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)

Cell growth and viability are dependent on the function of the multicatalytic proteinase complex (proteasome), a multisubunit particle that affects progression through the mitotic cycle by degradation of cyclins. Exposure of rodent fibroblasts and human lymphoblasts in culture to benzyloxycarbonyl-leucyl-leucyl-phenylalaninal (Z-LLF-CHO), a cell-permeable peptidyl aldehyde inhibitor of the chymotrypsin-like activity of the proteasome, resulted in the induction of apoptosis in a rapid, dose-dependent fashion. Fibroblasts transformed with ras and myc, lymphoblasts transformed by c-myc alone, and a Burkitt's lymphoma (BL) cell line that overexpresses c-Myc were up to 40-fold more susceptible to apoptosis than were either primary rodent fibroblasts or immortalized nontransformed human lymphoblasts, respectively. To determine whether such preferential apoptosis could impact upon tumor growth in vivo, toxicological studies were performed in mice with severe combined immunodeficiency and showed that mice tolerated single interscapular doses of Z-LLF-CHO without unacceptable toxicity. Severe combined immunodeficient mice bearing s.c. BL tumors in the flank were treated interscapularly with Z-LLF-CHO or a comparable dose of the peptidyl alcohol (Z-LLF-OH), which does not induce proteasome inhibition or apoptosis. Single doses of Z-LLF-CHO induced statistically significant (P < 0.0001) early tumor regression and a significant (P < 0.0001) delay in tumor progression. Analysis of tumor specimens revealed increased apoptosis in BL tumors from mice treated with Z-LLF-CHO. These results, showing a 42% tumor growth delay, indicate that proteasome inhibitors have the potential of curbing the growth of a c-myc-related tumor.
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PMID:Tumor growth inhibition induced in a murine model of human Burkitt's lymphoma by a proteasome inhibitor. 976 62

It has been reported that hepatitis C virus-related hepatocellular carcinoma (HCC) patients survive longer than hepatitis B virus-related patients. In this study, since HCC patients positive for anti-HCV antibody had significantly longer disease-free survival (p<0.05), we evaluated the proliferative activity of 58 resected HCCs and the status of their viral infections. Ki-67 (MIB-1) immunostaining, argyrophilic nucleolar organizer regions and c-myc gene amplification were examined as parameters of proliferation, and p53 overexpression was examined in relation to clinicopathologic features and prognosis. Thirty-nine patients with HCC (67%) were positive for anti-HCV antibody alone, five (9%) were negative for both anti-HCV and HBV antibodies, two (3%) were positive for both anti-HCV and HBV antibodies, and 12 (21%) had HBsAg alone. HCC patients with anti-HCV antibody had a lower MIB-1 labeling index (LI) than HCC patients negative for the antibody (p<0.05), irrespective of the serum HBsAg status. However, there was no significant correlation between anti-HCV antibody and other proliferative parameters. MIB-1 could simply be related to cellular proliferation. On the other hand, the other parameters may be related to tumor progression as well as proliferation. HCV-related HCC does have lower proliferative activity and a better prognosis.
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PMID:Low MIB-1 labeling index in anti-HCV positive hepatocellular carcinoma. 977 94

Little is known about stepwise deregulation of specific genes leading to lymphoid malignancy. Aberrant myc gene expression in transgenic mice is correlated with B cell lymphomagenesis. We generated a unique transgenic mouse model in which deregulated murine E mu-N-myc transgene expression leads to development of indolent B cell lymphoma. Tumor cells were monoclonal, morphologically mature and surface immunoglobulin expressing B cells. Tumors arose in a disease course and exhibited a cytoarchitectural appearance reminiscent of human follicular lymphoma. Yet tumor cells were staged as preB since they failed to rearrange the immunoglobulin light chain genes. Retroviral insertion mutagenesis analyses of adult transgenic mice infected as newborns with murine leukemia virus revealed decreased disease latency, increased lymphoma incidence and a histologically more mature tumor type. Proviral insertion sites were not equivalent when accelerated E mu-N-myc indolent lymphomas were compared to accelerated c-myc preB cell lymphomas. The bcl-2 gene was not disrupted in either spontaneous or provirally accelerated E mu-N-myc lymphomas. These findings suggest that tumor progression in N-myc-associated indolent B cell lymphoma can proceed along diverse pathways involving distinctly different combinations of deregulated and/or intact genes than those pathways described in highly aggressive forms of myc-related murine preB cell disease.
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PMID:Transgenic N-myc mouse model for indolent B cell lymphoma: tumor characterization and analysis of genetic alterations in spontaneous and retrovirally accelerated tumors. 979 78

