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

Tumor progression in rodent and human tumors is commonly associated with changes in glycoprotein glycosylation, in particular increased beta 1-6GlcNAc-branching, a regulatory step in expression of polylactosamine and extended-chain Lewis antigens. Loss of the branched oligosaccharides in murine tumor cells either due to somatic mutation, or treatment of the cells with the oligosaccharide processing inhibitor swainsonine, blocks tumor cells invasion in vitro and reduces solid tumor growth in vivo. Swainsonine and other inhibitors of N-linked oligosaccharide processing may be useful anti-cancer drugs, a premise which has begun to be tested in humans.
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PMID:Branching N-linked oligosaccharides in breast cancer. 798 45

Tumor progression (TP) is often accompanied by evolution of drug resistant clones. Decreased intracellular accumulation of cytotoxic agents is probably the major mechanism of drug resistance. In the present study, we tried to examine the possibility to overcome the resistance to adriamycin (ADR) treatment, by cyclosporin A (CS) in two models of TP in the Lewis lung carcinoma (3LL) system. The first model consisted in the comparison of primary tumor cells (3LL-PT) to metastatic cells (3LL-MT) and the second consisted in comparison of lung metastases of the highly malignant variant D122 to those of the parental 3LL tumor. Cyclosporin had a weak augmenting effect on ADR uptake, in the two more malignant cell variants and no influence on the 3LL-PT cells, according to FACS analysis. Cytofluorometry also showed practically no effect of CS on cell size, unlike the effect of other chemosensitizers, such as membrane active agents. In order to find out whether CS counteracts resistance to ADR despite the fact that it does not increase cytotoxic agent uptake, we examined its effect on in vitro proliferative capacity of the 3LL-PT cells. CS in combination with ADR had a more pronounced effect, as compared to single treatments on cell proliferation. The low effect of CS on ADR uptake according to FACS analysis, and by contrast, its efficiency to overcome resistance to ADR according to the in vitro growth results, suggest that the mechanism of the CS action as a chemosensitizer is not related to the p-glycoprotein (P-G-P), known to be overexpressed in the typical multidrug-resistance (MDR) phenotype. A better understanding of the complexity of MDR mechanisms may contribute to the design of new modalities to overcome this phenomenon, which still limits effectiveness of cancer cure, to the early stages of the disease.
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PMID:Drug resistance and its counteraction by cyclosporin A in function of metastatic potential in the Lewis lung carcinoma system. 806 72

Carcinogenesis requires a complex series of genetic changes often involving multiple oncogenes and the inactivation of multiple tumor-suppressor genes. We presently examined the effect of the Krev-1 tumor-suppressor gene on the tumorigenic and metastatic potential of Ha-ras-transformed cloned rat embryo fibroblast (CREF) cells. Ha-ras-transformed CREF cells are morphologically transformed and anchorage independent; produce reduced levels of nm23-H1 (a putative metastasis-suppressor gene product) and TIMP-1 (tissue inhibitor of metalloproteinase 1) transcripts and mRNA compared with CREF cells; produce increased levels of cripto, 94-kDa gelatinase/type IV collagenase (94-kDa GEL), osteopontin (OPN) and transin/stromelysin transcripts and mRNA compared with CREF cells; and are tumorigenic and metastatic in both nude mice and syngeneic rats. Ha-ras-transformed CREF cells coexpressing the Krev-1 gene display a reversion in cellular phenotype and gene expression to that of untransformed CREF cells. However, Ha-ras/Krev-1-coexpressing CREF cells retain, albeit with extended latency periods, both tumorigenic and metastatic potential that is not related directly to the final level of Ha-ras or Krev-1 mRNA or the Ha-ras p21 transforming protein. Development of metastatic potential is, however, directly correlated with a reduction in nm23-H1 and TIMP-1 transcription and mRNA levels and an enhanced expression of cripto, 94-kDa GEL, osteopontin and transin. In contrast, expression of additional tumor-suppressor genes, such as the RB gene and p53, or genes associated with tumorigenesis in other model systems, such as major excreted glycoprotein (MEP), 72-kDa gelatinase/type IV collagenase (72-kDa GEL), fibronectin (FIB), tenascin and intracellular adhesion molecule 1 (ICAM-1) is not altered in a consistent manner during in vitro transformation suppression or escape from tumorigenic and metastatic suppression. These results indicate that Krev-1 suppression of the Ha-ras-transformed/oncogenic phenotype is associated with a distinct program of gene expression changes manifested by altered rates of transcription and steady-state mRNA levels of specific oncogenic-suppressing and oncogenic-inducing genes. These data support a model of Ha-ras-induced metastasis in CREF cells that involves a direct modulation in the expression/suppression of specific combinations of oncogenic-suppressor genes and metastasis-promoting genes that are regulated coordinately in the process of tumor progression.
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PMID:Defining the critical gene expression changes associated with expression and suppression of the tumorigenic and metastatic phenotype in Ha-ras-transformed cloned rat embryo fibroblast cells. 847 44

