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Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Oncogene amplification has been observed in various primary tumors and tumor-derived cell lines. In several types of cancer, amplification of specific oncogenes is correlated with the stage of tumor progression. To estimate the frequency of gene amplification in other tumor types and to determine whether the ability to grow in vivo is associated with gene amplification in tumor cell lines, we have developed a modified version of the in-gel renaturation assay that detects human DNA sequences of unknown nature amplified as little as 7- to 8-fold. This assay was used to screen 16 cell lines derived from various solid tumors and leukemias. Amplified DNA sequences were detected in only one cell line, Calu-3 lung adenocarcinoma. This cell line was found to contain coamplified NGL (formerly termed neu) and ERBA1 oncogenes. However, when one of the amplification-negative cell lines, PC-3 prostatic carcinoma, was selected for in vivo growth in nude mice, amplified DNA sequences became detectable in these cells. The amplified sequences included the MYC oncogene, which showed no amplification in the parental cell line but was amplified 10- to 12-fold in the in vivo-selected cells. MYC amplification may, therefore, provide tumor cells with a selective advantage specific for in vivo growth.
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PMID:Analysis of gene amplification in human tumor cell lines. 341 26

The development of effective screening tests for colorectal tumors is essential given the high frequency of these cancers in the general population, and more especially in various groups at risk. Sporadic and hereditary colorectal cancers result from the accumulation of mutations in oncogenes, such as ras, myc, neu/HER2, and in tumor suppressor genes such as apc, dcc, p53. The detection of ras or p53 mutations in DNA extracted from stool has been shown to be feasible and might be useful for the development of new screening tests. Many mutations in these genes can also be used as new prognostic factors. Identification of mutation in the apc gene responsible for familial polyposis, or its indirect detection through the study of polymorphism in such families, is completely changing the previously recommended medical attitude for the screening of this disease, and therefore may decrease or even avoid major medical follow-up. These changes are also true for the nonpolyposis hereditary colorectal tumors, also called Lynch syndrome, since the responsible hMSH2, hMLH1, hPMS1 and hPMS2 genes have recently been cloned. Mutations in these genes do not seem to be limited to families with Lynch syndrome, and could account for a predisposition of some patients to develop colorectal or other tumors.
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PMID:Contribution of molecular oncology in the detection of colorectal carcinomas. 749 39

We have constructed, expressed, and purified a fusion protein, HAR-TX beta 2, consisting of heregulin-beta 2 fused to a binding-defective form of Pseudomonas exotoxin A, PE40. The fusion protein was found to induce receptor tyrosine phosphorylation in CEM cells transfected with HER4 alone or in combination with HER2 but not in cells transfected with HER2 or HER1 alone. The phosphorylation of receptor tyrosines was both dose-dependent and saturable in amounts similar to those shown to be active for native heregulin. HAR-TX beta 2 was specifically cytotoxic toward a variety of carcinoma cell lines in the ng/ml range. However, some tumor cell lines were found to be insensitive to the cytotoxic action of the fusion protein even at > 2 micrograms/ml. Relative amounts of HER4, HER3, and HER2 were determined on seven cell lines sensitive and four cell lines insensitive to HAR-TX beta 2. All lines that express HER4 were killed by HAR-TX beta 2, while none lacking HER4 were affected. HAR-TX beta 2 was able to bind to and signal via tyrosine phosphorylation in cell lines that co-express HER2 and HER3 in the absence of HER4 without inducing cytotoxicity. Thus HAR-TX beta 2 may prove to be a useful reagent for the targeting and elimination of HER4-positive tumor cells.
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PMID:HER4 expression correlates with cytotoxicity directed by a heregulin-toxin fusion protein. 753 74

The retinoid N-(hydroxyphenyl) retinamide (4-HPR) appears to be a promising tool for chemoprevention of breast carcinoma, and clinical trials to evaluate its effect are in progress. However, its action on tumor cells has remained largely undefined. We report here that 4-HPR induced apoptosis and/or differentiation in breast cancer cell lines, independent of hormone receptor status and retinoic acid receptor expression, although it was slightly more efficient in inhibiting proliferation of estrogen receptor-positive cells. 4-HPR up-modulated expression of several differentiation markers (class 1 HLA, laminin, and beta 1 integrin chain) and down-regulated expression of molecules associated with tumor progression, including the p185/HER2 oncoprotein, the epidermal growth factor receptor, and the M(r) 67,000 laminin receptor. These data suggest that 4-HPR could exert a beneficial effect by inhibiting cell proliferation and modulating breast tumor aggressiveness.
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PMID:Modulation of markers associated with tumor aggressiveness in human breast cancer cell lines by N-(4-hydroxyphenyl) retinamide. 754 8