Although elevated c-myc expression seems to be related to an unfavorable prognosis of human thyroid neoplasias, the role of c-myc overexpression in the process of thyroid carcinogenesis is still unknown. We analyzed c-myc expression in 7 human thyroid carcinoma cell lines, originating from different histotypes, and in 50 fresh thyroid tumors and found a higher level of c-myc mRNA in all the thyroid carcinoma cell lines and in several fresh thyroid tumors compared with normal thyroid. The highest increases occurred in the most malignant cell lines and in undifferentiated human thyroid carcinomas. The block of c-MYC protein synthesis with myc-specific antisense oligonucleotides reduced the growth rate of the thyroid carcinoma cell lines significantly. Our results indicate that c-myc overexpression plays a critical role in the growth of thyroid cancer cells, which supports the hypothesis that the myc proto-oncogene might be involved in the neoplastic progression of thyroid carcinogenesis.
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PMID:Block of c-myc expression by antisense oligonucleotides inhibits proliferation of human thyroid carcinoma cell lines. 981 98

Small cell lung cancer (SCLC) is a highly invasive and metastatic tumor, and the decreased expression of alpha3beta1 integrin may contribute to its virulence. Alpha3beta1 is a critical integrin for pulmonary development and epithelial integrity, and its reduced expression has been linked to the increased malignancy and invasion of other cancers. The amplification of the c-myc oncogene is seen frequently in relapsed SCLC tumors and is associated with a worsened prognosis. In the present study using a model of SCLC tumor progression, overexpression of c-myc in a classic SCLC cell line, NCI H209, enhanced in vitro features of tumorigenesis, altered the relationships between cell and environment, and markedly down-regulated the expression of the alpha3 integrin subunit at both the transcript and protein levels. This inverse relationship between the expression of the alpha3 integrin subunit and c-myc is mimicked by other c-myc-overexpressing SCLC cell lines. Restoring alpha3 expression in the myc-transfected 209 cells reversed the effects of c-myc: alpha3 transfection increased cell:cell adhesion and reduced soft agar cloning without affecting the in vitro doubling time. The diminished soft agar cloning produced by alpha3 transfection was reversed by an antibody that specifically engages alpha3beta1 integrins, P1B5. These results suggest first, that alpha3beta1 integrin mediates homotypic adhesion of SCLC cells, and second, that unengaged alpha3beta1 integrin suppresses the growth of disaggregated SCLC cells. Thus, the down-regulation of the alpha3 integrin subunit may contribute to the enhanced tumorigenicity of c-myc-overexpressing SCLCs by allowing the growth of tumor cells that have reduced contact with ligand-expressing substratum or cells, a condition that occurs during the growth of the primary tumor, tumor invasion, and metastasis.
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PMID:Association of the decreased expression of alpha3beta1 integrin with the altered cell: environmental interactions and enhanced soft agar cloning ability of c-myc-overexpressing small cell lung cancer cells. 985 91

Increased expression of nm23/nucleoside diphosphate kinase (NDP kinase) has been reported to be associated with both reduced metastatic potential in breast carcinoma and tumor progression in colon adenocarcinoma and lung adenocarcinoma. We examined effects of expression of nm23-R2 rat NDP kinase alpha isoform on mouse adenocarcinoma cells (Colon 26 line) and found a significant reduction of metastatic potential along with overexpression of c-myc. We also found that the proliferation rate of the transformed cells was the same as that of the control cells in culture. These results indicate that the cell growth potential in vitro is irrelevant to metastatic potential of the cells in vivo.
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PMID:Reduced metastatic potential and c-myc overexpression of colon adenocarcinoma cells (Colon 26 line) transfected with nm23-R2/rat nucleoside diphosphate kinase alpha isoform. 985 45

The human A and B subunits of nucleoside diphosphate kinase (NDP kinase), encoded by the nm23-H1 and nm23-H2 genes, respectively, associate as homo- or heterohexamers to be catalytically active for the synthesis of nucleoside triphosphates. Despite 88% identity, they appear to possess specific functions. The nm23-H1 gene is implicated in tumor progression and metastasis, and the nm23-H2 gene product is a transcription factor for c-myc. To determine if these distinct functions reflect different subcellular localizations, the distribution of the A and B NDP kinases was analyzed by immunocytofluorescence microscopy in human breast cancer cell lines (MCF-7 and MDA-MB-231) using highly specific polyclonal and monoclonal antibodies. Interphasic cells exhibited a granular and filamentous cytoplasmic staining, particularly intense around nuclei, with both anti-NDP kinase A and B antibodies. The filamentous component observed with either anti-A or anti-B antibodies was altered in parallel to tubulin labeling with compounds interacting with microtubules, such as taxol and colchicine. Confirming published biochemical data, a partial colocalization with the vimentin network was observed in the MDA-231 cell line. A nuclear and nucleolar localization of NDP kinase B was shown by confocal microscopy which was not observed with the A enzyme. In dividing cells, NDP kinase labeling was punctiform and was not colocalized with the mitotic spindle. In conclusion, the A and B NDP kinases are similarly distributed in cytosol, associated partly to microtubules supporting a role in nucleotide channeling. Only the B enzyme is present in nuclei in accord with its role as a DNA binding protein. Their altered localization in dividing cells suggests colocalization with yet unidentified structures which are not intermediate filament aggregates.
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PMID:Cytoskeletal association of the A and B nucleoside diphosphate kinases of interphasic but not mitotic human carcinoma cell lines: specific nuclear localization of the B subunit. 992 51

