic influence of gastrin, which is apparently responsible for the induction of the tumors associated with butachlor administration. Gastric tumor development involving gastrin is recognized as a secondary, hormonal mechanism of carcinogenesis, demonstrating a dose-threshold phenomenon.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Identity and pathogenesis of stomach tumors in Sprague-Dawley rats associated with the dietary administration of butachlor. 758 Jan 13

In a 70 year old woman with a tumor in the head of the pancreas, the lesion was predominantly composed of papillary adenocarcinoma protruding into the main pancreatic duct, with periductal invasion. The major portion of the adenocarcinoma was intraductal and was composed of tall columnar epithelial cells with pseudostratified nuclei, had the appearance of primitive endodermal epithelium and was positive for carcino-embryonic antigen. In contrast, in the other portion of the adenocarcinoma which had the predominant component of periductal invasion, neoplastic cells had an irregular, eosinophilic cytoplasm, resembled ordinary pancreas adenocarcinoma of ductal origin and was positive for CA19-9. Neuro-endocrine and alpha-fetoprotein-positive cells with a primitive appearance were scattered among the neoplastic epithelial linings. In addition, a vimentin-positive sarcomatoid component intermingled with the adenocarcinoma. These findings suggest that the adenocarcinoma observed in this tumor with the primitive appearance also had a primitive phenotype. This was evidenced by immunohistochemistry and the divergent directions of differentiation. This particular case illustrates that pancreas adenocarcinoma of the ordinary histologic type can arise secondarily from the more primitive neoplastic cells during carcinogenesis within the pancreatic duct.
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PMID:A case of AFP-positive pancreas papillary carcinoma suggestive of a primitive endoderm phenotype. 769 May 15


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