Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0178874 (tumor progression)
 40,807 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Gene amplification and related alterations in gene dosage were analyzed in a series of 34 cell lines derived from different human head and neck squamous cell carcinomas (SCCHN). INT2 gene amplification was observed in 62%, MYC gene amplification in 24%, and EGFR gene amplification in 21% of the cell lines. There was a strong correlation between EGFR gene amplification and increased copies of the ERBB2 gene on chromosome 17, suggesting a synergistic selection for these two genes either during cancer progression or in culture. Two abnormalities showed a significant correlation with clinical course: MYC gene amplification showed an inverse correlation with tumor recurrence (r = -0.44, p = 0.01), and a small increase in MYCL gene copies on chromosome I correlated with the presence of metastases (r = 0.61, p = 0.001). This altered MYCL gene dosage might represent a chromosome translocation rather than true gene amplification. In addition to gene amplification, 79% of the cell lines had increased copies of chromosome 8. Comparison of the cell lines with several of the corresponding primary tumors demonstrated that most gene amplifications were already present in the primary tumors, although some appeared de novo in cell culture. These studies indicate that gene amplification, especially of INT2, is a prominent abnormality in head and neck squamous cell cancer. Aneuploidy and chromosomal lesions other than gene amplification were also found to alter the dosage of several oncogenes specifically.
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PMID:Gene amplification and gene dosage in cell lines derived from squamous cell carcinoma of the head and neck. 138 84

Metastatic phenotype in human solid tumors is believed to follow stochastic acquisition of structural genetic aberrations-so-called multistep tumor progression. We tested this hypothesis in breast carcinoma by immunostaining 89 stage-heterogeneous cases for the products of three genes (p53, ERBB-2, and EGFR) which are frequently altered in this tumor system. Variable relationships were observed between advanced disease stage and immunostaining for individual gene products (ERBB-2 - p = 0.05, EGFR - p = 0.02, p53 - p = 0.12, Chi Square test). Regional or distant metastases at presentation correlated with multiple oncogene/tumor suppressor gene expression abnormalities: node negative -59% none positive, 29% one positive, 12% two or more positive, vs. node positive -37% none positive, 23% one positive, 39% two or more positive (p = 0.01). Only 2/12 (17%) of tumors with distant metastases at presentation were negative for abnormal expression of any of these gene products, and 7/12 (58%) were positive for two or three. Among axillary node negative patients who developed recurrences, 67% exhibited staining for at least one gene product, compared to only 27% of those without recurrences (p = 0.02). All 5 cases with abnormal staining for each gene product had regional or distant metastases at presentation and recurred. In multivariate analysis, individual expression of p53 outweighed expression of ERBB-2 and EGFR in correlation with outcome. These data suggest clinical neoplastic progression of breast carcinomas correlates with cumulative genetic events detectable by protein expression. Short term recurrence, however, may correlate more closely with abnormal expression of p53 than with EGFR or ERBB-2.
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PMID:Concurrent abnormal expression of ERBB-2, EGFR, and p53 genes and clinical disease progression of breast carcinoma. 791 62

Our primary objectives were to: 1) develop a system for the study of prostatic tumor evolution; and 2) examine the role of the epidermal growth factor/epidermal growth factor receptor (EGF/EGFR) pathway in prostate tumor progression. Adult human prostate epithelial cells previously immortalized by transfection with the SV40 T antigen gene (P69SV40T) produced tumors in only 2/18 mice with a 6 month latency period. Reinjection of cells recovered from these tumors after 1 or 2 cycles of growth in nude mice produced tumors in 2/4 and 2/3 mice with markedly decreased latent intervals of 12, 25, 25 and 25 days each. The chromosomal complement of each tumor was human, consistently pseudodiploid, and retained the Y chromosome. In both anchorage-independent and adherent cell growth assays, EGF stimulated proliferation by approximately 2-fold in both the parental P69SV40T line and the tumor sublines. The tumor sublines expressed less EGFR protein than the parental line, as assessed by Western immunoblotting and flow cytometric analysis. Immunoprecipitation revealed increased production of the 18 and 25 kDa TGF-alpha precursors parallel to decreases in detectable EGFR. The growth of both the parental P69SV40T line and the tumor sublines was inhibited by a neutralizing antibody to TGF-alpha under serum-free defined conditions. Inclusion of the TGF-alpha neutralizing antibody consistently inhibited the proliferation of the tumor sublines more than P69SV40T in both proliferation and [3H]thymidine incorporation assays. This finding suggests that the increased tumorigenicity and decreased latent interval observed among the human prostate tumor cells is partially due to activation of the TGF-alpha/EGFR autocrine network.
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PMID:Tumorigenicity of SV40 T antigen immortalized human prostate epithelial cells: association with decreased epidermal growth factor receptor (EGFR) expression. 807 59

