Achievement of balanced oncogenes and tumor-suppressor genes activity in normal and malignant cells in vitro and in vivo

2011 ◽  
Vol 3 (9) ◽  
Author(s):  
Iskra Ventseslavova Sainova
Keyword(s):  
Tumor Suppressor ◽  
Tumor Suppressor Genes ◽  
Malignant Cells ◽  
Suppressor Genes

Progression of colorectal cancer is associated with multiple tumor suppressor gene defects but inhibition of tumorigenicity is accomplished by correction of any single defect via chromosome transfer

1992 ◽  
Vol 12 (3) ◽  
pp. 1387-1395
Author(s):  
M C Goyette ◽  
K Cho ◽  
C L Fasching ◽  
D B Levy ◽  
K W Kinzler ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Tumor Suppressor ◽  
Tumor Suppressor Genes ◽  
Loss Of Function ◽  
Chromosome 18 ◽  
Chromosome 5 ◽  
Suppressor Genes ◽  
Single Defect

Carcinogenesis is a multistage process that has been characterized both by the activation of cellular oncogenes and by the loss of function of tumor suppressor genes. Colorectal cancer has been associated with the activation of ras oncogenes and with the deletion of multiple chromosomal regions including chromosomes 5q, 17p, and 18q. Such chromosome loss is often suggestive of the deletion or loss of function of tumor suppressor genes. The candidate tumor suppressor genes from these regions are, respectively, MCC and/or APC, p53, and DCC. In order to further our understanding of the molecular and genetic mechanisms involved in tumor progression and, thereby, of normal cell growth, it is important to determine whether defects in one or more of these loci contribute functionally in the progression to malignancy in colorectal cancer and whether correction of any of these defects restores normal growth control in vitro and in vivo. To address this question, we have utilized the technique of microcell-mediated chromosome transfer to introduce normal human chromosomes 5, 17, and 18 individually into recipient colorectal cancer cells. Additionally, chromosome 15 was introduced into SW480 cells as an irrelevant control chromosome. While the introduction of chromosome 17 into the tumorigenic colorectal cell line SW480 yielded no viable clones, cell lines were established after the introduction of chromosomes 15, 5, and 18. Hybrids containing chromosome 18 are morphologically similar to the parental line, whereas those containing chromosome 5 are morphologically distinct from the parental cell line, being small, polygonal, and tightly packed. SW480-chromosome 5 hybrids are strongly suppressed for tumorigenicity, while SW480-chromosome 18 hybrids produce slowly growing tumors in some of the animals injected. Hybrids containing the introduced chromosome 18 but was significantly reduced in several of the tumor reconstitute cell lines. Introduction of chromosome 5 had little to no effect on responsiveness, whereas transfer ot chromosome 18 restored responsiveness to some degree. Our findings indicate that while multiple defects in tumor suppressor genes seem to be required for progression to the malignant state in colorectal cancer, correction of only a single defect can have significant effects in vivo and/or in vitro.

scholarly journals Progression of colorectal cancer is associated with multiple tumor suppressor gene defects but inhibition of tumorigenicity is accomplished by correction of any single defect via chromosome transfer.

1992 ◽  
Vol 12 (3) ◽  
pp. 1387-1395 ◽  
Author(s):  
M C Goyette ◽  
K Cho ◽  
C L Fasching ◽  
D B Levy ◽  
K W Kinzler ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Tumor Suppressor ◽  
Tumor Suppressor Genes ◽  
Loss Of Function ◽  
Chromosome 18 ◽  
Chromosome 5 ◽  
Suppressor Genes ◽  
Single Defect

Carcinogenesis is a multistage process that has been characterized both by the activation of cellular oncogenes and by the loss of function of tumor suppressor genes. Colorectal cancer has been associated with the activation of ras oncogenes and with the deletion of multiple chromosomal regions including chromosomes 5q, 17p, and 18q. Such chromosome loss is often suggestive of the deletion or loss of function of tumor suppressor genes. The candidate tumor suppressor genes from these regions are, respectively, MCC and/or APC, p53, and DCC. In order to further our understanding of the molecular and genetic mechanisms involved in tumor progression and, thereby, of normal cell growth, it is important to determine whether defects in one or more of these loci contribute functionally in the progression to malignancy in colorectal cancer and whether correction of any of these defects restores normal growth control in vitro and in vivo. To address this question, we have utilized the technique of microcell-mediated chromosome transfer to introduce normal human chromosomes 5, 17, and 18 individually into recipient colorectal cancer cells. Additionally, chromosome 15 was introduced into SW480 cells as an irrelevant control chromosome. While the introduction of chromosome 17 into the tumorigenic colorectal cell line SW480 yielded no viable clones, cell lines were established after the introduction of chromosomes 15, 5, and 18. Hybrids containing chromosome 18 are morphologically similar to the parental line, whereas those containing chromosome 5 are morphologically distinct from the parental cell line, being small, polygonal, and tightly packed. SW480-chromosome 5 hybrids are strongly suppressed for tumorigenicity, while SW480-chromosome 18 hybrids produce slowly growing tumors in some of the animals injected. Hybrids containing the introduced chromosome 18 but was significantly reduced in several of the tumor reconstitute cell lines. Introduction of chromosome 5 had little to no effect on responsiveness, whereas transfer ot chromosome 18 restored responsiveness to some degree. Our findings indicate that while multiple defects in tumor suppressor genes seem to be required for progression to the malignant state in colorectal cancer, correction of only a single defect can have significant effects in vivo and/or in vitro.