Amplification and/or overexpression of HER2/neu and HER3 genes have been implicated in the development of cancer in humans. The fact that these receptor tyrosine kinases (RTKs) are frequently coexpressed in tumor-derived cell lines and that heterodimers form high affinity binding sites for heregulin (HRG) suggests a novel mechanism for signal definition, diversification or amplification. In cells expressing HER2 and HER3, tyrosine phosphorylation of HER3 is markedly increased upon exposure to recombinant HRG. ATP binding site mutants of HER2 and HER3 demonstrate transphosphorylation of HER3 by HER2, but not vice versa. HRG-induced transphosphorylation of HER3 results in a substrate phosphorylation pattern distinct from HER2 cells and enhances association of the receptor with SHC and phosphoinositol 3-kinase in transfected 293 and mammary carcinoma-derived MCF-7 cells. The physiological relevance of HER2/HER3 heterodimerization is demonstrated by HRG-dependent transformation of NIH 3T3 cells coexpressing the two receptors. These findings demonstrate the acquisition of expanded signaling capacities for HER2 by HRG-induced heterodimerization with HER3 and provide a molecular basis for the involvement of receptor heteroactivation in the development of human malignancies.
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PMID:Heregulin-dependent regulation of HER2/neu oncogenic signaling by heterodimerization with HER3. 755 68

A tumor-specific cytotoxic T lymphocyte (CTL) immune response has been well documented in melanoma, renal cell carcinoma, and ovarian cancer. Conflicting evidence exists regarding the existence of tumor-specific CTL populations in breast cancer. Tumor cells and tumor-associated lymphocytes (TAL) were isolated from the pleural effusions of six consecutive patients with metastatic breast cancer. After solid-phase anti-CD3 stimulation, TAL cultures were expanded with weekly autologous tumor stimulation and low-dose IL-2 for 3 wk. T cell populations were characterized using flow cytometric analysis and ranged from 49 to 91% CD8+, > 98% CD3+, and < 3% CD16+. Functionally, tumor-stimulated TAL showed tumor-specific recognition of autologous tumor cells (241 +/- 142 LU20/10(7)) and no detectable lysis of autologous fibroblasts, Daudi or K562. Cytotoxicity of TAL against HLA-A2+ allogeneic targets was significantly higher when compared with HLA-A2- tumor cell lines (127 +/- 76 vs 6 +/- 18 LU, p = 0.0001). This cytotoxicity against autologous and allogeneic tumor cells was blocked by anti-HLA-A2 mAb and cold HLA-A2+ targets in cold-target inhibition assays. TAL from all HLA-A2+ patients recognized GP2, a known, HER2/neu-derived tumor-associated peptide Ag that is HLA-A2 restricted. We have shown that TAL obtained from metastatic effusions of breast cancer patients contain lymphocytes that can recognize and lyse autologous and allogeneic tumor cells in a tumor-specific, HLA-A2-restricted fashion. In addition, tumor-specific TAL derived from breast cancer patients can selectively lyse HLA-A2+ pancreatic and ovarian tumor cell targets, suggesting a common HLA-A2-restricted tumor-associated Ag between these distinct epithelial cancers. Further elucidation of the cell-mediated immune response to breast cancer and the identification of shared TAA could result in the development of broadly applicable vaccine therapies for many cancers.
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PMID:Tumor-specific and HLA-A2-restricted cytolysis by tumor-associated lymphocytes in human metastatic breast cancer. 759 11

