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

We have investigated the in vivo role of 2 different adhesion molecules, LFA-1 and LECAM-1, in the immune reaction to Moloney-murine-sarcoma-virus(M-MSV)-induced tumors, which undergo a peculiar spontaneous regression due to generation of a strong virus-specific cytotoxic-T-lymphocyte(CTL) response. Repeated administration of anti-LFA-1 monoclonal antibody (FD441.8 MAb), i.p. or at the site of virus inoculation, enhanced tumor growth and delayed regression, while i.p. administration of anti-LECAM-1 MEL-14 MAb gave rise to tumors that grew progressively and caused host death. Evaluation of the immunological response in MAb-treated mice showed reduced generation of virus-specific CTL precursors (p) in the spleen of animals given FD441.8 MAb i.p.; CTLp frequency in locally treated mice overlapped with that of control mice injected with virus only. FD441.8 MAb treatment did not interfere with CTL homing in the tumor, since the frequency of M-MSV-specific CTLps in sarcomas was similar in treated and control mice. Cytofluorimetric analysis indicated that the majority of tumor-infiltrating lymphocytes (TIL) from MAb-treated mice were covered by anti-LFA-1 MAb, and lacked cytotoxic activity when assayed against target cells bearing relevant tumor antigens. Instead, in mice injected i.p. with MEL-14 MAb, a very low frequency of CTLps was detected in lymph nodes draining the tumor area, and within the tumor. Our results indicate that enhanced tumor growth, depending on the MAb used, is the resultant of an inhibitory effect on different T-lymphocyte functions. Tumor progression in anti-LFA-1 MAb-injected mice is explained mostly by blockage of CTL lytic activity at the tumor site; in mice receiving i.p. MEL-14 MAb treatment, by the failure of naive T lymphocytes to enter peripheral lymph nodes and subsequently by the lack of generation of tumor-specific CTLs.
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PMID:Role of adhesion molecules in the immune reaction to M-MSV-induced tumors. 138 41

The lack of HLA class I antigen expression by the melanoma cell line SK-MEL-33 is caused by a unique lesion in beta 2-microglobulin (beta 2-mu). Sequencing of beta 2-mu mRNA detected a guanosine deletion at position 323 in codon 76 that causes a frameshift with a subsequent introduction of a stop codon at a position 54 base upstream of the normal position of the stop codon in the message. The loss of 18 amino acids and the change of 6 amino acids, including a cysteine at position 80 in the carboxy terminus of beta 2-mu, are likely to cause marked changes in the structure of the polypeptide. The latter may account for the inability of beta 2-mu to associate with HLA class I heavy chains and for its lack of reactivity with the anti-beta 2-mu mAb tested. HLA class I antigen expression on SK-MEL-33 cells was reconstituted after transfection with a wild-type B2m gene, therefore indicating that the abnormality of endogenous B2m gene is the only mechanism underlying lack of HLA class I antigen expression by SK-MEL-33 cells. The guanosine deletion in B2m gene was detected also in the melanoma tissue from which SK-MEL-33 cells had originated. Therefore, the molecular lesion identified in the SK-MEL-33 melanoma cell line is not caused by a mutation acquired during growth in vitro but is likely to reflect a somatic mutation during tumor progression.
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PMID:Lack of HLA class I antigen expression by melanoma cells SK-MEL-33 caused by a reading frameshift in beta 2-microglobulin messenger RNA. 843 69

SPARC (secreted protein acidic and rich in cysteine) is an extracellular protein associated with tissues exhibiting high rates of cell proliferation and matrix remodeling. The current work shows that the human melanoma cell lines IIB-MEL-LES, IIB-MEL-IAN, and IIB-MEL-J and different human metastatic melanomas expressed high levels of SPARC mRNA and protein. By western blot analysis we detected a single secreted 42-kDa band in human diploid fibroblasts-conditioned medium and a 45- to 40-kDa doublet in the three melanoma cell lines and all the metastatic melanomas tested. Part of the melanoma samples and cell lines showed an additional doublet of 36-34 kDa. SPARC mRNA was expressed by the three established cell lines, 14 metastatic melanoma samples, and tumors raised in nude mice, and no spliced variants were found. The heterogeneous pattern of SPARC secreted by human melanoma cells is the result of post-translational glycosylation and a specific extracellular leupeptin-inhibitable cleavage. Unlike human fibroblasts, melanoma cells did not overexpress SPARC on addition of TGF-beta. Immunohistochemical analysis showed that SPARC was strongly expressed in 100% of primary melanomas (7 of 7) and metastatic melanomas (29 of 29), moderately expressed in most of the positive dysplastic nevi (13 of 14), and only weakly expressed in nevocellular nevi (4 of 25). Normal melanocytes did not express SPARC. The data suggest that the expression of SPARC is associated with the neoplastic progression of human melanoma.
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PMID:The expression of the secreted protein acidic and rich in cysteine (SPARC) is associated with the neoplastic progression of human melanoma. 900 36

