Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C1326912 (tumorigenesis)
 57,481 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Murine gammaherpesvirus (MHV)-68-infected mice are well-known as models for Epstein-Barr virus (EBV)-related lymphoproliferative diseases. MHV-72 may be a relative of MHV-68, but any genetic comparison between the two (except for the M7 gene) has never been reported. The genetic compositions of MHV-72 and MHV-68 were compared and the pathology of MHV-72 infection studied in CB-17 severe combined immunodeficiency (scid/scid; SCID) and CB17 wild-type (CB17+/+) mice. The MHV-72 DNA sequence was almost identical to MHV-68 except for approximately 7000 bp corresponding to the MHV-68 M1-M3 genes. Twenty-seven of 30 MHV-72-infected SCID mice (90%) died from generalized infection with intranuclear viral inclusions for approximately 1 month, while MHV-72-infected CB17+/+ mice recovered from acute infection. Long observation and pathological study of 68 MHV-72-infected mice for up to 24 months revealed that the survival rate (29.4%) and survival time (21.3 months) of MHV-72-infected CB17+/+ mice were significantly lower (P = 0.0127) and shorter (P = 0.0065) than those of the controls (61.1% and 22.9 months), respectively. The malignancy development rate (60.3%) of the infected CB17+/+ mice was also significantly higher (P = 0.004) than those of the controls (22.2%). However, no MHV-72 DNA was detected in the tumors of infected mice. MHV-72 may have some tumor-promoting effects but the tumorigenesis in infected CB17+/+ mice is different from EBV-associated tumors.
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PMID:Analysis of genomic homology of murine gammaherpesvirus (MHV)-72 to MHV-68 and impact of MHV-72 on the survival and tumorigenesis in the MHV-72-infected CB17 scid/scid and CB17+/+ mice. 1614 31

Colorectal cancer arises after a series of mutational events in the colon epithelia and is often used as a model of the multistep progression of tumorigenesis. Mutations in Ki-Ras have been detected in some 50% of cases and are thought to occur at an early stage. Almost never do mutations arise in the loci of other Ras isoforms (Ha- and N-), leading to the assumption that Ki-Ras plays a unique role in tumorigenesis. In order to examine the distinctive function that Ki-Ras plays in cancer development in the colon, we introduced constitutively active mutant Ki- and Ha-Ras genes into an intermediate-stage colon adenoma cell line (Caco-2). We found that mutant active Ha-RasV12 was more efficient at transforming these colon epithelial cells as assessed by anchorage-independent growth, tumor formation in SCID mice and the development of mesenchymal morphology compared to transformation by Ki-RasV12. We conducted microarray analysis in an attempt to reveal the genes whose aberrant expression is a direct result of overexpression of either Ki-RasV12 or Ha-RasV12. We used Clontech's Atlas cancer cDNA (588 genes) and RZPD's Onco Set 1 (1,544 genes) arrays. We identified fewer genes that were commonly regulated than were differentially expressed between Ki- and Ha-RasV12 isoforms. Specifically, we found that Ki-RasV12 regulated genes involved in cytokine signaling, cell adhesion and colon development, whereas Ha-RasV12 mainly regulated genes involved in controlling cell morphology, correlating to an epithelial-mesenchymal transition only observed in these cells. Our results demonstrate how 2 Ras isoforms regulate disparate biologic processes, revealing a number of genes whose deregulated expression may influence colon carcinogenesis (supplementary material for this article can be found on the International Journal of Cancer website at http://www.interscience.wiley.com/jpages/0020-7136/suppmat/index.html).
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PMID:Microarray analysis of the differential transformation mediated by Kirsten and Harvey Ras oncogenes in a human colorectal adenocarcinoma cell line. 1615 23

Loss of imprinting (LOI), commonly observed in human tumors, refers to loss of monoallelic gene regulation normally conferred by parent-of-origin-specific DNA methylation. To test the function of LOI in tumorigenesis, we developed a model by using transient demethylation to generate imprint-free mouse embryonic stem cells (IF-ES cells). Embryonic fibroblasts derived from IF-ES cells (IF-MEFs) display TGFbeta resistance and reduced p19 and p53 expression and form tumors in SCID mice. IF-MEFs exhibit spontaneous immortalization and cooperate with H-Ras in cellular transformation. Chimeric animals derived from IF-ES cells develop multiple tumors arising from the injected IF-ES cells within 12 months. These data demonstrate that LOI alone can predispose cells to tumorigenesis and identify a pathway through which immortality conferred by LOI lowers the threshold for transformation.
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PMID:Global loss of imprinting leads to widespread tumorigenesis in adult mice. 1622 3