In 68 cases of surgically resected gastric carcinomas, expression of human epidermal growth factor (EGF) and its receptor (EGFR) were examined immunohistologically using the Avidin-Biotin Peroxidase Complex Method, and their relation with DNA contents and nuclear protein synthesis in the tumor progression were studied by measuring DNA ploidy patterns and nucleolar organizer regions (NORs), respectively with cytofluorometry and AgNO3 stain method. EGF and EGFR expression were respectively found only in 2 (7%) and 1 (4%) in 28 early cancers, and significantly increased in advanced cancers, 25 (63%) and 9 (23%) out of 40 cases. The ratio of aneuploid tumor and the NORs numbers per tumor cell also increased in advanced cancers, compared with in early cancers. EGF and EGFR respectively expressed in 19 (51%) and 9 (23%) in 37 aneuploid cancers, significantly more frequent than 8 (26%) and 1 (3%) in 31 diploid cancers. In the EGF-positive tumors, the NORs numbers showed 4.11 +/- 0.72, significantly higher than 2.68 +/- 0.61 in the EGF-negative tumors. These results suggested that expression of EGF and EGFR in the gastric carcinomas increases during the tumor progression from the early to advanced stage, stimulates synthesis of DNA and nuclear protein, and consequently enhances (strengthens, heightens, or intensifies) the proliferative activity of the tumors.
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PMID:[Expression of human epidermal growth factor and its receptor of the gastric carcinomas with special reference to DNA ploidy patterns and nucleolar organizer regions]. 817 99

The effects of regional heterogeneity on the accuracy of histological grading of gliomas are well known, but little has been reported about its implications for other diagnostic modalities. This study investigated the relationships of regional heterogeneity in tumor proliferative activity, measured by Ki-67 labeling indices (LI), and histological grades for 16 regionally sampled glioma resections. There was a strong correlation between histological grades and Ki-67 LI in individual regions (p < 0.001), and both methods demonstrated comparable heterogeneity. Heterogeneity increased with tumor grade, probably as an expression of the increased genetic instability that accompanies tumor progression. Similarly, regions with comparable proliferative activity tended to cluster, paralleling clonal expansion. Thus, both histological grading and Ki-67 LI are subject to heterogeneity-induced sampling errors that limit their diagnostic accuracy, particularly in small biopsies. However, fewer grading errors occurred when using both methods together than when using either method alone, suggesting that the use of multiple techniques may reduce the adverse effects of regional heterogeneity on diagnostic accuracy. Regional heterogeneity appears to be a ubiquitous feature of gliomas: it also has been reported in karyotype, p53 oncogene mutations, and PDGF and EGFR expression. The effects of regional heterogeneity on new methods for studying gliomas need to be considered.
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PMID:Regional heterogeneity in the proliferative activity of human gliomas as measured by the Ki-67 labeling index. 822 80