Erythroleukemia induced by the anemia strain of Friend virus occurs in two stages. The first stage results in rapid expansion of pre-leukemic proerythroblasts (FVA cells) dependent on erythropoietin (Epo) for differentiation and survival in vitro. The second stage is characterized by emergence of erythroleukemic clones (MEL cells) which typically bear activation of the ets-oncogene, PU.1/spi.1, and loss of functional p53. We developed a Friend virus-sensitive, p53-deficient mouse model to investigate the biological advantage conferred by p53-loss during tumor progression. Here we report p53 was not required for cell survival or growth arrest during differentiation of FVA cells, nor was p53 required for induction of apoptosis upon Epo withdrawal. However, we detected induction of the p21Cip1 cyclin-dependent kinase inhibitor gene during differentiation, which was markedly enhanced in the presence of p53. p53-dependent expression of p21Cip1 occurred in the absence of an increase in p53 mRNA and protein levels and was specific for p21Cip1, since expression of gadd45, mdm-2, cyclin G and bax were unaffected by p53. In contrast, treatment of FVA cells with DNA damaging agents led to rapid accumulation of p53 protein resulting in transcription of multiple p53-regulated genes, leading to either apoptosis or growth arrest, depending on the agent used. These data demonstrate that p53-dependent activities during differentiation of preleukemic erythroblasts are distinct from those observed in response to genotoxic agents. We propose that enhancement of p53-dependent gene expression during differentiation may represent a tumor suppressor function which is necessary to monitor differentiation of preleukemic cells and which is selected against during tumor progression.
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PMID:Endogenous p53 regulation and function in early stage Friend virus-induced tumor progression differs from that following DNA damage. 976 22

Melanoma line LG2-MEL expresses several antigens recognized by autologous CTLs. One of them consists of a peptide derived from tyrosinase and presented by HLA-B*3503. We have identified another antigen of LG2-MEL as a peptide presented by HLA-B*4403 and resulting from a point mutation in gene OS-9. This gene is expressed in various normal tissues. It is located on chromosome 12 in the vicinity of the CDK4 locus and is frequently co-amplified with CDK4 in human sarcomas. The mutation, a C-to-T transition, changes a proline residue into a leucine at position 446 of the OS-9 protein. Mutated transcripts were found in all the melanoma sublines of LG2-MEL. None of the 184 tumor samples collected from other cancer patients expressed the mutated transcript, indicating that this is a rare mutational event. Interestingly, some of the melanoma sublines of LG2-MEL have lost the wild-type allele of gene OS-9. Those sublines appear to grow faster in vitro than the sublines that retained the wild-type allele, suggesting that this loss of heterozygosity may favor tumor progression. The mutation we have identified in gene OS-9 might therefore participate in the oncogenic process by affecting the function of this potential tumor-suppressor gene.
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PMID:Identification of a new peptide recognized by autologous cytolytic T lymphocytes on a human melanoma. 1274 54