Thrombospondin (TSP-1) is a large glycoprotein secreted by platelets and synthesized by many cell types, including endothelial and tumor cells. Although controversy exists about the biological function of TSP-1, the following observations suggest that TSP-1 may potentiate tumor progression. (1) Tumor metastases in mice are promoted by TSP-1 and inhibited by anti-TSP-1 antibodies. (2) TSP-1 promotes tumor cell adhesion, migration and invasion. (3) TSP-1 promotes angiogenesis in the rat aorta model. (4) TSP-1 up-regulates the plasminogen activator system through a mechanism involving the activation of TGF-beta 1. (5) Human tumors express increased levels of the CSVTCG-specific TSP-1 receptor. (6) Tumor stroma is enriched in TSP-1. (7) Cancer patients have high blood levels of TSP-1. (8) Poor patient survival correlates with a higher expression of the CSVTCG-specific TSP-1 receptor on tumor cells. In this paper we discuss the evidence that TSP-1 promotes tumor progression and present a hypothetical scheme for its mechanism of action.
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PMID:The role of thrombospondin-1 in tumor progression and angiogenesis. 859 67

Studies about the function of mucin molecules as surface molecule of adenocarcinoma of gastrointestinal tract had just started, and several important function of mucins had been revealed. In the process of the malignant transformation, class of the expressed mucin core protein and content of glycochain of mucin molecule was changed. Changes of glycoprotein of mucin molecule during transformation affect immunogenesity, tumorigenesity, metastatic ability and sensitivity for anti-cancer drugs. Glycosylated mucin acts important roles during metastatic sequence and prognosis of the gastrointestinal cancer was collerated with expression of immatured mucin of cancer cells. A type of mucin with immature type of glycochain, MUC1, had a protective function for cytotoxicity, e.g. natural killer cell and cytotoxic T-cell, and deglycosilation of MUC1 sensitize cancer cells for cytotoxicity. And MUC1 reduce sensitivity for anti-cancer drugs and MUC1 was glycosilated during process to get resistance for anti-cancer drug. The functions of mucin molecules is not fully revealed, but further studies will indicate importance of mucin molecules in tumor progression.
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PMID:[Functions of mucin molecules in gastrointestinal cancer]. 863 44

Thrombospondin-1 (TSP-1), a trimeric high molecular weight glycoprotein, is one of the major secreted proteins of human platelets and an extracellular matrix component of a variety of cells including vascular endothelial cells and tumor cells. TSP-1 has been shown to be highly expressed in human malignant tissues and present in higher than normal levels in the plasma of cancer patients. TSP-1 has also been shown to promote hematogenous tumor spread, tumor cell adhesion and invasion, and angiogenesis. Overall these studies provide compelling evidence for the conclusion that TSP-1 plays an important role in tumor progression.
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PMID:Expression of thrombospondin-1 in cancer: a role in tumor progression. 867 65

Thrombospondin-1 (TSP1) is an extracellular matrix glycoprotein that influences cell adhesion, motility, and growth. Based on its effects on tumor and endothelial cell behavior, this member of the thrombospondin gene family has attracted interest as a potential regulator of tumor growth and metastasis. Initial studies have confirmed that increased TSP1 expression suppresses growth or metastasis of some tumors in vivo and inhibits angiogenesis. These activities are cell type specific, however, since overexpression of TSP1 in some tumors causes increased tumor progression. One basis for these apparently conflicting observations may be the complexity of the protein. TSP1 interacts specifically with several cell-surface receptors, heparan sulfate proteoglycans, growth factors, and other matrix components. These multiple binding specificities, combined with the ability of TSP1 to activate latent transforming growth factor beta and inhibit several proteases, suggest that exposure to TSP1 may initiate several intracellular signals. The integration of these signals may allow varied responses to TSP1. Furthermore, these signals may be received by the tumor cells, endothelial cells responsible for neovascularization, stromal cells, or cells of the host immune system. TSP1 influences specific behaviors of each cell type. Relating these phenomena to the molecular interactions of TSP1 observed in vitro may lead to novel therapeutic strategies for controlling cancer progression and metastasis.-Roberts, D. D. Regulation of tumor growth and metastasis by thrombospondin-1.
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PMID:Regulation of tumor growth and metastasis by thrombospondin-1. 875 20

