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)

To determine the frequency and clinical significance of oncogene abnormalities in colon cancer, deoxyribonucleic acids from 45 colon carcinomas and 15 benign adenomas were hybridized with 14 different protooncogene probes. Abnormalities of oncogenes were found in 22% of cancers at the time of resection. Amplification of c-myc or c-erbB-2 and allelic deletion of c-ras-Ha or c-myb were the most frequent abnormalities. The presence of altered oncogenes did not correlate with Dukes' stage, tumor progression, or patient survival after resection. One adenoma had an allelic deletion of the c-myb oncogene which was not seen in either the normal colon or an adjacent carcinoma. These data indicate that the spectrum of altered protooncogenes in colon carcinoma is similar to that of other adenocarcinomas, and that unstable oncogenes can be found before overt malignancy develops.
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PMID:Protooncogene abnormalities in colon cancers and adenomatous polyps. 355 13

The effects of two agents, 12-O-tetradecanoylphorbol-13-acetate (TPA) and deoxycholic acid (DOC), which act as tumor promoters in the gastrointestinal epithelium of experimental animals, were compared using primary cultures of human premalignant colonic epithelial cells at different stages in tumor progression. Both DOC and TPA enhanced the size of the proliferative fraction in colonies of early-stage premalignant cells, with DOC providing more stimulation. TPA-treated intermediate- and late-stage premalignant cells elongated and then disrupted the monolayer by forming rills several cells in thickness and then multicellular clusters. This multilayering was reminiscent of the areas of carcinoma found within adenomas. DOC had no such effects on morphology. Cell clustering was concomitant with secretion of a protease with characteristics of a plasminogen activator. Premalignant cells secreted severalfold higher levels of protease in response to TPA than did either TPA-treated primary cultures of colonic adenocarcinomas or established colon carcinoma cell lines. These results suggest that (a) DOC and TPA act sequentially during tumor promotion and (b) cell clustering and protease release may be associated with the transition of premalignant epithelial cells to colonic carcinoma.
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PMID:Differential response of premalignant epithelial cell classes to phorbol ester tumor promoters and to deoxycholic acid. 703 Apr 77

A positive correlation between tumor progression in human colon and increased beta 1,6 branching in oligosaccharides has recently been demonstrated. The present study was undertaken to elucidate whether such a correlation can be extended to variants of metastasizing human colon carcinoma HCT116 cells. The Phaseolus vulgaris leukoagglutinating lectin, which binds to beta 1,6 branched oligosaccharides, was employed. In blots, a band of approximately 140 kd was detectable in both the HCT116a and HCT116b sublines. However, in the more aggressive subline HCT116a, the intensity of this band was increased by 100%, and additional reactive bands of approximately 100 kd and approximately 170 kd were observed. Analysis by electron microscopy revealed lectin labeling in the Golgi apparatus, lysosomal elements, mucus droplets, cytoplasmic vesicles, and at the plasma membrane. Quantification of the lectin plasma membrane labeling revealed a significantly higher labeling intensity in HCT116a cells than in HCT116b cells. The difference in lectin plasma membrane labeling intensity could also be observed in paraffin sections. Thus, variants of metastatic HCT116 colon carcinoma cells differ quantitatively and qualitatively in glycoproteins carrying beta 1,6 branches.
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PMID:Cytochemical staining for beta 1,6 branching of asparagine-linked oligosaccharides in variants of metastatic human colon carcinoma cells. 751 29

Expression of carbohydrate ABH blood group antigens is oncodevelopmentally regulated and their presence on tumor cells constitutes a prognostic factor. However, it is not clear whether they directly affect tumor behavior. Using a rat model of colon carcinoma, we previously observed an association between the presence of H blood group antigens and tumorigenicity in syngeneic animals. In the present study, we show by immunoprecipitation experiments that cell surface H blood group antigens of a highly tumorigenic clone (PROb) are essentially carried by splice variants of the CD44 molecule containing exon V6. PROb cells were then transfected with an antisense fragment of the gene coding for a rat alpha (1-2)fucosyltransferase. This enzyme allows synthesis of H antigens from various beta-galactoside precursors. Transfected subclones of PROb cells were obtained which had significantly decreased enzymatic activity and H antigenic cell surface levels. In contrast, no such changes were observed in control cells transfected with either the empty vector or with a sense fragment of the gene. Compared to controls, the antisense-transfected cells were far less tumorigenic in syngeneic animals. These results show that H blood group antigens at the surface of PROb colon carcinoma cells contribute to tumor progression. The presence of the fucosylated structures on CD44 could modulate the functions of this adhesion molecule.
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PMID:H blood group antigen carried by CD44V modulates tumorigenicity of rat colon carcinoma cells. 752 57