Cloretazine (VNP40101M; 101M; 1,2-bis(methylsulfonyl)-1-(2-chloroethyl)-2-[(methylamino)carbonyl]hydrazine) is a sulfonylhydrazine prodrug that generates both chloroethylating and carbamoylating species on activation. To explore the molecular mechanisms underlying the broad anticancer activity observed in preclinical studies, cloretazine and chloroethylating-only [i.e., 1,2-bis(methylsulfonyl)-1-(2-chloroethyl)hydrazine] and carbamoylating-only (i.e., 1,2-bis(methylsulfonyl)-1-[(methylamino)carbonyl]hydrazine) analogues were evaluated in five murine hematopoietic cell lines. These cell lines were separable into two groups by virtue of their sensitivity to 1,2-bis(methylsulfonyl)-1-(2-chloroethyl)hydrazine; the sensitive group included L1210, P388, and F-MEL leukemias (IC50s, 6-8 micromol/L) and the resistant group consisted of Ba/F3 bone marrow and WEHI-3B leukemia cells (IC50s, 50-70 micromol/L). Resistant cells expressed O6-alkylguanine-DNA alkyltransferase (AGT), whereas sensitive cells did not. A correlation existed between AGT expression and the functional status of p53; AGT- cells possessed defective p53, whereas AGT+ cells contained wild-type p53. Based on recent findings on regulation of AGT gene expression by others, we suspect that silencing of the AGT gene by promoter hypermethylation frequently occurs during tumor progression involving p53 inactivation. O6-Chloroethylguanine is the initial DNA lesion that progresses to lethal interstrand DNA cross-links. Cloretazine exhibited a much higher preference toward the O6-chloroethylation of guanine, as measured by the difference in IC50s to wild-type and AGT-transfected L1210 cells, than 1,3-bis(2-chloroethyl)-1-nitrosourea, which targets the same site in DNA. Preferential toxicity of cloretazine against AGT- tumor cells coupled with decreased toxicity to AGT+ cells in host tissues constitute the therapeutic basis for cloretazine.
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PMID:Role of O6-alkylguanine-DNA alkyltransferase in the cytotoxic activity of cloretazine. 1627 97

The expression of melanotransferrin (MTf), a membrane-bound glycoprotein highly expressed in melanomas, is correlated with tumor vascularization and progression, suggesting a proinvasive function associated with MTf in malignant tumors. To test this hypothesis, we silenced MTf in human melanoma SK-MEL-28 cells using small interfering RNA (siRNA) and examined the plasmin activity and invasiveness of MTf-silenced melanoma. In vitro, the siRNA-mediated MTf knockdown inhibited by 58% the cell surface activation of plasminogen into plasmin. In addition, decreased expression of MTf in melanoma cells reduced cell migration. In vivo, we used a nude mice invasion model in which tissue factor (TF) induces vascular [125I]-fibrin deposition following injection. Using this metastasis model, the invasive potential of MTf-silenced cells into the lungs was reduced by fivefold. Altogether, these findings strongly suggest that MTf overexpression in melanoma cells contributes to tumor progression by stimulating plasmin generation as well as cell migration and invasion.
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PMID:Melanotransferrin induces human melanoma SK-Mel-28 cell invasion in vivo. 1719 52

KAI1/CD82, a metastasis suppressor gene of prostate cancer, is located on the human chromosome 11p11.2. Down-regulation of KAI1/CD82 during tumor progression and metastasis has been reported in several cancers, but the mechanism of this down-regulation remains unknown. The relationship between down-regulation of KAI1/CD82 mRNA expression and KAI1/CD82 gene alterations in human melanoma cell lines were investigated. The promoter methylation status was examined after a 331-bp GC-rich fragment of the promoter region was amplified in G361, SK-MEL-24 and SK-MEL-28 cell lines treated with bisulfite. In order to detect methylated CpGs in all three cell lines, 331-bp fragments were sequenced. To examine the restoration of KAI1/CD82 mRNA and protein expression, the cells were exposed to methylase inhibitor, 5-aza-2'-deoxycytidine (5-AzaC). Bisulfite-sequencing data showed no methylation in G361 and SK-MEL-24 cells, and slight methylation in SK-MEL-28 cells at CpG sites 23-26 in the promoter. Real-time PCR and flow cytometry analysis showed that 5-AzaC-treated cells restored KAI1/CD82 mRNA and protein expression in SK-MEL-24 and SK-MEL-28 cells, compared to the controls. The restoration of KAI1/CD82 mRNA and protein expression detected no significant difference between SK-MEL-24 and SK-MEL-28 cells. This means that 5-AzaC did not affect the methylated cells only. Loss of heterozygosity (LOH) at polymorphic microsatellite loci on the human chromosome 11 in the human melanoma cells was also examined. Microsatellite analysis showed LOH at D11S1344 in SK-MEL-24 and SK-MEL-28 cells, and G361 showed allelic imbalance. In conclusion, this study suggests that down-regulation of KAI1/CD82 mRNA expression in human melanoma cell lines is related to LOH or allelic imbalance, but not to methylation of the KAI1/CD82 gene region.
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PMID:Decreased expression of KAI1/CD82 metastasis suppressor gene is associated with loss of heterozygosity in melanoma cell lines. 1908 57

