UMLS:C0178874 - FACTA Search

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

Many tumors are surrounded by a highly fibrous stroma composed of fibroblasts and extracellular matrix. This desmoplastic response has been suggested to both inhibit and favor tumor progression. The present study deals with the effects of tumor cells on the fibroblastic reactions they cause and relates this to progression or regression of tumors. Two rat colon carcinoma cell lines, one which develops progressive tumors when injected s.c. in syngeneic animals (PROb cell line) and the other which develops regressive tumors in similar conditions (REGb cell line), were compared by the fibroblastic reaction which they cause. Comparative histological analysis of progressive and regressive tumors developed by the two cell lines showed a significant but opposite response of fibroblastic compartment. The progressive tumor nodules were observed to grow within a loose tissue, whereas the regressive tumor cells were surrounded by a fibrous capsule. Immunohistological labelings revealed the presence of alpha-smooth muscle actin-positive myofibroblasts during the tumor expansion, while these specific cells disappeared during the tumor regression. Immunostainings of transforming growth factor beta 1 showed an increasing staining of the progressive tumor cells during tumor development but a slight expression by tumor cells and stroma during the tumor regression. This growth factor was demonstrated to facilitate initial steps of the tumor progression by addition of active transforming growth factor beta 1 at the time of s.c. injection of PROb cells in syngeneic rat models. In vitro experimental analysis with the use of neutralizing antibody showed that active transforming growth factor beta produced by the progressive cells inhibited fibroblast proliferation and facilitated their differentiation into myofibroblasts. Since the number of myofibroblasts increased with time in progressive tumors, their presence may constitute a potential growth advantage for tumor growth. In contrast, our results indicated involvement of platelet-derived growth factor-like protein(s) in fibroblast proliferation under the control of regressive cells and the presence of an important sheath of alpha-smooth muscle actin-negative fibroblasts in regressive tumors may support a role for this growth factor in vivo. Thus, the ability of tumor cells to produce or induce the production of transforming growth factor beta or platelet-derived growth factor may give rise to a specific fibroblast reaction, which in turn may determine consequent tumor evolution.
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PMID:The role of transforming growth factor beta 1 in the fibroblastic reaction associated with rat colorectal tumor development. 798 52

Matrix metalloproteinases have been implicated in the growth and spread of metastatic tumors. This role was investigated in an orthotopic transplant model of human colon cancer in nude mice using the matrix metalloproteinase inhibitor BB-94 (batimastat). Fragments of human colon carcinoma (1-1.5 mm) were surgically implanted orthotopically on the colon in 40 athymic nu/nu mice. Administration of BB-94 or vehicle (phosphate buffered saline, pH 7.4, containing 0.01% Tween 80) commenced 7 days after tumor implantation (20 animals/group). Animals received 30 mg/kg BB-94 i.p. once daily for the first 60 days and then 3 times weekly. Treatment with BB-94 caused a reduction in the median weight of the primary tumor from 293 mg in the control group to 144 mg in the BB-94 treated group (P < 0.001). BB-94 treatment also reduced the incidence of local and regional invasion, from 12 of 18 mice in the control group (67%) to 7 of 20 mice in the treated group (35%). Six mice in the control group were also found to have metastases in the liver, lung, peritoneum, abdominal wall, or local lymph nodes. Only two mice in the BB-94 group had evidence of metastatic disease, in both cases confined to the abdominal wall. The reduction in tumor progression observed in the BB-94-treated group translated into an improvement in the survival of this group, from a median survival time of 110 days in the control group to a median survival time of 140 days in the treated group (P < 0.01). Treatment with BB-94 was not associated with any obvious toxic effect, and these results suggest that such agents may be effective as adjunctive cancer therapies.
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PMID:Matrix metalloproteinase inhibitor BB-94 (batimastat) inhibits human colon tumor growth and spread in a patient-like orthotopic model in nude mice. 806 71