We have used proviral tagging in tumor-prone transgenic mice to identify collaborating oncogenes and genes contributing to tumor progression. This has yielded a series of oncogenes that could be assigned to different complementation groups in transformation: the myc, Pim, Bmi1, and Frat1 complementation groups. Frat1 is involved in tumor progression and appears to function in the Wnt signaling pathway. Overexpression of Fratl confers a growth advantage to transplanted tumor cells in vivo and to cells grown in vitro at high density. Frat1 might exert its activity by impairing the kinase activity of Gsk3beta, which is involved in the degradation of beta-catenin. Pim genes appear to act in tumor initiation and show strong synergism with myc in lymphomagenesis. Overexpression of Pim1 can also overcome some of the proliferative defects caused by defective interleukin signaling supporting a role of Pim1 in cell proliferation. We have applied proviral tagging in compound mutant Emu-myc/Pim1-/-/Pim2-/- mice to identify genes that can complement for the loss of Pim1 and Pim2 and, therefore, are able to synergize with c-myc in lymphomagenesis. A number of new as well as known genes have been found by this "complementation tagging." The latter included c-kit, Tp12, and cyclin D2, suggesting that Pim kinases might act upstream of or parallel to these known proto-oncogenes.
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PMID:Identification and characterization of collaborating oncogenes in compound mutant mice. 1019 95

v-myc is the viral homolog of c-myc transduced by several acute transforming retroviruses, many of which encode this gene as a Gag-Myc fusion protein. The v-myc oncogene can transform several lineages of mammalian and avian cells either alone or in cooperation with other oncogenes. While the Gag portion of the Gag-Myc fusion protein and the nuclear localization signal each appear to be dispensable for transformation, the N- and C-termini of the Myc sequence have been found to be essential for transformation. All v-myc genes contain point mutations which seem to confer a greater potency to v-myc in the process of transformation, proliferation, and apoptosis. In v-myc-transformed myelomonocytic cells, secondary events occur, such as the expression of colony stimulating factor-1 (CSF-1) which play a critical role in immortalization and subsequent tumor progression. Inhibition of the autocrine loop of CSF-1 was found to induce apoptosis in the immortalized cells. While overexpression of v-Myc blocks terminal differentiation of hematopoietic cells, this is not sufficient to block the differentiation of certain neural and skeletal muscle cells. Recent developments on the effects of v-myc on cell growth, transformation, differentiation and apoptosis are discussed in this review.
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PMID:The v-myc oncogene. 1037 95

The majority of inflammation-induced peritoneal BALB/c plasmacytomas (approximately 90%) harbor a balanced T(12;15) chromosomal translocation that deregulates the expression of the proto-oncogene c-myc. Recent evidence suggests that the T(12;15) is an initiating tumorigenic mutation that occurs in early plasmacytoma precursor cells. However, plasmacytomas take a long time to develop (average tumor latency approximately 220 days), which suggests that additional tumor progression events may be required to complete oncogenesis. We hypothesized that such tumor progression events may take the form of secondary chromosomal aberrations that can be detected by spectral karyotyping (SKY). We screened the entire chromosome complement of 18 primary BALB/c plasmacytomas carrying the T(12;15) and found in nine tumors (50% recurrence) secondary cytogenetic aberrations that involved bands D, E and F chromosome (Chr) 5. The Chr 5D-F rearrangements were manifested predominantly as unbalanced translocations with various partner chromosomes. This finding led us to propose the existence of an important plasmacytoma progression locus in the central region of Chr 5, which presumably becomes involved in peritoneal plasmacytoma development by promiscuous chromosomal translocations.
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PMID:Recurrent non-reciprocal translocations of chromosome 5 in primary T(12;15)-positive BALB/c plasmacytomas. 1039 54


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