A recent trend in cancer control programmes is the development of early detection strategies and chemoprevention of premalignant lesions. The present study evaluates the potential of selected markers in the biological staging of tumor progression in oral mucosa for better management of the disease. The expression patterns of various cytokeratin protein types such as 10/11, 13 & 16, 19, 18, 14 and pancytokeratin, involucrin, ras p21, epidermal growth factor (EGF) and its receptor (EGFR) were assessed immunohistochemically in various stages of tumor progression in oral mucosa. Statistical analyses such as the Kruskal-Wallis one-way ANOVA, Spearman's rank correlation and multiple regression analysis were carried out to see which proteins have a significant association with tumor progression in oral mucosa. Statistical analysis showed that the expression patterns of cytokeratin types 10/11, 14 and 19, involucrin and epidermal growth factor were significantly correlated with tumor progression in oral mucosa in both univariate and multivariate analysis. Thus the biological stage of a lesion can be calculated from the multiple regression equation derived for these proteins, which could be more useful in assessing the stage of tumor progression in oral mucosa than histopathological grading.
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PMID:Potential biological markers for the staging of tumor progression in oral mucosa: a multivariate analysis. 877 6

Xiphophorus fish have been the subject of intensive genetic research for more than 60 yr, primarily because of the availability of a number of interspecific hybrids that are malignant melanoma models with apparently simple oncogene and tumor suppressor gene determinants. The gene map of Xiphophorus is one of the most extensive among nonhuman vertebrates, with about 100 genes assigned to at least 20 independently assorting linkage groups (LGs), as well as more than 250 anonymous DNA sequence markers, providing coverage for most of the genome for genetic mapping studies. This characteristic has resulted in the mapping of a tumor suppressor locus, DIFF, which is one of two genetic determinants of melanoma formation in the best-studied hybrid melanoma, the Gordon-Kosswig melanoma model. The other gene responsible for melanoma formation in this model is a sex-linked tyrosine kinase gene related to EGFR and called Xiphophorus melanoma receptor kinase (Xmrk). The cellular oncogene homologues of the non-receptor tyrosine kinase family orthologous toyes and fyn have also been found to be overexpressed in malignant melanomas of Xiphophorus and may be involved in tumor progression. We report here the map location of a Xiphophorus yes gene, YES1, in LG VI, closest to the EGFR gene and the assignment of a fyn gene homologue to newly designated LG XV, linked to the gene for cytosolic alpha-galactosidase. We also confirmed that an EGFR-related sequence (EGFRL1) that we previously assigned to Xiphophorus LG VI by cross-hybridization to a viral erbB probe was the EGFR orthologue. Our results suggest that the presence of expressed duplicates of members of the tyrosine kinase gene family in teleost fishes may increase the potential number of targets in oncogenic cascades in fish tumor models.
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PMID:Mapping of tyrosine kinase gene family members in a Xiphophorus melanoma model. 968 40

Esophageal SCC is a complex disease involving multiple etiologic factors. A number of preventive approaches could be taken to reduce the occurrence of the disease including changes in lifestyle and improved nutrition, for example, the inclusion of higher quantities of fruits and vegetables in the diet. Unfortunately, these primary prevention approaches are not easily implemented and often fall short in achieving marked reductions in disease occurrence. Chemoprevention offers another approach to reducing the risk of esophageal SCC that is likely to be useful, even though the clinical trials to date have not resulted in the identification of agents that produce marked inhibitory effects on the development of the disease. Given esophageal SCC's complex etiology, it would appear that the most effective chemoprevention strategy would be to employ agents that reduce mutational events associated with exposure to esophageal carcinogens in combination with agents that inhibit the progression of epithelial dysplasia to esophageal SCC. The feasibility of addressing carcinogen-induced mutational events is underscored by the fact that many of the suspected esophageal carcinogens are known, and inhibitors of these carcinogens have been identified in animal model systems. In addition, biomarkers to assess the efficacy of anti-initiation agents, such as levels of phase I and II enzyme activities and of carcinogen: DNA adducts, can be measured. The identification of agents that inhibit the progression of dysplastic lesions to esophageal SCC has proven difficult; however, the results of the trial with ATB and retinamide are encouraging. Clearly, it seems important to identify the active chemopreventives in the antitumor-B herbal mixture. Further studies to identify strong inhibitors of tumor progression in the rat model for esophageal SCC are also needed. Biomarkers of cell proliferation (e.g., PCNA, Ki67), cell differentiation (keratins), apoptosis, gene expression (EGFR, cyclin D1, p53), and nuclear/nucleolar morphometry can be used in studies to assess the efficacy of chemopreventives to either reverse esophageal dysplastic lesions or slow their rate of progression. The development of viable approaches toward the chemoprevention. of esophageal SCC is truly an important goal in view of the poor prognosis of this disease.
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PMID:Clinical models of chemoprevention for the esophagus. 988 21

