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

A dominant negative H-ras mutant, N116Y, was transfected into a variety of human tumor cell lines. N116Y extremely inhibited the proliferation of A431 (vulva), PC3 (prostate), T24 (bladder), MCF7 (breast), NKPS and TMK1 (stomach) cancer cell lines. A431 and PC3 cells were particularly susceptible to N116Y. In order to examine the effects of N116Y on the neoplastic phenotypes, we transfected a less efficient N116Y expression vector into A431 cells. Almost all clones survived after G418 selection. However, they did not retain the N116Y gene and only one clone faintly expressed N116Y. This N116Y-expressing clone had no tumorigenicity in vivo, and revealed deformed morphology and DNA fragmentation, suggesting that N116Y might have induced apoptotic cell death. Thus, N116Y may be applicable for gene therapy of a wide spectrum of human tumors.
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PMID:Suppression of various human tumor cell lines by a dominant negative H-ras mutant. 758 6

Studies on the molecular basis of human breast cancer have demonstrated that mutational inactivation of the p53 tumor suppressor gene may be an essential step in the development of this cancer. We and others have previously shown that transfer of the wild-type p53 gene into cultured breast cancer cells reduced their malignant potential. We report here on a p53 gene transfer protocol based on a replication-incompetent retrovirus to efficiently inhibit tumor formation of cancer cells with endogenous mutant p53. The susceptibility of the cells to retroviral infection was determined with LZRNL transducing the lacZ reporter gene. A multiplicity of infection (moi) of 2 resulted in 90% of the exposed cell population in cytochemically detectable beta-galactosidase activity. Using the p53 vector Lhp53RNL with a moi of 2 was sufficient to completely supress tumor formation by the highly tumorigenic MDAMB231 breast cancer cells carrying a point missense mutation in codon 280. Even after 12 weeks, no vital tumors were histologically detectable. For comparison, established protocols were used to infect MDAMB231 cells with low moi with the p53 virus. Clones were expanded in G418-selective media for few weeks, pooled and injected into nude mice. Tumor formation occurred already after 1 week from G418-selected cells. Long-term expression of the p53 transgene was more stable in retrovirally bulk-infected and nonselected cells resulting in an efficient suppression of tumor formation. This approach may facilitate future studies on other growth suppressive genes that potentially qualify for in vivo gene therapy.
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PMID:p53 trans-dominantly suppresses tumor formation of human breast cancer cells mediated by retroviral bulk infection without marker gene selection: an expeditious in vitro protocol with implications towards gene therapy. 759 Jul 73

Selective outgrowth of v-H-ras-infected 10T1/2 cells based on the cointroduction of a gene for resistance to geneticin (G418), yielded cells which exhibited an increased capacity to bind polyclonal serum natural antibody (NAb). This demonstrated an NAb-susceptible phase of tumor development which would be a basic requirement for NAb-mediated surveillance of tumors. The ras-oncogene dependence of the high-NAb-binding phenotype provided a model for assessing NAb resistance against ras transformants in vivo and for a comparative analysis of phenotypic and genetic alterations contributing to the progression of ras transformants. Variants were developed through in vitro and in vivo models of tumor progression. T24-H-ras and v-H-ras transformants were isolated in vitro through more rigorous growth conditions, focus formation in the presence of untransformed cells with no selecting drug. These clones expressed p21ras but exhibited little or no increase in NAb binding. Variants recovered following growth from intravenous or threshold subcutaneous (s.c.) inocula of high-NAb-binding ras transformants in syngeneic C3H/HeN mice exhibited decreases in NAb binding but no uniform change in p21ras. Concurring inverse correlations between NAb binding and s.c. tumorigenicity were exhibited by the T24-H-ras transformant clones, the ras transformants grown in vivo, and the v-H-ras-transformed clones isolated in the presence versus the absence of untransformed cells. This consistent inverse correlation, together with the reduced NAb binding of the ras transformants grown in vivo, provides strong evidence that NAb participates in the defense against ras-transformed cells in vivo. The lack of any direct correlation between p21ras expression and the reduction in NAb binding or the increase in tumorigenicity of cells generated through progression in vivo suggested the regulatory action of additional genes. Hybridization studies between high- and low-NAb-binding clones implicated the activation of an additional oncogene and inactivation of an antioncogene in the down-regulation of the ras-induced increases in NAb binding associated with tumor progression.
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PMID:p21ras independent down-regulation of ras-induced increases in natural antibody binding during tumor progression. 759 59

A conditional expression system was established whereby the human K-ras, v-src, and v-mos genes were cloned into a conditional expression vector downstream of the dexamethasone-inducible mouse mammary tumor virus long terminal repeat. Rat-1 fibroblasts were transfected with these constructs and selected in medium containing G418. Cloned transfectants were isolated and characterized for absolute dependence on dexamethasone for expression of oncogene products and anchorage-independent growth in soft agar. Expression of activated p21K-ras(val12) enabled the fibroblasts to degrade extracellular matrix collagen secreted by murine microvessel endothelial cells. Concurrent with p21K-ras(val12) induction a proteinase with the characteristic size and substrate specificity of transin, the murine homologue of the human matrix metalloproteinase stromelysin, was expressed and secreted. Induction of v-mos and v-src oncogenes resulted in little or no detectable transin expression respectively coinciding with a relative or absolute failure to increase degradation of extracellular matrix collagen. This study suggests that in this system the expression of the ras oncogene can contribute to the in vitro invasive behavior of tumor cells by upregulating the production of a metalloproteinase capable of degrading collagen synthesized by vascular endothelial cells.
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PMID:Degradation of endothelial cell matrix collagen is correlated with induction of stromelysin by an activated ras oncogene. 760 86

