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A Balmain

Publications and source records attributed to A Balmain.

At least 19 recordsLinked to original sources
PubMed2004

Forty years of cancer modelling in the mouse.

Mouse models of human cancer have played an important role in formulating modern concepts of multistage carcinogenesis, and are providing us with a new armoury of tools for the testing of novel therapeutic approaches to cancer treatment. The development of inducible and conditional technologies provide us with greater opportunity to generate mouse models which faithfully recapitulate human tumorigenesis, in terms of both the biology and the genetics of this disease. It is now feasible to control, in time and space, the development of tumours in almost any mouse tissue, such that we now have available mouse models of all major human cancers. Moreover, novel non-invasive approaches to tumour imaging will enable us to follow tumour development and metastasis in vivo, as well as the effects of candidate therapeutic drugs. Such new generation tumour models, which accurately emulate the disease state in situ, should provide a useful platform with which to experimentally test drugs targeted to specific gene products, or combinations of genes that control rate-limiting steps of tumour development.

Animals↗
PubMed2001

Epistatic interactions between skin tumor modifier loci in interspecific (spretus/musculus) backcross mice.

The development of cancer is influenced both by exposure to environmental carcinogens and by the host genetic background. Epistatic interactions between genes are important in determining phenotype in plant and animal systems and are likely to be major contributors to cancer susceptibility in humans. Several tumor modifier loci have been identified from studies of mouse models of human cancer, and genetic interactions between modifier loci have been detected by genome scanning using recombinant congenic strains of mice (R. Fijneman et al., Nat. Genet., 14: 465-467, 1996; T. van Wezel et al., Nat. Genet., 14: 468-470, 1996; W. N. Frankel et al., Nat. Genet., 14, 371-373, 1996). We demonstrate here that strong genetic interactions between skin tumor modifier loci can be detected by hierarchical whole genome scanning of a complete interspecific backcross [outbred Mus spretus X Mus musculus (NIH/Ola)]. A locus on chromosome 7 (Skts1) showed a highly significant interaction with Skts5 on chromosome 12 (P < 10(-16)), whereas additional significant interactions were detected between loci on chromosomes 4 and 5, and 16 and 15. Some of these quantitative trait loci and their interactions, in particular the Skts1-Skts5 interaction, were confirmed in two completely independent backcrosses using inbred spretus strains (SEG/Pas and SPRET/Ei) and NIH/Ola. These results, therefore, illustrate the general use of interspecific crosses between Mus musculus and Mus spretus for the detection of strong genetic interactions between tumor modifier genes.

Animals↗
PubMed2001

Role of matrix metalloproteinase-9 in progression of mouse skin carcinogenesis.

Invasion of malignant tumor cells is required for the formation of metastatic colonies. Uncontrolled expression of matrix metalloproteinase (MMP)-2 and MMP-9 is a critical part of the invasive potential of tumor cells and is affected by the balance between the enzymes and the inhibitors secreted by the cell. Here we analyzed the expression and activity of the two gelatinases (MMP-2 and MMP-9) as well as the expression levels of the tissue inhibitor of metalloproteinase (TIMP2)-, in different stages of carcinogenesis using mouse skin cell lines derived from tumors induced by chemical mutagens. Our results suggested that the expression of MMP-9 was implicated in the progression to spindle cell carcinomas in mouse keratinocytes. MMP-2 levels remained steady in all cell lines, whereas levels of TIMP-2 were increased in normal and spindle cells. The AP-1 DNA binding and transcriptional activity on the MMP-9 promoter were increased in the malignant cell lines, indicating the requirement of this binding site for its activation. The results of this study clearly suggested the important role of MMP-9, but not of MMP-2, in the metastatic properties of mouse keratinocytes.

Animals↗
PubMed2001

Building 'validated' mouse models of human cancer.

As a model system for the understanding of human cancer, the mouse has proved immensely valuable. Indeed, studies of mouse models have helped to define the nature of cancer as a genetic disease and demonstrated the causal role of genetic events found in tumors. As the scientific and medical community's understanding of human cancer becomes more sophisticated, however, limitations and potential weaknesses of existing models are revealed. How valid are these murine models for the understanding and treatment of human cancer? The answer, it appears, depends on the nature of the research requirement. Certain models are better suited for particular applications. Using novel molecular tools and genetic strategies, improved models have recently been described that accurately mimic many aspects of human cancer.

Animals↗
PubMed2001

Cancer genetics: from Boveri and Mendel to microarrays.

The human genome has now been sequenced, a century after the re-discovery of Mendel's Laws, and the publication of Theodor Boveri's chromosomal theory of heredity. Tracing the historical landmarks of cancer genetics from these early days to the present time not only gives us an appreciation of how far we have come, but also emphasizes the challenges that we face if we are to unravel the genetic basis of hereditary and sporadic cancers in the next century.

Animals↗
PubMed2001

TGF-beta signaling in tumor suppression and cancer progression.