scholarly journals Genetic and Biochemical Evidence That Haploinsufficiency of the Nf1 Tumor Suppressor Gene Modulates Melanocyte and Mast Cell Fates in Vivo

2000 ◽  
Vol 191 (1) ◽  
pp. 181-188 ◽  
Author(s):  
David A. Ingram ◽  
Feng-Chun Yang ◽  
Jeffrey B. Travers ◽  
Mary Jo Wenning ◽  
Kelly Hiatt ◽  
...  
Keyword(s):  
Mast Cell ◽  
Mast Cells ◽  
Tumor Suppressor ◽  
Tumor Suppressor Genes ◽  
Biological Effects ◽  
Malignant Neoplasms ◽  
Protein Kinase Activity ◽  
Cell Fates ◽  
Suppressor Genes

Neurofibromatosis type 1 (NF1) is a common autosomal-dominant disorder characterized by cutaneous neurofibromas infiltrated with large numbers of mast cells, melanocyte hyperplasia, and a predisposition to develop malignant neoplasms. NF1 encodes a GTPase activating protein (GAP) for Ras. Consistent with Knudson's “two hit” model of tumor suppressor genes, leukemias and malignant solid tumors in NF1 patients frequently demonstrate somatic loss of the normal NF1 allele. However, the phenotypic and biochemical consequences of heterozygous inactivation of Nf1 are largely unknown. Recently neurofibromin, the protein encoded by NF1, was shown to negatively regulate Ras activity in Nf1−/− murine myeloid hematopoietic cells in vitro through the c-kit receptor tyrosine kinase (dominant white spotting, W). Since the W and Nf1 locus appear to function along a common developmental pathway, we generated mice with mutations at both loci to examine potential interactions in vivo. Here, we show that haploinsufficiency at Nf1 perturbs cell fates in mast cells in vivo, and partially rescues coat color and mast cell defects in W41 mice. Haploinsufficiency at Nf1 also increased mast cell proliferation, survival, and colony formation in response to Steel factor, the ligand for c-kit. Furthermore, haploinsufficiency was associated with enhanced Ras–mitogen-activated protein kinase activity, a major downstream effector of Ras, via wild-type and mutant (W41) c-kit receptors. These observations identify a novel interaction between c-kit and neurofibromin in vivo, and offer experimental evidence that haploinsufficiency of Nf1 alters both cellular and biochemical phenotypes in two cell lineages that are affected in individuals with NF1. Collectively, these data support the emerging concept that heterozygous inactivation of tumor suppressor genes may have profound biological effects in multiple cell types.

Antitumor Activity of Cda-2, An Extract from Unine, in a High-Risk Myelodysplastic Syndrome Cells in Vitro

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 5099-5099
Author(s):  
Lin Qiu ◽  
Xiao-dan Wang ◽  
Bing-hong Han ◽  
Zhao-min Zhan ◽  
Zhang Bo-long ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
High Risk ◽  
Tumor Suppressor ◽  
Myelodysplastic Syndrome ◽  
Tumor Suppressor Genes ◽  
Dna Methyltransferase ◽  
Dependent Manner ◽  
Suppressor Genes ◽  
Specific Pcr

Abstract DNA methyltransferase inhibitors (DNMTI), including 5-azacytidine and 5-aza-2′- deoxycytidine, are a new class of epigenetic drug, which exhibit higher response rates in myelodysplastic syndrome (MDS) patients. Cell differentiation agent (CDA-2) is a kind of urine extracts, which contains several DNMTIs. A phase IV clinical trials for MDS showed total response rate is 69.22%. In the present study, we investigated the mechanism of CDA-2 on MDS using high-risk MDS cell line namely MuTz-1. MTT assay results showed that CDA-2 significantly inhibit the cell growth at a dose and time-dependent manner. Flow cytometer anlyasis showed that this growth inhibition was remarkblely associated with cycle arrest in G1-phase, but not associated with apoptosis. In addition, CDA-2 increased the expression of CD11b/CD14, a pair markers representing cell differentiation. we found the spectrum of hypermethylated tumor suppressor genes (TIMP3, CDKN2B, CHFR, CD44, RASSF1, TP73, IGSF4, CDH13 and DAPK) in MuTz-1 cells by Methylation-Specific Multiplex ligation-dependent Probe amplification (MS-MLPA), but the hypermethylation of these genes were remarkable decreased, as well as the expressions of DNA methyltransferase genes DNMT1 and DNMT3B at mRNA and protein level were downregulated in the treatment for 3 days with CDA-2. Also, we used CDA-2 for treatment of three MDS patients, whose several tumor suppressor genes are hypermethylated. After tour weeks of treatment, all the hypermethylation genes were undetected, part of this result was verified by methylation specific PCR (MSP) and bisulphite sequencing. In conclusion, our results demonstrated that CDA-2 may be an effective agent targeting hepermethylated tumor suppressor genes on MDS.