With chemotherapy, the in vitro and clinical dose-response curve is steep in some situations, but is relatively flat in others, possibly due to the mechanism by which tumors are resistant to chemotherapy. For tumors with resistance due to factors that actively decrease chemotherapy efficacy (e.g., p-glycoprotein, glutathione, etc.), one would predict that high dose chemotherapy and therapy with some resistance modulating agents would increase therapeutic efficacy. Such "active" resistance would most likely generally arise from gene amplification or over expression, and would be characterized by a shoulder on the log response vs. dose curve, with eventual saturation of the protective mechanism. On the other hand, one would expect that high dose chemotherapy and most resistance modulating agents would be of little value for tumors with resistance due to defective apoptosis or due to a deficiency in or decreased drug affinity for a drug target, drug activating enzyme, drug active uptake system, or essential cofactor. Such "passive" resistance would most likely generally arise from gene down regulation, deletion, or mutation, and would probably be characterized by a relatively flat log response vs. dose curve, or by a curve in which a steep initial section is followed by a plateau, as target, etc., is saturated. (If response were plotted vs. log dose, then compared to the curve for a sensitive cell line, the curve for active resistance would be analogous to the pharmacodynamic curve seen with competitive antagonism [i.e., a sigmoid curve shifted to the right], and the curve for most types of passive resistance would be analogous to the pharmacodynamic curve seen with noncompetitive antagonism [i.e., a sigmoid curve with reduced maximal efficacy]. As such, one might also refer to active vs. passive resistance as competitive vs. noncompetitive resistance, respectively.) Many tumor types probably possess a combination of active and passive mechanisms of resistance. New in vivo strategies could be helpful in defining dose-response relationships, mechanisms of resistance, and targets for resistance modulation. Such in vivo studies would be conducted initially in animals, but might also be tested clinically if animal studies demonstrated them to be feasible and useful. These in vivo studies would be conducted by randomizing 5-25 subjects to one of 10-20 dose levels over a potentially useful therapeutic range. Nonlinear regression analysis would then be used to define the characteristics of a curve generated by plotting against dose the log percent tumor remaining after the first course of therapy. While this might offer insight into the nature of resistance mechanisms present initially, plotting further tumor shrinkage vs. dose-intensity vs. course number for each later treatment course (or plotting dose-intensity vs. time to tumor progression) might provide information on how tumors become increasingly resistant to drugs following treatment.
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PMID:Active vs. passive resistance, dose-response relationships, high dose chemotherapy, and resistance modulation: a hypothesis. 891 32

In this report we describe the characteristics of an immunosuppressive molecule from an Abelson Leukemia Virus transformed highly malignant and metastatic RAW117-H10 murine large cell lymphoma cells. Our studies have shown that the mitomycin-c treated or irradiated RAW117-H10 cells very significantly (p < 0.001) inhibited the nitrogen induced proliferation of normal Balb/c splenocytes. The cell surface extracts from the immunosuppressive RAW117-H10 lymphoma cells significantly inhibited the in vitro T cell or NK/LAK cell functions. Our in vivo studies demonstrated that there was a significant suppression of immune response in the Balb/c mice bearing RAW117-H10 cells when compared with mice bearing low metastatic parental RAW117-P cells or control mice. Subsequently we isolated and purified the main molecule responsible for this immunosuppression and found that the molecule is a glycoprotein with a molecular weight of 70 kD with an isoelectric point of 4.3, which cross reacted with antibodies to murine leukemia virus envelope gp70 molecules. Further analysis using immunoelectrophoresis, molecular probing techniques, and mannose specific lectin binding assay revealed that the immunosuppressive 70 kD molecule, is different from the wild type MLV envelope gp70 molecule and thus appears to be an altered gp70 molecule. These studies demonstrate that the metastatic lymphoma associated immunosuppression may facilitate the growth and metastasis of tumor cells. Our results also elucidate the possible mechanism(s) of retrovirus induced immunosuppression and the molecular basis of this retroviral envelope-mediated process in viral pathogenesis and tumor progression.
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PMID:Immunosuppression by metastatic lymphoma derived altered retroviral gp70 molecule. 920 41

Laminin is a glycoprotein of the basement membrane (BM), involved in a variety of normal and pathological cellular events including tumour invasion and metastasis. Cells bind laminin through different types of receptor. The 67-kD laminin receptor (67LR) is a cell-surface protein which binds laminin with high affinity. 67LR expression has been shown to increase in neoplastic cells, compared with normal tissues, and 67LR seems to play an important role during the first steps of neoplastic progression. In this study, 67LR expression was analysed during the morphological phases of breast cancer progression from normal tissue to invasive carcinoma. A total of 506 formalin-fixed, paraffin-embedded normal breast structures and lesions were stained by immunohistochemistry usign the MLuC5 monoclonal antibody, which is specific for 67LR. The results show that in normal breast and in any kind of breast lesion, myoepithelial and endothelial cells express 67LR. While 67LR is not seen in the epithelium of normal breast, cysts, adenosis, and benign tumours, it is expressed in the epithelial cells of several hyperplasias and carcinomas in situ, both ductal and lobular, as well as in all invasive carcinomas. The 67LR-positive cell subpopulation expands from hyperplastic lesions to invasive carcinoma, suggesting that 67LR could be related to the induction and progression of breast cancer.
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PMID:The spectrum of 67-kD laminin receptor expression in breast carcinoma progression. 922 40


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