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Query: UMLS:C0178874 (tumor progression)
 40,807 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Ovarian carcinomas are thought to arise in the ovarian surface epithelium (OSE). Although this tissue forms a simple epithelial covering on the ovarian surface, OSE cells exhibit some mesenchymal characteristics and contain little or no E-cadherin. However, E-cadherin is present in metaplastic OSE cells that resemble the more complex epithelia of the oviduct, endometrium and endocervix, and in primary epithelial ovarian carcinomas. To determine whether E-cadherin was a cause or consequence of OSE metaplasia, we expressed this cell-adhesion molecule in simian virus 40-immortalized OSE cells. In these cells the exogenous E-cadherin, all three catenins, and F-actin localized at sites of cell-cell contact, indicating the formation of functional adherens junctions. Unlike the parent OSE cell line, which had undergone a typical mesenchymal transformation in culture, E-cadherin-expressing cells contained cytokeratins and the tight-junction protein occludin. They also formed cobblestone monolayers in two-dimensional culture and simple epithelia in three-dimensional culture that produced CA125 and shed it into the culture medium. CA125 is a normal epithelial-differentiation product of the oviduct, endometrium, and endocervix, but not of normal OSE. It is also a tumor antigen that is produced by ovarian neoplasms and by metaplastic OSE. Thus, E-cadherin restored some normal characteristics of OSE, such as keratin, and it also induced epithelial-differentiation markers associated with weakly preneoplastic, metaplastic OSE and OSE-derived primary carcinomas. The results suggest an unexpected role for E-cadherin in ovarian neoplastic progression.
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PMID:E-cadherin induces mesenchymal-to-epithelial transition in human ovarian surface epithelium. 1033 73

Benign and malignant HaCaT-ras clones, derived from immortalized HaCaT cells were grown as nude mouse surface transplants rendering a human tumor progression model. Searching for malignancy-related alterations, the deposition, localization and mRNA of basement membrane and hemidesmosome components were analysed by immunofluorescence, in situ hybridization and electron microscopy. Initially, at 1 week epithelia of benign and malignant cells revealed a similarly low polarity and an enlarged 'activated basal' compartment, reflected by partial dislocation and extended pericellular staining of the hemidesmosome constituent integrin alpha 6 beta 4 seen by immunofluorescence. Whereas benign grafts eventually normalized, closely resembling grafts of HaCaT cells, malignant growth was correlated with a persisting epithelial activation state and continuing higher expression of alpha 6 (by immunofluorescence and in situ hybridization). The basement membrane components bullous pemphigoid antigen 1, laminin-5 and collagen IV exhibited a largely linear distribution at 1 week. However, in the malignant cell transplants initially minor basement membrane discontinuities became more severe at around 2 weeks, associated with close stromal cell contacts, angiogenesis and invasion. Most striking were basement membrane alterations seen by electron microscopy. At 1 week stretches of basement membrane had developed in malignant transplants, though to a much lesser extent than in benign specimens. With invasion these basement membrane structures mostly disappeared despite persistent although variable immunofluorescence, suggesting high turnover without ultrastructural assembly. The hemidesmosome structures were defective throughout, completely lacking anchoring plaques with keratin filaments, whereas they were still associated with basement membrane deposits. Thus, malignant HaCaT-ras transplants, while initially resembling regenerating wounds, revealed an increasing loss of tissue polarity and basement membrane structures, which seemed to be accelerated upon stromal cell contacts.
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PMID:Defects of basement membrane and hemidesmosome structure correlate with malignant phenotype and stromal interactions in HaCaT-Ras xenografts. 1037 63