In vitro human prostate cell culture models are critical for clarifying the mechanism of prostate cancer progression and for testing preventive and therapeutic agents. Cell lines ideal for the study of human primary prostate tumors would be those derived from spontaneously immortalized tumor cells; unfortunately, explanted primary prostate cells survive only short-term in culture, and rarely immortalize spontaneously. Therefore, we recently have generated five immortal human prostate epithelial cell cultures derived from both the benign and malignant tissues of prostate cancer patients with telomerase, a gene that prevents cellular senescence. Examination of these cell lines for their morphologies and proliferative capacities, their abilities to grow in low serum, to respond to androgen stimulation, to grow above the agar layer, to form tumors in SCID mice, suggests that they may serve as valid, useful tools for the elucidation of early events in prostate tumorigenesis. Furthermore, the chromosome alterations observed in these immortalized cell lines expressing aspects of the malignant phenotypes imply that these cell lines accurately recapitulate the genetic composition of primary tumors. These novel in vitro models may offer unique models for the study of prostate carcinogenesis and also provide the means for testing both chemopreventive and chemotherapeutic agents.
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PMID:Phenotypic characterization of telomerase-immortalized primary non-malignant and malignant tumor-derived human prostate epithelial cell lines. 1641 16

Activating BRAF or NRAS mutations have been found in 80% of human sporadic melanomas, but only one of these genetic alterations could be detected in each tumour. This suggests that BRAF and NRAS 'double mutants' may not provide advantage for tumour growth, or may even be selected against during tumorigenesis. However, by applying mutant-allele-specific-amplification-PCR method to short-term melanoma lines, one out of 14 tumours was found to harbour both BRAFV600E and the activating NRASQ61R mutations. On the other hand, analysis of 21 melanoma clones isolated by growth in soft agar from this tumour indicated that 16/21 clones harboured a BRAFV600E, but were wild-type for NRAS, whereas the remaining had the opposite genotype (NRASQ61R/wild-type BRAF). When compared to BRAFV600E clones, NRASQ61R clones displayed reduced growth in soft agar, but higher proliferative ability in vitro in liquid medium and even in vivo after grafting into SCID/SCID mice. These data suggest that NRAS and BRAF activating mutations can coexist in the same melanoma, but are mutually exclusive at the single-cell level. Moreover, the presence of NRASQ61R or BRAFV600E is associated with distinct in vitro and in vivo growth properties of neoplastic cells.
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PMID:Mutually exclusive NRASQ61R and BRAFV600E mutations at the single-cell level in the same human melanoma. 1646 68

The microenvironment plays a critical role in facilitating cancer progression and metastasis. We previously demonstrated the ability of osteoclasts to support primary myeloma plasma cell (MM PC) growth. Our study on the role of the bone marrow (BM) microenvironment in myeloma, using global gene expression profiling, has identified fibroblast activation protein (FAP) as one of 28 genes significantly overexpressed in cocultured osteoclasts. Because FAP has been previously implicated in tumorigenesis and shown to be selectively expressed by the reactive stroma of epithelial tumours, we focused our study on the role of this serine protease in myeloma. Using quantitative polymerase chain reaction amplification, we demonstrated upregulation of FAP by cocultured osteoclasts and mesenchymal stem cells, and in whole myelomatous human bone in SCID-hu mice. Immunohistochemical analysis of myelomatous bone sections revealed FAP expression by osteoclasts, osteogenic cells, fibrotic stroma and certain adipocytes and vascular endothelial cells. FAP was not expressed in PCs by all these methods. Inhibition of FAP expression with the use of small-interference RNA reduced MM PC survival in cocultures. Our results indicate that FAP is critical for the interaction of MM cells with the BM microenvironment--a potential therapeutic target in myeloma.
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PMID:Fibroblast activation protein (FAP) is upregulated in myelomatous bone and supports myeloma cell survival. 1651 33

Probiotic bacteria are microorganisms that benefit the host through improvement of the balance of intestinal microflora and possibly by augmentation of host defense systems. We examined the mechanisms for the up-regulation of innate immune responses by a probiotic Lactobacillus casei ATCC27139, in vivo. Using mouse models of systemic Listeria monocytogenes infection and MethA fibrosarcoma tumorigenesis in combination with BALB/c and SCID mice, we found that parenteral administration of L. casei ATCC27139 confers a protective effect against L. monocytogenes infection and anti-tumor activity against MethA fibrosarcoma by activation of innate immunity, while L. casei ATCC27139-J1R strains, which are J1 phage-resistant strains that have been selected from MNNG-treated clones, lacked these activities. Substantial differences between ATCC27139 and ATCC27139-J1R strains were observed in the capacity to induce innate cytokines such as TNF-alpha, IL-12, IL-18, and IFN-gamma, and pathogen-associated molecular pattern receptors, TLR2 and Nod2, by spleen cells. In addition, although phosphorylation of NF-kappaB p65 in spleen was equally enhanced in the ATCC27139- and the ATCC27139-J1R-treated groups, phosphorylation of both p38 MAPK and MAPKAPK-2 was significantly induced only by ATCC27139. Furthermore, inhibitors of NF-kappaB (sulfasalazine) and p38 MAPK (SB203580) significantly reduced cytokine production by the spleen cells of the mice treated with L. casei ATCC27139, suggesting that both NF-kappaB and p38 MAPK signaling pathways play important roles in the augmentation of innate immunity by the probiotic L. casei.
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PMID:Probiotic Lactobacillus casei activates innate immunity via NF-kappaB and p38 MAP kinase signaling pathways. 1651 92