The cell-surface receptor for hyaluronic acid, CD44, is expressed by both normal and malignant cells. Numerous CD44 isoforms have recently been identified that are derived by alternative ribonucleic acid splicing. The expression of some CD44 isoforms has been shown to be involved in tumor progression and metastatic spread in a rat carcinoma model and in human carcinomas. In the present study, CD44 isoform expression was evaluated by reverse transcriptase-polymerase chain reaction (PCR) analysis in frozen sections derived from three samples of normal brain tissue and from 40 brain tumors, including samples of glioblastoma multiforme, anaplastic astrocytoma, low-grade astrocytoma, cerebral primitive neuroectodermal tumor, medulloblastoma, metastatic colon carcinoma, and metastatic melanoma. Normal brain tissue adjacent to the tumors was also examined in 14 of 18 glioblastomas. In all normal brain and tumor samples, with the exception of metastases from colon carcinoma, PCR analysis demonstrated one prominent product that corresponded to the CD44H hematopoietic form of CD44. Metastases from colon carcinoma demonstrated two prominent PCR amplification products corresponding to CD44H and CD44R1. These results suggest that CD44H is the predominant isoform of this protein in normal human brain tissue and in human neuroectodermal tumors of varying degrees of malignancy. The ability of CD44H to mediate tumor cell motility and invasiveness (in contrast to CD44R1) suggests that the CD44 alternative splicing pattern of neuroectoderm-derived tumors may enhance their local biological aggressiveness and intracerebral spread. The lack of expression of larger molecular weight CD44 variants by primary brain tumors may also partially explain why these tumors rarely metastasize to distant sites.
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PMID:Alternative RNA splicing of the hyaluronic acid receptor CD44 in the normal human brain and in brain tumors. 753 36

nm23H1 has properties of a metastasis suppressor gene. Although its mechanism of action is unknown, nm23 has been implicated in transforming growth factor beta 1 (TGF beta 1) signal transduction. In an earlier study we decreased nm23 mRNA levels 2- to 8-fold by antisense phosphorothiolated oligonucleotides in two HT29 colon carcinoma sublines at different stages in tumor progression with different responses to TGF beta 1: the HD3 subline, which shows TGF beta 1-induced growth arrest and differentiation; and the more tumorigenic U9 subline, whose growth and invasion are stimulated by TGF beta 1. Only TGF beta 1-mediated responses in HD3 cells were inhibited by nm23 antisense oligos, suggesting that nm23 functions in only one TGF beta 1 signaling pathway. In the current report we have extended this study to cell motility. HD3 motility was increased by nm23 phosphorothiolated antisense oligos which decrease nm23 mRNA levels, while HD3 cell motility was conversely decreased by TGF beta 1 which increases nm23 mRNA levels. HD3 motility was not increased by basic FGF, TGF beta 1 or TGF alpha, while the 13-fold higher basal motility of U9 cells was stimulated 3-fold by basic FGF, 4-fold by TGF beta 1 and 5-fold by TGF alpha, but not by scatter factor. Differences in motility and response to motility factors could not be ascribed to differences in either basal levels of proteases or modulation of their levels by TGF beta 1. Both HD3 and U9 cells displayed equal levels of urokinase activity and mRNA, equal expression of the metalloproteinase inhibitor TIMP-1, and no detectable collagenases by zymography. No differential response to TGF beta 1 was seen in any of these assays. Thus limited cell motility and lack of response to motility factors in HD3 colon cancer cells could be correlated with expression of nm23 active in signal transduction.
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PMID:Colon carcinoma cells with inactive nm23 show increased motility and response to motility factors. 755 87

CD44 is a transmembrane glycoprotein occurring in several isoforms with different extracellular regions. The various transcripts are encoded by one gene locus containing 20 exons, of which at least 10 can be alternatively spliced in nascent RNA. Isoforms encoded by the variant exons (termed CD44v) are highly restricted in their distribution in nonmalignant tissue as opposed to the standard form of CD44 (CD44s) abundant in many tissues. Specific variant isoforms containing exon 6v have been shown to render nonmetastatic rat tumor cells metastatic. Based on the prominent role in rat metastasis formation, CD44v isoforms were suggested to be involved in human tumor progression. Correlations between prognosis and expression of CD44v have been reported for gastric and colon carcinoma, for non-Hodgkin's lymphoma, and recently for breast carcinoma. We evaluated the expression of CD44 isoforms in node-positive (n = 119) and node-negative (n = 108) cases of breast carcinoma by immunohistochemistry using CD44v exon-specific mAbs. In a subset of 43 cases of high-risk patients, reverse transcription-PCR was used to determine the exon composition of the transcripts. Protein and RNA expression data were probed statistically for their correlation to survival of the patients and clinical risk factors. In contrast to recently published data (M. Kaufmann et al., Lancet, 345: 615-619, 1995), in our cohort disease-free and overall survival data did not indicate significant correlations with the expression of the analyzed isoforms in univariate and multivariate analyses. Comparison of CD44 protein expression with established clinical risk factors for survival such as tumor size (pT1+pT2) and histological grading revealed correlations with the presence of CD44s (P = 0.02 and P = 0.03, respectively) and CD44-9v (P = 0.05 for histological grading). Carcinoma tissues with elevated estrogen and progesterone receptor levels showed positive correlation with CD44-6v (P = 0.001), while a trend for significant coexpression of CD44s and CD44-9v isoforms was observed in estrogen receptor-positive tissues (P = 0.08 and 0.06, respectively). In breast cancer, CD44s, CD44-9v, and CD44-6v are apparently markers for cellular differentiation but not for tumor progression. Our data suggest that steroid hormone receptors may be associated with the in vivo expression of CD44-6v-containing isoforms in human mammary carcinoma.
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PMID:CD44 isoforms correlate with cellular differentiation but not with prognosis in human breast cancer. 758 12