Highly malignant and metastatic tumor cells are thought to arise within primary tumors and become predominant during cancer progression. We demonstrated, by the analysis of > 500 surgical specimens, that colorectal carcinomas with increased metastatic potential were characterized by an increased expression of sialyl-Le(x) antigens expressed on mucins. The biological role of sialyl-Le(x) antigens expressed on mucins produced by colon carcinoma cells has been investigated using variant cell lines selected for their expression of this antigen. KM12-HX and KM12-LX, high and low expresser variant cells, differed in their metastatic potential in nude mice after intrasplenic injection. KM12-HX cells contain higher levels of polyA+mRNA for alpha(1-3/4) fucosyltransferase than KM12-LX cells. Sialyl-Le(x) antigenic carbohydrate chains were attached to mucins as well as glycoproteins with various M(r). KM12-HX cells adhered more strongly than KM12-LX cells to human umbilical vein endothelial cells treated with tumor necrosis factor-alpha and to mouse hepatic sinusoidal endothelial cells. We have retrospectively evaluated post-operative survival of colon carcinoma patients for their sialyl-Le(x) antigen levels in the primary tumors according to the percentage of stained cells by specific antibodies. The adjusted survival rate of the patients with high levels of sialyl-Le(x) antigen in their primary tumors was much lower due to recurrence and metastasis than that of the patients with tumors containing low levels of sialyl-Le(x) antigen. The results suggested that sialyl-Le(x) antigen has a potential to be used as a predictive marker for colorectal cancer metastasis.
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PMID:[Ectopic expression of carbohydrate antigens that determine the metastatic potential of human colorectal carcinoma]. 809 51

Retrovirus-mediated gene transfer was employed to introduce two different cDNAs of the human tumor necrosis factor alpha gene (TNF) into colon carcinoma cell lines either sensitive (LoVo) or resistant (LS174T) to the external addition of TNF. The TNF variants differed in their 5'-sequences (HTNF: authentic TNF cDNA, SPTNF: TNF cDNA with a signal sequence of the IgG heavy chain). The integration of TNF-specific DNA into the genomic DNA, the expression of TNF-specific mRNA and the translation into TNF protein was shown by Southern-, Northern- and Western analysis with TNF-specific DNA- and RNA probes and anti-TNF-antibodies, respectively. Neomycin selected tumor cell clones expressed biologically active TNF up to 40 pg/ml. As shown in a growth assay, both variants of TNF caused an up to 80% growth inhibition in colon carcinoma cells. Furthermore, the cells constitutively producing TNF had a distinguishable morphological appearance and a reduced colony growth in soft agar compared to the parental cells. The subcutaneous injection of 1 x 10(6) TNF-expressing tumor cells into nude mice resulted in a reduced tumor progression in comparison to the controls.
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PMID:Retrovirus-mediated gene transfer of tumor necrosis factor alpha into colon carcinoma cells generates a growth inhibition. 823 36

Tumor stroma is a specialized form of tissue that is associated with epithelial neoplasms. Recent evidence indicates that significant changes in proteoglycan content occur in the tumor stroma and that these alterations could support tumor progression and invasion as well as tumor growth. Our main hypothesis is that the generation of tumor stroma is under direct control of the neoplastic cells and that, via a feedback loop, altered proteoglycan gene expression would influence the behavior of tumor cells. In this review, we will focus primarily on the work from our laboratory related to the altered expression of chondroitin sulfate proteoglycan and its role in tumor development and progression. The connective tissue stroma of human colon cancer is enriched in chondroitin sulfate and the stromal cell elements, primarily colon fibroblasts and smooth muscle cells, are responsible for this biosynthetic increase. These changes can be reproduced in vitro by using either tumor metabolites or co-cultures of human colon carcinoma cells and colon mesenchymal cells. The levels of decorin, a leucine-rich proteoglycan involved in the regulation of matrix assembly and cell proliferation, are markedly elevated in the stroma of colon carcinoma. These changes correlate with a marked increase in decorin mRNA levels and a concurrent hypomethylation of decorin gene, a DNA alteration associated with enhanced gene expression. Elucidation of decorin gene structure has revealed an unexpected degree of complexity in the 5' untranslated region of the gene with two leader exons that are alternatively spliced to the second coding exon. Furthermore, a transforming growth factor beta (TGF-beta)-negative element is present in the promotor region of decorin gene.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Altered proteoglycan gene expression and the tumor stroma. 829 47