We measured tyrosinase mRNA levels by real-time quantitative reverse transcription-PCR (qRT-PCR), in the blood of patients with uveal melanoma. Results were correlated with clinical data and, in a subgroup of patients, with the number of circulating tumor cells (CTC) assessed using isolation by size of epithelial tumor cells (ISET). Forty-one patients with uveal melanoma were longitudinally investigated over a period of 5 years. The standard curve of the qRT-PCR method used melanoma cell line SK-MEL-28, added to the blood of normal donors and it was calibrated on a synthetic RNA standard (1 SK-MEL-28 cell corresponding to 18 tyrosinase mRNA copies) to improve the procedural standardization to facilitate the comparison of data collected at different laboratories. Increased tyrosinase mRNA levels were found in at least one of the blood samples in 20 of 41 (49%) uveal melanoma patients (median 0.8 SK-MEL-28 cell equivalents/ml blood; range 0.1-14.4). A significant correlation was found between mRNA tyrosinase levels and tumor dimension (P<0.01), disease-free and overall survival (P<0.05). CTC were isolated by ISET in five of 16 patients (5.8, 2.33, 2.00, 1.25, and 0.75 CTC/ml of blood) and the corresponding tyrosinase mRNA levels were 2.13, 1.37, 0.83, 0.58, and 0.35 SK-MEL-28 cell equivalents/ml of blood. Tyrosinase was undetectable in 11 ISET-negative patients. Tyrosinase assay by qRT-PCR is a noninvasive method for the detection of tumor progression in uveal melanoma patients. The mRNA tyrosinase levels can be taken as an indirect parameter correlated to the number of CTC isolated from blood by ISET.
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PMID:Tyrosinase mRNA levels in the blood of uveal melanoma patients: correlation with the number of circulating tumor cells and tumor progression. 2044 76

The S100B-p53 protein complex was discovered in C8146A malignant melanoma, but the consequences of this interaction required further study. When S100B expression was inhibited in C8146As by siRNA (siRNA(S100B)), wt p53 mRNA levels were unchanged, but p53 protein, phosphorylated p53, and p53 gene products (i.e. p21 and PIDD) were increased. siRNA(S100B) transfections also restored p53-dependent apoptosis in C8146As as judged by poly(ADP-ribose) polymerase cleavage, DNA ladder formation, caspase 3 and 8 activation, and aggregation of the Fas death receptor (+UV); whereas, siRNA(S100B) had no effect in SK-MEL-28 cells containing elevated S100B and inactive p53 (p53R145L mutant). siRNA(S100B)-mediated apoptosis was independent of the mitochondria, because no changes were observed in mitochondrial membrane potential, cytochrome c release, caspase 9 activation, or ratios of pro- and anti-apoptotic proteins (BAX, Bcl-2, and Bcl-X(L)). As expected, cells lacking S100B (LOX-IM VI) were not affected by siRNA(S100B), and introduction of S100B reduced their UV-induced apoptosis activity by 7-fold, further demonstrating that S100B inhibits apoptosis activities in p53-containing cells. In other wild-type p53 cells (i.e. C8146A, UACC-2571, and UACC-62), S100B was found to contribute to cell survival after UV treatment, and for C8146As, the decrease in survival after siRNA(S100B) transfection (+UV) could be reversed by the p53 inhibitor, pifithrin-alpha. In summary, reducing S100B expression with siRNA was sufficient to activate p53, its transcriptional activation activities, and p53-dependent apoptosis pathway(s) in melanoma involving the Fas death receptor and perhaps PIDD. Thus, a well known marker for malignant melanoma, S100B, likely contributes to cancer progression by down-regulating the tumor suppressor protein, p53.
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PMID:The calcium-binding protein S100B down-regulates p53 and apoptosis in malignant melanoma. 2058 15


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