Infection of CMS5 tumor cells with retroviral constructs containing interleukin-2 (IL-2) cDNA and selection in medium supplemented with G418 resulted in the isolation of clones which secreted IL-2. Whereas injection of parental tumor cells resulted in progressive tumor growth, tumor cells secreting high levels of IL-2 were rejected. Furthermore, in animals vaccinated with IL-2-secreting cells, the immunosuppression associated with the inoculation of parental tumor cells did not develop, and these animals resisted a challenge with viable tumor cells. To better understand the functional differences in the anti-tumor responses of immune and tumor-bearing mice which are at the basis for these diverse responses, we used an in vitro model to analyze interactions between splenic lymphocytes and tumor cells. Spleen cells isolated from either tumor-bearing or immune mice proliferated vigorously when cultured alone for 6 days, but much less in the presence of parental tumor cells. This effect could not be transferred with supernatant from tumor cell lines. Spleen cells from tumor-bearing mice remained unresponsive, while those from immune mice proliferated well in response to IL-2-secreting tumor cells. Only spleen cells from immune animals were able to develop cytotoxicity against CMS5 cells following in vitro restimulation. These results are consistent with the interpretation that exposure to parental tumor cells inhibited cell-mediated anti-tumor responses by a mechanism that involved cell-to-cell contact.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Vaccination with IL-2-secreting tumor cells stimulates the generation of IL-2-responsive T cells and prevents the development of unresponsiveness. 762 Dec 37

Intercellular adhesion molecule-1 (ICAM-1) plays an essential role in lymphocyte adhesion to endothelium and migration across endothelial cell barriers. We undertook this study to determine the growth of a murine fibrosarcoma transfected with the ICAM-1 gene. MCA-105 tumor cells were cotransfected with ICAM-1 and the plasmid for neomycin resistance (NeoR). Selected G418-resistant clones were expanded and cell surface ICAM-1 expression was verified using a fluorescence-activated cell sorter. Integration of the ICAM-1 gene and ICAM-1 mRNA expression were verified by Southern and Northern blot hybridization analysis, respectively. C57BL/6 mice were divided into five groups (six animals/group): Control, NeoR only, ICAM-1 (low expressing, Clone 25), ICAM-1 (high expressing, Clone 81), and a 1:1 mixture of NeoR:Clone 81; animals received 1 x 10(6) cells on Day 0 and tumor measurements began on Day 7 and were measured in mm2. At 19 days, tumors from cell lines expressing ICAM-1 were significantly (P < .05) smaller than both the parental cell line and tumor-containing NeoR only (364 mm2 vs 466 mm2 and 527 mm2, respectively). This decrease in tumor growth may be a result of increased lymphocyte migration or increased anti-tumor cytotoxicity by infiltrating lymphocytes. The results from the mixed tumor experiment suggest a possible paracrine effect by cells expressing ICAM-1. Studies are currently under way to investigate the effect of immunotherapy on tumors derived from ICAM-1-cloned transfectants.
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PMID:Enhanced expression of ICAM-1 in a murine fibrosarcoma reduces tumor growth rate. 763 Jan 39

The retrovirus mouse mammary tumor virus (MMTV) 3' long terminal repeat (LTR) contains an open reading frame (ORF) for a 36-kDa protein and encodes a superantigen activity [pORF(sag)]. We have tested the potential oncogenic activity of pORF(sag) in two immortalized mouse mammary epithelial cells. We subcloned MMTV LTR ORF DNA into the pRc/CMV mammalian expression vector in order to place LTR ORF transcription under the control of the constitutive CMV promoter. Mouse mammary epithelial cell lines TM3 and FSK7e4 were transfected and G418-resistant cell clones were isolated. Reverse transcription-polymerase chain reaction and Northern blot analyses revealed modest overexpression of LTR RNA in several transfected cell clones of each line. Individual cell clones were transplanted into cleared mammary gland fat pads of syngeneic BALB/c mice. The parental cell lines and FSK7e4-derived clones did not form tumors, whereas ORF-transfected clones derived from the TM3 cells formed tumors within 8 weeks in 100% of transplanted fat pads in multiple experiments. The tumor cells expressed exogenous LTR ORF RNA and were proven to be derivatives of TM3 cells based on a marker p53 mutation. Immunohistochemistry using a polyclonal antiserum raised against pORF(sag) expressed in insect cells revealed a cytoplasmic reaction in TM3-CMV-LTR tumor cells; a much weaker cytoplasmic reaction was detected in the transfected tissue culture cells. These observations suggest that MMTV pORF(sag) may act as an oncogene in certain mouse mammary epithelial cells and raise the possibility that pORF(sag) may have a role in mammary tumorigenesis. As the parental FSK7 cell line has produced only ductal outgrowths upon transplantation in vivo and the TM3 cell line produces a nontumorigenic hyperplasia, the results suggest further that pORF(sag) may influence the latter stages of mammary tumorigenesis, namely, the preneoplastic to neoplastic transformation.
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PMID:Expression of the mouse mammary tumor virus long terminal repeat open reading frame promotes tumorigenic potential of hyperplastic mouse mammary epithelial cells. 764 39