We have used a keratinocyte in vivo/in vitro cell model to test the hypothesis that hydrogen peroxide acts as a signaling molecule, contributing to proliferation and tumorigenesis. A cell line, 6M90, that produces squamous cell carcinoma (SCC), has high levels of ROS and low levels of catalase. A new cell line, MTOC2, generated from parental 6M90 cells by introduction of a Tet-responsive catalase transgene, effectively expressed higher peroxisomal catalase. Increased catalase expression diminished constitutive ROS and enhanced viability after treatment with hydrogen peroxide. Protein tyrosine phosphatase activity was higher in the MTOC2 cells with high catalase, consistent with detection of a lower level of phosphorylation at tyrosine 1068 of the epidermal growth factor receptor (EGF-R). Transcription of downstream c-fos, AP-1 transactivation and cell proliferation were higher in the low catalase cells. An EGF-R inhibitor, AG1478, blocks the higher AP-1 transactivation and cell proliferation of the low catalase 6M90 cells. Tumorigenesis in SCID mice was greatly diminished in the high catalase cells. Our data suggest that hydrogen peroxide functions as a signaling molecule that can modulate activity of a protein tyrosine phosphatase/(s) resulting in phosphorylation of tryrosine/(s) on the EGF-R. Therefore, catalase acts as a tumor-suppressor gene in part by decreasing EGF-R signaling.
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PMID:Catalase reverses tumorigenicity in a malignant cell line by an epidermal growth factor receptor pathway. 1652 Feb 38

Decay-accelerating factor (CD55) is a member of membrane-bound complement-regulatory proteins. CD55 expression correlates with poor survival in patients with colorectal cancer and has been implicated in the survival and tumorigenesis of blood-borne malignancies. Histologic analysis of clinical specimens from patients with advanced prostate cancer revealed an increase in CD55 expression in prostate tumor epithelial cells. CD55 was shown to be functionally active and to inhibit complement-mediated lysis in PC-3 and DU145 cells. The percentage of lysis was correlative with the CD55 expression profile observed in these prostate cancer cell lines. These data suggest that CD55 is an important regulator of prostate cancer cell survival. As a result, we have hypothesized that CD55 expression on prostate cancer cells promotes cell survival and contributes to the metastatic potential of prostate cancer cells. To determine the role of CD55 in prostate cancer tumorigenesis and metastasis, we generated PC-3(Luc) prostate cancer cells with CD55 siRNA-targeted disruption. We found that PC-3(Luc)/CD55 siRNA constructs in SCID mice resulted in a significant attenuation of overall tumor burden. Further investigation into the mechanisms of CD55-mediated tumor cell/microenvironment interaction is necessary to understand the role of CD55 in tumor cell survival and metastatic lesion formation.
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PMID:Inhibition of decay-accelerating factor (CD55) attenuates prostate cancer growth and survival in vivo. 1653 28

Aims-(1) To study the frequency of putative malignancy associated point mutations and a 30 base pair (bp) deletion in exon 3 of the C-terminus of the Epstein-Barr virus (EBV) encoded latent membrane protein (LMP)-1 (BNLF-1) gene in wild type EBV strains. (2) To assess the influence of these mutations on the tumorigenicity of lymphoblastoid cell lines (LCL).Methods-Eight spontaneous EBV (wild type) infected LCL were established from seven subjects. Deletions and single base mutations in the C-terminus of the BNLF-1 gene were demonstrated using bi-directional solid phase dideoxy sequencing following PCR amplification of viral DNA from the LCL. Tumorigenicity of the LCL was assessed in SCID and nude mice. Serum dependent growth and ability to form colonies in soft agarose were assessed for representative LCL.Results-All LCL showed sequence differences compared with the prototypic EBV strain B95-8. The 30 bp deletion could be detected in three of eight LCL and a 69 bp deletion (including the 30 bp deletion) was identified in an additional LCL. A range of single base mutations (including those described previously in association with EBV related neoplasias) was also seen in some of the LCL. In transformation studies, the genetic variations did not seem to influence the in vitro behaviour of the LCL. In the tumorigenicity studies, the presence of the 30 bp deletion had no influence on the behaviour of the LCL which were, as expected, tumorigenic in SCID mice but not in nude mice. In contrast, the LCL carrying the 69 bp deletion was tumorigenic in both SCID and nude mice.Conclusions-Genetic changes described previously in the C-terminus of the LMP-1 gene in various malignancy derived EBV strains are also present frequently in wild type viruses and do not simply define tumour specific EBV strains. Changes within this region may, however, still be important for the tumorigenicity of LMP-1 and thus play a role in EBV oncogenesis.
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PMID:Mutations in the Epstein-Barr virus latent membrane protein-1 (BNLF-1) gene in spontaneous lymphoblastoid cell lines: effect on in vitro transformation associated parameters and tumorigenicity in SCID and nude mice. 1669 91


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