Epithelial ovarian carcinomas are thought to originate in the ovarian surface epithelium (OSE), i.e., the mesothelium covering the ovary, but experimental evidence for this origin has been lacking. Contrary to most epithelia, where neoplastic progression is associated with a reduction of E-cadherin, this cell-cell adhesion molecule is sparse in normal human OSE but its expression increases with the development of ovarian epithelial metaplasia and neoplasia. Concurrently, the tumors tend to acquire characteristics of the complex epithelia of the oviduct and uterus. The high proportion of ovarian cancers where such aberrant Mullerian differentiation occurs suggests that this change may confer a selective advantage on the transforming cells. We previously demonstrated that increased E-cadherin expression may be a cause, rather than a consequence, of such Mullerian differentiation. E-cadherin was transfected into SV40 large T antigen-immortalized, E-cadherin-negative cells derived from normal OSE. Constitutive expression of E-cadherin re-established normal epithelial markers that had been lost in culture, such as keratin, and induced markers of metaplasia and neoplasia, such as CA125. In the present study, SV40-immortalized, E-cadherin-transfected cells, but not the E-cadherin-negative controls, were found to be anchorage-independent and to form transplantable, invasive s.c. and i.p. adenocarcinomas in 100% of injected SCID mice. Tumor cells injected i.p. seeded the mesenteries and omentum, invaded the liver and thigh musculature and produced ascites. The presence of SV40 large T antigen in the tumor cell nuclei confirmed their origin as transfected OSE cells. Our results demonstrate that ovarian adenocarcinomas can be derived by genetic manipulation of normal human OSE.
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PMID:An ovarian adenocarcinoma line derived from SV40/E-cadherin-transfected normal human ovarian surface epithelium. 1065 37

A unique series of epidermal cell lines representing different stages of malignant transformation were spontaneously derived from a single adult immunosuppressed individual. Four keratinocyte lines (PM1-4) established from forehead skin are here compared with 4 squamous cell carcinoma (SCC) lines (MET1-4) derived respectively from a primary cutaneous tumour, two local recurrences and a distant metastasis of invasive SCC. Despite altered growth properties, the PM lines retained many features of normal keratinocytes including keratin phenotype, differentiation capacity and non-tumorigenicity in athymic mice. In contrast, from early passage, the MET lines displayed markedly reduced growth requirements, abnormal differentiation, aberrant K18 expression and tumorigenicity in athymic mice. The abnormal keratin profile of individual MET lines closely reflected the keratin phenotype of the tumour of origin. Although unusual HPV types were identified in the original tissue, there was no evidence of persistent virus within any cell line and it appears that HPV is not critical for maintenance of the immortal phenotype. The PM lines were distinctly different from invasive SCC lines and are likely to be useful for studies of mutations important early in neoplastic progression. The SCC series represent primary, recurrent and metastatic carcinoma. Availability of such a series from the same individual will facilitate genetic analysis of the malignant process.
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PMID:Spontaneous keratinocyte cell lines representing early and advanced stages of malignant transformation of the epidermis. 1077 84

Alternative models using fish species have been tested in liver toxicity and carcinogenesis bioassays. Similar models have not been developed for skin. The brown bullhead (Ameiurus nebulosus) has shown potential as a model for skin carcinogenesis studies due to its sensitivity to environmental chemical pollutants. The present study is an initial morphologic and biochemical characterization of the normal and neoplastic brown bullhead skin to assess its suitability as a model of skin carcinogenesis. Brown bullhead were removed from Back River in the Chesapeake Bay region, an area historically polluted with heavy metals and polycyclic aromatic hydrocarbons. Histology, histochemistry, and electron microscopy were used to stage the morphologic development and progression of neoplasia in skin. The distribution of keratin, a family of structural proteins with altered expression in mammalian tumorigenesis, was analyzed with one and two dimensional gel electrophoresis and nitrocellulose blots of extracts from normal skin. Keratin expression in skin and other organs was also assessed with immunohistochemistry using AE1, AE3, and PCK 26 antibodies, and the proliferation index in skin and neoplasms with PCNA antibody. Skin lesions appeared to progress from hyperplasia through carcinoma, and the proliferation index was increased in papilloma. Also in papilloma, intercellular interdigitations appeared increased and desmosomes decreased which may in future studies correlate with changes in expression of other molecular markers of neoplastic progression. Both Type I and Type II keratin subfamilies were detected in skin using gel electrophoresis with the complimentary keratin blot-binding assay. For further development of the brown bullhead model, future studies can compare and relate these baseline data to alterations in expression of keratin and other markers in fish neoplasms and to molecular events which occur in man.
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PMID:Brown bullhead (Ameiurus nebulosus) skin carcinogenesis. 1093 Jan 21