Tumor stroma is a specialized form of tissue that is associated with epithelial neoplasms. Recent evidence indicates that significant changes in proteoglycan content occur in the tumor stroma and that these alterations could support tumor progression and invasion as well as tumor growth. Our main hypothesis is that the generation of tumor stroma is under direct control of the neoplastic cells and that, via a feedback loop, altered proteoglycan gene expression would influence the behavior of tumor cells. In this review, we will focus primarily on the work from our laboratory related to the altered expression of chondroitin sulfate proteoglycan and its role in tumor development and progression. The connective tissue stroma of human colon cancer is enriched in chondroitin sulfate and the stromal cell elements, primarily colon fibroblasts and smooth muscle cells, are responsible for this biosynthetic increase. These changes can be reproduced in vitro by using either tumor metabolites or co-cultures of human colon carcinoma cells and colon mesenchymal cells. The levels of decorin, a leucine-rich proteoglycan involved in the regulation of matrix assembly and cell proliferation, are markedly elevated in the stroma of colon carcinoma. These changes correlate with a marked increase in decorin mRNA levels and a concurrent hypomethylation of decorin gene, a DNA alteration associated with enhanced gene expression. Elucidation of decorin gene structure has revealed an unexpected degree of complexity in the 5' untranslated region of the gene with two leader exons that are alternatively spliced to the second coding exon.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Altered proteoglycan gene expression and the tumor stroma. 850 May 99

CD44 is a cell surface receptor of hyaluronate that is implicated in the regulation of tumor growth and metastatic potential. Transformation of colon mucosa to carcinoma is associated with overexpression of several CD44 alternative splice variants. The functional roles of CD44 isoforms in colon carcinoma tumor progression remain unclear. CD44H expression is downregulated in colon carcinomas compared to paired normal mucosa. In the present study we demonstrate that reintroduction of CD44H back into colon carcinoma cells by stable transfection reduces their in vitro growth rate and tumorigenicity. Examination of several colon carcinoma cell lines and use of mutant CD44H reveal that this in vitro and in vivo growth reduction requires the ability of CD44H to bind hyaluronate. These observations indicate that the CD44H downregulation associated with transformation of mucosa to colon carcinoma may provide the carcinoma cells with a growth advantage. Furthermore, the reduction in tumor growth rate mediated by reintroduction of CD44H into colon carcinoma cells is dependent on its ability to bind hyaluronate.
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PMID:CD44 hyaluronate binding influences growth kinetics and tumorigenicity of human colon carcinomas. 857 Jan 72

CD44 alternative splicing has been implicated in the regulation of CD44 function. CD44 undergoes significant posttranslational modification in all cells, but the functional consequences of these modifications are poorly understood. In the current study, we have demonstrated that keratan sulfate modification of CD44 significantly modulates its ability to bind to hyaluronate. We observed naturally occurring differences in CD44 keratan sulfate substitution between two clonal variants of the KM12 human colon carcinoma cell line. CD44 on the highly metastatic KM12L4 clone is more heavily substituted with keratan sulfate than CD44 on the poorly metastatic KM12C6 clone. Moreover, CD44H on KM12L4 bound to hyaluronate poorly compared to CD44H on KM12C6. Removal of keratan sulfate from CD44 greatly enhanced CD44-mediated cell adhesion to hyaluronate. Removal of keratan sulfate from CD44H-immunoglobulin fusion proteins also enhanced their adhesion to hyaluronate. The influence of glycosaminoglycan substitution on CD44 function was specific to keratan sulfate substitution; treatment to remove chondroitin sulfate, heparan sulfate, or hyaluronate did not affect CD44-mediated cell adhesion to hyaluronate. Use of site-directed CD44H cDNA mutants with arginine changed to alanine at position 41 indicated that keratan sulfate modification of CD44 modulates hyaluronate adhesion through its B loop domain. These findings suggest that keratan sulfate modification of CD44 may play an important regulatory role in the broad spectrum of biological processes attributed to CD44, including normal development, tumor progression, and lymphocyte function.
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PMID:Keratan sulfate modification of CD44 modulates adhesion to hyaluronate. 862 20