Various mechanisms of epithelial cell plasticity in morphogenesis have been studied at the genetic and molecular levels. Several control genes have been identified including genes encoding transcription factors and growth factor receptors. These mechanisms may be reactivated during the progression of carcinomas. One of the mechanisms underlying epithelial plasticity is the epithelial-mesenchymal transition. This process has been extensively studied using the NBT-II bladder carcinoma cell line. Cells of this line undergo a reversible transition following exposure to several growth factors including FGF-1, EGF, TGFalpha and SF/HGF, which activate tyrosine kinase surface receptors. Two separate transduction pathways have been identified. The transient activation of c-Src is involved in cytoskeleton remodeling whereas the Ras pathway controls the transcription of genes such as the transcription factor Slug which is involved in the internalization of desmosomes. These two pathways cooperate to induce the morphological transition, scattering and locomotion of fibroblast-like cells. Growth/scatter factor-producing NBT-II cells are more invasive than cells that do not contain this factor, in orthotopic confrontation assay. In vivo, these cells are very tumorigenic and may confer a more malignant phenotype on parental cells via a community effect. The role of several growth factors and their receptors has been investigated in human bladder carcinomas. A subset of these tumors with poor outcomes produce low levels of FGFR2-IIIb. The synthesis of this receptor de novo in bladder cell lines reduces proliferation in vitro and tumor growth in nude mice. FGFR2-IIIb functions as a tumor suppressor, consistent with the differentiation-inducing capacities of FGF receptors in the suprabasal cells of the skin. FGFR2-IIIb signaling may be involved in the maintenance of E-cadherin, the prototype epithelial adhesion molecule, which is only downregulated in a fraction of tumors with low FGFR2-IIIb synthesis. Human bladder tumors may also activate autocrine loops such as that for EGFR and their ligands, as already demonstrated for murine bladder tumors. Therefore, our results suggest that multifunctional growth factors and their receptors are involved in cell proliferation and epithelial cell plasticity, acting either as positive or negative regulators of tumor progression. The effect on the morphological transition is also clearly relevant to the mechanism governing dissemination and the formation of micrometastatic tumor cells. The extrapolation of these discoveries to human carcinomas should provide markers facilitating the more accurate prediction of the biological behavior of a given tumor and identify clinically and pathologically significant parameters. The identification of critical changes in the growth factor pathways involved in tumor progression will not only provide insight into the genetic and molecular basis of this process, but should also identify targets for new therapies.
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PMID:Epithelial cell plasticity in development and tumor progression. 1050 44

The genetic abnormality most frequently identified in glioblastomas is loss of alleles on chromosome 10. We have performed a comprehensive study of the PTEN tumor suppressor gene on 10q23, including loss of heterozygosity (LOH) analysis, multiplex PCR, mutation analysis, and reverse transcription PCR (RT-PCR). In total, 151 glioblastomas, 41 anaplastic astrocytomas, 15 astrocytomas, and 13 glioma cell lines were analyzed as well as 23 xenografts derived from primary glioblastomas, which allows a comparison of the PTEN gene status in primary tumors versus xenografts. Homozygous deletions were found in 7% of the glioblastomas and 40% showed mutation of a single retained allele. This mutation frequency is higher than reported previously. The large number of mutations identified allows the presentation of a mutational profile along the coding sequence. The majority of mutations appear to affect conserved residues or structurally conserved regions. PTEN alterations were selected for in xenografts, and there is evidence that they may even facilitate establishment of xenografts. No alterations were found in astrocytomas and only 5% of anaplastic astrocytomas had mutations. Thus, loss of wild type PTEN represents one of the major abnormalities associated with astrocytic tumor progression to glioblastoma and provides a strong selective growth advantage when cultivating glioblastoma tissue in xenografts. No correlation with EGFR amplification was evident.
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PMID:Mutational profile of the PTEN gene in primary human astrocytic tumors and cultivated xenografts. 1056 Jun 60


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