One differentiated squamous cell carcinoma (SCC) cell line (RSC3-E2) and two undifferentiated tumor cell lines (RSC3-LM and RSC3-E2R) with different metastatic potential were established from a 4-nitroquinoline N-oxide (4NQO)-induced differentiated SCC in F344 rat tongue. The RSC3-E2 subline was isolated from a parental cell line (RSC3-P) by single cell cloning in vitro, whereas the RSC3-LM subline was isolated from a lung metastatic focus after subcutaneous (s.c.) injection of RSC3-P cells. The RSC3-E2R cell line was isolated from a lung metastatic focus following s.c. injection of RSC3-E2 cells after X-irradiation in vitro. The RSC3-E2 cell line is keratin-positive and grows as a keratinizing tumor in nude mice, whereas RSC3-LM and RSC3-E2R cells are keratin-negative, vimentin-positive and form undifferentiated tumors. When s.c. injected into nude mice, the RSC3-E2 cell line proved to be non-metastatic, while the RSC3-LM cell line was metastatic by both hematogenous and lymphogenous routes, and the RSC3-E2R cell line was metastatic only hematogenously. In vitro relative growth rates and in vitro invasion activity of these cell lines were in the order RSC3-LM > RSC3-E2R > RSC3-E2. Chromosome analysis revealed two peaks with modal chromosome numbers of 83 and 78 for RSC3-P cells and single peaks at 83, 78 and 56 for RSC3-LM, RSC3-E2 and RSC3-E2R cell lines, respectively. Common structural abnormalities on chromosome 11 were shared by all cell lines. Mutation analysis of the p53 gene using a yeast functional assay demonstrated RSC3-LM cell line to have a point mutation at codon 269, whereas RSC3-E2 and RSC3-E2R had double mutations at codons 106 and 170 on each allele. These results suggest that the two undifferentiated RSC3-LM and RSC3-E2R tumor cell lines with different metastatic potential were generated from differentiated SCC cells via different genetic pathways as a consequence of tumor progression in vivo and in vitro, respectively. These cell lines should provide a useful model for understanding mechanisms of hematogenous and lymphogenous metastasis, as well as tumor progression of oral SCCs.
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PMID:Isolation of differentiated squamous and undifferentiated spindle carcinoma cell lines with differing metastatic potential from a 4-nitroquinoline N-Oxide-induced tongue carcinoma in a F344 rat. 1112 19

Nuclear translocation of beta-catenin and its association with Tcf/Lef factors are key steps in transduction of the Wnt signal, which is aberrantly activated in a variety of human cancers. In a search for new beta-catenin-Tcf target genes, we analyzed beta-catenin-induced alterations of gene expression in primary human hepatocytes, after transduction of either dominant stable beta-catenin or its truncated, transactivation-deficient counterpart by means of a lentiviral vector. cDNA microarray analysis revealed a limited set of up-regulated genes, including known Wnt targets such as matrilysin and keratin-1. In this screen, we identified the CXC chemokine interleukin 8 (IL-8) as a direct target of beta-catenin-Tcf4. IL-8 is constitutively expressed in various cancers, and it has been implicated in tumor progression through its mitogenic, motogenic, and angiogenic activities. The IL-8 promoter contains a unique consensus Tcf/Lef site that is critical for IL-8 activation by beta-catenin. We show here that the p300 coactivator was required for efficient transactivation of beta-catenin on this promoter. Ectopic expression of beta-catenin in hepatoma cells promoted IL-8 secretion, which stimulated endothelial cell migration. These data define IL-8 as a Wnt target and suggest that IL-8 induction by beta-catenin might be implicated in developmental and tumorigenic processes.
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PMID:Transcriptional activation of interleukin-8 by beta-catenin-Tcf4. 1220 Apr 48