There is a direct correlation between the overexpression of the c-myc product and the clinicopathological state of patients with colorectal carcinomas. This study was carried out to understand the reasons for this. In vitro, S-phase synchronous culture was performed using the human colon carcinoma cell lines, COLO201 and SW480; and thymidine-hydroxyurea blockage was carried out. The proportion of c-myc protein-positive cells decreased gradually with progressive stage of the cell cycle, as determined by flow cytometry (FCM) and Western blot analysis. A rapid decrease in the number of c-myc protein-positive cells in the GO G1-phase was the main reason for the complete loss of c-myc protein expression in the S-phase of synchronous culture, although the percentage of these cells was higher in the S and G2M-phases than in the GOG1-phase after each initiation of synchronous culture. These findings suggest that the c-myc protein-positive cells which were arrested in the G1-phase could play an important role in cell proliferation. In another study, 46 paraffin-embedded specimens of human colorectal carcinomas were examined for c-myc protein expression by flow cytometry (FCM). Patients with higher expression in the GOG1-phase (% positive cells > or = mean) showed significantly lower rates of survival (p = 0.004), as determined using the generalized Wilcoxon's method, and this higher expression correlated with aneuploid carcinoma (p = 0.005), with metastasis to the lymph nodes (p = 0.003), with the degree of regional lymph node metastasis (p = 0.02), and with the depth of wall-infiltration by the carcinoma (p = 0.006), as determined using the chi square test. Liver metastases and peritoneal dissemination did not correlate with c-myc protein expression. Analyses of all phases were carried out, however, similar results were obtained by analyzing only the GOG1-phase of the cell cycle. Therefore, it would seem that determination of c-myc protein expression in a carcinoma, especially in the G1-phase of the cell cycle, would be useful as a marker of tumor progression and for evaluation of the clinical prognosis of patients with colorectal carcinomas.
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PMID:Correlation between c-myc protein expression and phases of the cell cycle in human colorectal carcinomas. 882 91

CD44 alternative splicing patterns differ between normal and malignant tissue, and accordingly, modulation of CD44 splicing has received the most attention in studies that have examined the role of CD44 in tumor progression. Many investigators have examined functional differences between individual CD44 alternative splice variants. However, specific CD44 isoforms function uniquely depending on the type of cell on which they are expressed, thereby suggesting that additional tissue-specific mechanisms regulate CD44 function. In the present study we have demonstrated that colon carcinoma cells modify CD44 with O-linked glycosyl groups, and blockade of this glycosylation enhances their CD44-mediated adhesion to hyaluronate. This enhancement is attributable principally to CD44H (CD44s) rather than high molecular weight CD44 variants. Use of site-directed mutant CD44H cDNA transfectants demonstrated that CD44 O-linked glycosylation modulates interaction between hyaluronate and the B loop domain of CD44. The influence of glycosylation on CD44 function in colon carcinoma cells is specific to the presence of O-linked sugars; inhibition of N-linked glycosylation had minimal influence on CD44 function. These findings indicate that O-linked glycosylation may be as important as alternative splicing in the regulation of CD44 function and the broad spectrum of biological processes attributed to it, including normal development, tumor metastases, and lymphocyte function.
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PMID:O-linked glycosylation modifies CD44 adhesion to hyaluronate in colon carcinoma cells. 885 11

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