We previously constructed a humanized anti-p185HER2/anti-CD3 bispecific antibody variant, BsF(ab')2 v1 which retargets the cytotoxic activity of human T cells in vitro against human breast tumor cells which overexpress the p185HER2 product of the HER2/neu (c-erbB-2) protooncogene. Subsequently we identified an improved anti-CD3 variant, v9, which binds to T cells with approx. 100-fold higher affinity than the original variant, v1. Here we demonstrate that BsF(ab')2 v9 is more potent than BsF(ab')2 v1 in stimulating the proliferation of both resting peripheral blood lymphocytes (PBL) and IL-2-activated, long-term cultured T lymphocytes (ATL). In addition, at low concentrations (0.01-1 ng/ml) BsF(ab')2 v9 is much more efficient than BsF(ab')2 v1 in directing lysis of p185HER2-overexpressing tumor cells by IL-2 activated PBL. In contrast, at higher concentration BsF(ab')2 v9 and BsF(ab')2 v1 have similar potency in retargeted cytotoxicity. At BsF(ab')2 v9 concentrations of > or = 1 ng/ml the susceptibility of p185HER2-expressing tumor cells to lysis is apparently independent of the level of p185HER2 expression. At lower concentrations of BsF(ab')2 v9 and/or lower ratios of effector to target cells the extent of lysis is reduced, in some cases improving the selectivity of lysis of high p185HER2 expressors over low expressors. Thus selection of a high affinity anti-CD3 arm is likely important in the design of BsF(ab')2 for retargeting the cytotoxicity of T cells to tumors. The dose of BsF(ab')2 v9 in any future clinical evaluation will require optimization to maximize anti-tumor efficacy whilst minimizing potential toxicity against normal tissue expressing p185HER2.
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PMID:Engineering high affinity humanized anti-p185HER2/anti-CD3 bispecific F(ab')2 for efficient lysis of p185HER2 overexpressing tumor cells. 762 74

73 women suffering from primary carcinoma of the fallopian tube underwent surgical excision of their tubes. The tissue was embedded in paraffin and investigated for HER-2 oncogene amplification with a quantitative polymerase chain reaction method. DNA could be extracted and successfully prepared in 65/73 samples. None of the tissue samples exhibited amplified the HER-2 oncogene. Data suggest that the HER-2 oncogene does not play a role in tumor transformation and progression in fallopian tube carcinomas. This contrasts with observations in ovarian carcinomas, with which fallopian tube carcinomas share many clinical, histological and biochemical similarities.
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PMID:HER-2 oncogene is not amplified in primary carcinoma of the fallopian tube. Austrian Cooperative Study Group for Fallopian Tube Carcinoma. 763 58

The HER2/neu (c-erbB2) protooncogene, which encodes a transmembrane receptor (p185neu), contributes to tumor cell invasion/metastasis through mechanism(s) which are, at present, poorly defined. Since basement membrane degradation is a prerequisite for tumor progression, we undertook a study to determine if the expression of urokinase, a key protease implicated in extracellular matrix proteolysis, was regulated by this oncogene. Stable overexpression of a cDNA encoding HER2/neu in H460 lung cancer cells led to elevated secretion of urokinase which was a consequence of a higher level of protease mRNA. Transfection of the HER2/neu-overexpressing B 104-1 cells with a CAT reporter construct driven by the urokinase promoter, gave rise to increased CAT activity when compared with parental NIH3T3 cells, which have low levels of HER2/neu, suggesting that the protooncogene can enhance urokinase promoter activity. Since the enhanced expression of HER2/neu results in increased tumor invasion/metastasis (1), these data suggest that, at least in vitro, HER2/neu-induced expression of urokinase may contribute to tumor progression in p185neu-positive cancers.
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PMID:Up-regulation of urokinase-type plasminogen activator expression by the HER2/neu proto-oncogene. 765 95

We have previously shown the importance of human leukocyte antigen (HLA)-A2 and the proto-oncogene HER2/neu in the T cell recognition of ovarian cancer. Since these proteins are ubiquitously expressed in epithelial-derived tumors, we have acid-eluted HLA-bound peptides from ovarian cancers, fractionated the peptides, and reconstituted T cell epitopes on the HLA-A2+ T2 cell line to determine if common tumor-associated antigens exist among HLA-A2+, HER2/neu+ epithelial cancers. We demonstrate that tumor-specific cytotoxic T lymphocytes (CTL) generated from tumor-infiltrating lymphocytes isolated from three ovarian, two breast, and two non-small-cell lung cancers recognize at least three of the same peptide fractions from multiple elutions. One of these peptide fractions coelutes with a HER2/neu-derived peptide which has been shown recently to be recognized by these same CTL. These findings demonstrate that a common peptide-based tumor vaccine is theoretically possible for many different epithelial-derived cancers.
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PMID:Shared T cell epitopes in epithelial tumors. 765 35


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