scholarly journals Identification of new tumor suppressor genes based on in vivo functional inactivation of a candidate gene

FEBS Letters ◽  
1999 ◽  
Vol 451 (3) ◽  
pp. 289-294 ◽  
Author(s):  
Jingfeng Li ◽  
Alexei I Protopopov ◽  
Rinat Z Gizatullin ◽  
Csaba Kiss ◽  
Vladimir I Kashuba ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
Candidate Gene ◽  
Tumor Suppressor Genes ◽  
Suppressor Genes ◽  
Functional Inactivation

scholarly journals Functional Identification of Tumor-Suppressor Genes through an In Vivo RNA Interference Screen in a Mouse Lymphoma Model

Cancer Cell ◽  
2009 ◽  
Vol 16 (4) ◽  
pp. 324-335 ◽  
Author(s):  
Anka Bric ◽  
Cornelius Miething ◽  
Carl Uli Bialucha ◽  
Claudio Scuoppo ◽  
Lars Zender ◽  
...  
Keyword(s):  
Rna Interference ◽  
Tumor Suppressor ◽  
Tumor Suppressor Genes ◽  
Functional Identification ◽  
Suppressor Genes ◽  
Mouse Lymphoma

Identification of Putative New Tumor Suppressor Genes in Highly Purified CD34+ Bone Marrow Cells from Patients with Myelodysplastic Syndromes.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 204-204 ◽  
Author(s):  
Saskia Gueller ◽  
Martina Komor ◽  
Julian C. Desmond ◽  
Oliver G. Ottmann ◽  
Dieter Hoelzer ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
Myelodysplastic Syndromes ◽  
Tumor Suppressor Genes ◽  
Target Genes ◽  
Bone Marrow Cells ◽  
Damage Control ◽  
Metabolic Effects ◽  
Suppressor Genes ◽  
Cd34 Cells

Abstract Activation of transcription of DNA by demethylation and hyperacetylation is known to cause hematologic improvement in patients with myelodysplastic syndromes (MDS). In this study we discriminated genes not expressed in CD34+ cells from untreated patients with MDS but activated by in vitro demethylation (2-aza-5-deoxycytidine, Decitabine) and hyperacetylation (suberoylanilide hydroxamic acid, SAHA). Highly purified CD34+ cells from normal individuals (n=3) and patients with low (n=3) and high (n=3) risk MDS were cultured with SCF (50 ng/ml), IL-3 (10 ng/ml) and GM-CSF (10 ng/ml). The cells were treated with 5 μmol Decitabine on day 1 and supplemented with 2.5 μmol SAHA on day 4 of culture. On day 5, global gene expression in these cells was compared to untreated cells (HG-U133A, Affymetrix, Santa Clara, CA). We identified 50 genes which are not expressed in untreated MDS CD34+ cells but 3-fold induced in all MDS samples by Decitabine and SAHA. Thirty-one of these genes were found to be expressed in normal CD34+ cells underlining the importance of such genes for normal hematopoiesis. This set of genes includes two genes for growth arrest and DNA damage control, the inducible protein beta (GADD45B), a regulator of growth and apoptosis and neural cell adhesion molecule 1 (NCAM1) that plays an important role in cell migration. Furthermore, hematological and neurological expressed 1 (HN1) which was not expressed in MDS CD34+ cells is known to have an anti-proliferative effect on tumor cell lines. N-myc downstream regulated 3 (NDRG3) is up-regulated during normal cell differentiation and suppressed in several tumor cells. In normal CD34+ cells, after in vitro treatment with Decitabine and SAHA we have discriminated 52 genes to be 3-fold up-regulated compared to untreated cells. Thirty-eight of these genes (73 %) were not inducible by demethylation and hyperacetylation in MDS CD34+ cells. These genes include chemokine receptor 3 (CCR3), a receptor for a C-C type chemokine involved in signal transduction, integrin beta-7 (ITGB7) that plays a role in adhesive interactions of leukocytes, preferentially expressed antigen in melanoma (PRAME) which is frequently expressed in human solid cancers and acute leukemia and tumor necrosis factor receptor superfamily member 1B (TNFRSF1B) that recruits apoptotic suppressors and mediates most of the metabolic effects of TNF-alpha. The silencing of these genes is independent of methylation and acetylation state and might be due to other mechanisms. This study shows that in CD34+ cells from MDS patients several genes are suppressed by methylation and hypoacetylation but can be activated by treatment with Decitabine and SAHA. Some of these genes are present in normal untreated CD34+ cells which leads to the assumption that they might function as tumor suppressor genes. Low or absent expression of these genes may contribute to the clonal expansion of MDS CD34+ which can be overcome by treatment with Decitabine or SAHA. Furthermore, the knowledge about these target genes may enable a more specific evaluation of the mechanisms of action of demethylating/hyperacetylating agents.

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