raf oncogenes have been implicated in hepatic carcinogenesis. We studied the effects of the v-raf of murine retrovirus 3611-MSV on the growth and differentiation of a simian virus 40 (SV40)-immortalized rat liver cell line (ALB-8) which maintained many of characteristics of differentiated hepatocytes. Cells were co-transfected with v-raf and the neo gene followed by selection with G418 for transfectants. In culture, the expression of v-raf stimulated cell proliferation without altering cell morphology or expression of liver-specific genes: albumin, fibrinogen, alpha-1-antitrypsin and alpha-1-acid glycoprotein. The v-raf-transfected cells induced rapidly growing tumors in 100% of nude mice, while control DNA-transfected cells were only weakly tumorigenic, producing slowly growing tumors in 2/7 mice after a long latency. These slowly growing tumors were histologically moderately to well-differentiated hepatocellular carcinomas in which the liver-specific genes were highly expressed. In contrast, v-raf-induced tumors were histologically poorly differentiated and showed a dramatic decline in the expression of the liver-specific genes. In a tumor cell culture established from a v-raf-induced tumor, however, expression of the liver-specific genes was coordinately recovered. These observations indicate that v-raf is capable of inducing progression of SV40-immortalized hepatocytes into highly malignant cells and the progression is accompanied by loss, in vivo, of the hepatic differentiation.
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PMID:The v-raf oncogene enhances tumorigenicity and suppresses differentiation in vivo in a rat hepatocyte cell line. 768 80

Rat 2 cells stably transformed by murine v-fms (pB5 cells) were infected with retroviruses containing a human cDNA encoding either a full-length human T-cell protein tyrosine phosphatase (TC.PTP) or a truncated form (delta C11.PTP) in which an 11-kDa carboxy-terminal extension had been removed. This segment is responsible for enzyme localization and regulation. Clonal cell lines were isolated following G418 selection and their transforming properties analysed; pB5 cells containing the vector alone or TC.PTP remained transformed. These cells grew readily in soft agar, formed tumors in nude mice and were morphologically indistinguishable from the parental pB5 cells. In contrast, cells expressing delta C11.PTP showed dramatic changes in cell morphology, loss of anchorage-independent growth in soft agar and reduced or lack of tumor formation in nude mice. Both increases and decreases in tyrosine phosphorylation of specific proteins in the cells overexpressing the truncated enzyme were detected. These results indicate that coexpression of the deregulated, soluble tyrosine phosphatase with a constitutively active, oncogenic receptor tyrosine kinase leads to the suppression of the transformed phenotype.
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PMID:Suppression of v-fms-induced transformation by overexpression of a truncated T-cell protein tyrosine phosphatase. 768 29

The author examined the ability of human chromosomes derived from normal fibroblast cells to suppress the tumorigenicity of HHUA and Ishikawa cells, human endometrial carcinoma cell lines. Using DNA transfection, the human chromosome tagged with a selectable marker (the pSV2neo gene, which encodes resistance to the antibiotic, G418) was transferred to mouse A9 cells by cell hybridization and microcell fusion techniques. Thus, a library of mouse A9 clones containing individually a different human chromosome tagged with the pSV2neo plasmid DNA was constructed. Transfer by microcell fusion of either chromosome 1, 6, 9, 11 or 19 into the HHUA and Ishikawa cell lines was performed, and the abilities of the microcell hybrids to form tumors in nude mice were examined. The introduction of chromosome 19 had no effect on the tumorigenicity, whereas microcell hybrid clones with an introduced chromosome 1, 6 and 9 completely suppressed the tumorigenicity of the both lines. A decrease in tumor-take incidence in some but not all clones of HHUA cells was observed following the introduction of a chromosome 11. The nontumorigenic microcell hybrids with an introduced chromosome 1 differed from the nontumorigenic microcell hybrids with an introduced chromosome 6, 9, or 11. A large percentage of hybrids with chromosome 1 sensed and/or showed alterations in cellular morphology and transformed growth properties in vitro on the both cell lines. These results indicate that more than one chromosome carries a tumor suppressor gene(s) for human endometrial carcinoma cell lines, and indicate that normal human chromosome 1 carries gene(s) which suppresses the immortalization. This supports the hypothesis that multiple tumor suppressor gene(s) control the various tumorigenic phenotypes at the different step during process of neoplastic development.
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PMID:Suppression of tumorigenicity and induction of senescence on human endometrial carcinoma cell lines by transfer of normal human chromosomes. 770 53


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