Within a panel of 15 colon carcinoma cell lines we have characterized the p53 gene status using immunocytochemistry (ICC), SSCP and direct sequence analysis. Extension of this analysis to the use of ICC on 104 colonic lesions, representative of different stages of colonic neoplastic progression, showed an absence of detectable p53 nuclear staining in preneoplastic polyp lesions (20 cases) with staining of 52% (25/48) of primary colon carcinomas and 81% (29/36) of hepatic metastases, suggestive of an increased incidence of p53 mutations in late stage lesions of colonic cancer. To address this issue more directly, we analysed 18 primary colon carcinomas and hepatic metastases excised coincidentally from the same patients. In ICC, p53 nuclear staining was recorded in matching lesions from eight individuals where direct sequencing revealed identical mutations in each case. In four individuals no ICC staining was detected in either lesion and molecular analysis revealed wild type sequence in exons 4-9. In six individuals p53 nuclear staining was observed in the hepatic metastases of patients but not the primary lesion. Molecular analysis revealed point mutation events in hepatic metastases from these patients which were not detected in the primary tumor. The point mutations identified in colon carcinomas were predominantly transition events (83%) located in previously characterized colon hotspot regions. These results demonstrate an increased incidence of p53 mutations associated with secondary lesions of colorectal tumors suggestive of a role for p53 in the establishment of colorectal hepatic metastases.
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PMID:Increased incidence of p53 mutations is associated with hepatic metastasis in colorectal neoplastic progression. 765 27

nm23 has properties of a metastasis suppressor gene and also has been implicated in the control of response to transforming growth factor beta 1 (TGF beta 1) by studies in melanoma cells. In this report, we have examined the role of nm23 in two HT29 colon carcinoma sublines at different stages in tumor progression with different responses to TGF beta 1: the HD3 subline, which shows TGF beta 1-induced growth arrest and differentiation; and the more invasive and tumorigenic U9 subline, which induces tumors 7-fold as large as those induced by HD3 cells with one-half the latency. Analysis by semiquantitative reverse transcription-polymerase chain reaction showed that antisense phosphorothiolated oligonucleotides to the nm23 initiation site (nm23 AS oligos) decreased nm23 mRNA levels 2-8-fold in HD3 and U9 cells when normalized to beta-actin mRNA levels. However, a role for nm23 in TGF beta 1-mediated responses could only be found in HD3 cells. nm23 AS oligos inhibited the differentiation property of cell adherence over 90% in HD3 cells, and this loss of adherence could be partially blocked by concurrent treatment with TGF beta 1. In contrast, U9 cell adherence was not detectably altered by nm23 AS oligos, whether added in the presence or absence of TGF beta 1. The TGF beta 1-induced inhibition of HD3 cell proliferation was blocked by nm23 AS oligos, whereas the TGF beta 1-induced proliferation of U9 cells was unaffected by nm23 AS oligos.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The role of nm23 in transforming growth factor beta 1-mediated adherence and growth arrest. 781 28

Tumour progression is thought to be determined, at least in part, by the balance between available cell surface receptors and the nature of the surrounding extracellular matrix. The integrin family of transmembrane adhesion receptors involved in tumour cell-matrix interactions mediates cell adhesion, migration, and differentiation. Certain patterns of integrin receptor expression on normal and malignant colon epithelial cells are emerging, and it is now clear that integrins can also regulate such divergent processes as cell proliferation and programmed cell death in this tumour type. This implies that integrins are involved in signal transduction events within colon carcinoma cells consequent upon their adhesive interaction with matrix molecules. A better understanding of the mechanisms involved in these events may lead to useful therapeutic strategies in the management of this disease.
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PMID:Colorectal cancer and the integrin family of cell adhesion receptors: current status and future directions. 785 18


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