Epithelial-mesenchymal transition (EMT) may be critical for neoplastic progression and its eventual tumorigenicity of epithelia. In this context, we investigated whether EMT and EMT-associated features occurred after chronic ethanol treatment of human gingival keratinocytes immortalized with the E6/E7 oncogenes of human papillomavirus (HPV) type 16. Following a nine-week treatment of cells with 30 mM ethanol in keratinocyte growth medium, they were cultured in normal DMEM with 10% serum. These cell populations were able to proliferate in this medium gradually exhibiting elongated morphology indicating that these cells underwent EMT. Control cells without ethanol treatment did not survive subcultures in DMEM. Upon long-term subcultures of ethanol-treated cells, two phenotypes were obtained exhibiting epithelium-like and spindle-shape fibroblast-like morphology (respectively, termed as EPI and FIB cells), the latter indicating EMT. In comparison to EPI cells, the phenotypic transition to FIB cells was concomitant with a decrease in the expression of keratins, desmoplakins and a complete loss of K14. Moreover, FIB cell transition strongly correlates with an increase in the expression of vimentin and simple epithelial keratin K18. These alterations in FIB cells were associated with the ability of these cells to exhibit anchorage-independent growth, while EPI cells exhibited anchorage-dependent growth. Concerning the transformation stage, FIB cells represent a progressively more advanced transformed phenotype which may reflect an early step during HPV- and ethanol-dependent multi-step carcinogenesis.
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PMID:Epithelium and fibroblast-like phenotypes derived from HPV16 E6/E7-immortalized human gingival keratinocytes following chronic ethanol treatment. 1286 99

Cytokeratin 8 (CK8) is one of the cytoskeletal components and shows caspase-mediated degradation when cells undergo apoptosis. We previously reported that CK8 is highly expressed in non-small cell lung cancer (NSCLC) cell lines and increasing values of serum CK8 are significantly associated with tumor progression in patients with NSCLC. In this investigation, reverse transcriptase-polymerase chain reaction (RT-PCR) analysis in lung cancer cell lines, revealed a shorter PCR product, which differed from the wild-type product of CK8. The nucleotide sequence of the shorter PCR products and genomic DNA for CK8 demonstrated that the shorter product was an aberrantly spliced form of CK8 (AS-CK8) which lacked a caspases cleavage site within the linker lesion in exon 5. The putative protein products predicted by the mRNA of AS-CK8 were demonstrated by Western blotting with monoclonal antibodies for CK8. In addition, AS-CK8 mRNA and its protein products were highly expressed in NSCLC cell lines compared with small-cell lung cancer (SCLC) cell lines. Tissue samples obtained from NSCLC patients also expressed mRNA of AS-CK8. In conclusion, we identified aberrantly spliced CK8 (AS-CK8) which lacked a caspases cleavage site in lung cancer cell lines and primary tumors of NSCLC. AS-CK8 was preferentially expressed in NSCLC, rather than SCLC. These findings lead to speculation that cancer cells expressing AS-CK8 may have a resistance to apoptosis and may perturb keratin network formation.
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PMID:Aberrant messenger RNA splicing of the cytokeratin 8 in lung cancer. 1456 82

We report a rare case of basaloid squamous cell carcinoma of the lung in a young Japanese woman. An 18-year-old woman presented with productive cough. Chest radiogram and computed tomography (CT) revealed a tumor in the left hilum accompanied by partial atelectasis of the left upper lobe and pleural effusion. Transbronchial fine-needle aspiration cytology supported a tentative diagnosis of primary squamous-cell carcinoma of the lung. The clinical stage was T4N2M1, with multiple bone metastases. Despite a transient response to chemotherapy consisting of carboplatin and paclitaxel, the patient died because of tumor progression 2 months after the start of the chemotherapy. Necropsy established the diagnosis of basaloid squamous-cell carcinoma of the lung. Immunohistochemical studies of the necropsy specimen indicated that the tumor was positive for keratin, vimentin, and S100, and negative for chromogranin A, cytokeratin CAM5.2, and bcl-2. Besides the rarity of the disease itself, the present case seemed to have additional uniqueness in that the patient was 18 years old and female. This is the youngest patient with a case of basaloid squamous cell carcinoma of the lung ever reported.
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PMID:Basaloid squamous-cell carcinoma of the lung in a young woman. 1650 33


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