Epithelial and hematopoietic cells have a high turnover and their progenitor cells divide continuously, making them prime targets for genetic and epigenetic changes that lead to cell transformation and tumorigenesis. The consequent changes in cell behavior and responsiveness result not only from genetic alterations such as activation of oncogenes or inactivation of tumor suppressor genes, but also from altered production of, or responsiveness to, stimulatory or inhibitory growth and differentiation factors. Among these, transforming growth factor beta (TGF-beta) and its signaling effectors act as key determinants of carcinoma cell behavior. The autocrine and paracrine effects of TGF-beta on tumor cells and the tumor micro-environment exert both positive and negative influences on cancer development. Accordingly, the TGF-beta signaling pathway has been considered as both a tumor suppressor pathway and a promoter of tumor progression and invasion. Here we evaluate the role of TGF-beta in tumor development and attempt to reconcile the positive and negative effects of TGF-beta in carcinogenesis.

Animals↗
PubMed2001

Replication and cytolysis of an E1B-attenuated adenovirus in drug-resistant ovarian tumour cells is associated with reduced apoptosis.

Therapeutic approaches which are effective in tumour cells resistant to conventional chemotherapy would be of value. An E1B 55 kDa-deleted adenovirus (ONYX-015) induces lysis in cells with mutant p53, although the specificity of these observations for different cell types is unclear. We have used a matched set of drug-resistant human ovarian tumour cell lines to examine the potential of ONYX-015 for preferential replication and lysis of drug-resistant ovarian tumour cells with documented alterations in p53 function. Marked preferential replication of ONYX-015 is observed after infection of mutant p53 transfectant and cisplatin-resistant derivatives, compared to the wild-type p53 expressing parental A2780 line. Infection causes increased cytopathic effects in vitro and inhibition of tumour growth in vivo of the drug-resistant derivatives, but not the parental line. In apparent contrast, increased apoptosis and reduced clonogenic survival is induced by ONYX-015 infection of the chemosensitive parental cell line. ONYX-015 induces increased pro-apoptotic BAX and reduced anti-apoptotic BCLX(L) in parental cells, but not in the resistant derivative A2780/cp70. We propose that induction of apoptosis is one factor which prevents ONYX-015 spread and cytolysis after infection of chemosensitive cells, while it is the failure to engage apoptosis in drug-resistant cells that allows preferential viral replication, spread and cytolysis.

Adenoviridae↗
PubMed2000

Allele-specific loss or imbalance of chromosomes 9, 15, and 16 in B-cell tumors from interspecific F1 hybrid mice carrying Emu-c-myc or N-myc transgenes.

Mice carrying an immunoglobulin enhancer (Emu-) linked c- or N-myc transgene develop fatal monoclonal or oligoclonal pre-B or B-cell lymphomas. This indicates that, beside the Emu-activated myc gene, additional genetic changes are required for tumor development. To trace these additional changes, we carried out a genome-wide search for loss of heterozygosity (LOH) and allelic imbalance (AI). This was done at 53 microsatellite markers in a panel of 34 lymphomas and four plasmacytomas from c- or N-myc transgene carrying (BALB/c x Mus spretus)F1 hybrids. An additional 43 lymphomas and three plasmacytomas from non-transgenic F1 mice were also investigated. Losses of one or more spretus-derived chromosome 9 markers were detected in 19 of 23 (83%) of the lymphomas, but in none of the four plasmacytomas that developed in N-myc F1 mice. No LOH-9 was found in any of the 11 lymphomas from Emu-c-myc F1 mice and only in 1 of 46 (2%) tumors derived from non-transgenic (BALB/c x spretus)F1 hybrid controls. These results suggest that a gene on spretus chromosome 9 confers resistance to the development of N-myc but not c-myc-induced lymphomas. AI of chromosome 15 markers (AI-15) was detected in 57 of 77 (74%) lymphomas and in 5 of 7 (72%) plasmacytomas, independently of the transgenic status and the mode of induction. All of the lymphomas and plasmacytomas with AI-15 revealed a relative gain of the spretus-derived D15Mit6 allele (located at 13.7 cM from the centromere), together with a gain of the BALB/c allele of the more distal (29.6 cM) D15Mit64 marker, suggesting somatic recombination. LOH in the region close to c-myc was detected in a proportion of tumors with AI-15. The observation of complex genetic alterations includes somatic recombination, AI and LOH involving chromosome 15 in tumors induced by a myc transgene. This indicates that at least two genes in addition to c-myc on this chromosome can be involved in lymphoma development.

Allelic Imbalance↗
PubMed2000

TGF-beta inhibits p70 S6 kinase via protein phosphatase 2A to induce G(1) arrest.

On TGF-beta binding, the TGF-beta receptor directly phosphorylates and activates the transcription factors Smad2/3, leading to G(1) arrest. Here, we present evidence for a second, parallel, TGF-beta-dependent pathway for cell cycle arrest, achieved via inhibition of p70(s6k). TGF-beta induces association of its receptor with protein phosphatase-2A (PP2A)-Balpha. Concomitantly, three PP2A-subunits, Balpha, Abeta, and Calpha, associate with p70(s6k), leading to its dephosphorylation and inactivation. Although either pathway is sufficient to induce G(1) arrest, abrogation of both, the inhibition of p70(s6k), and transcription through Smad proteins is required for release of epithelial cells from TGF-beta-induced G(1) arrest. TGF-beta thereby modulates the translational and posttranscriptional control of cell cycle progression.

Activin Receptors, Type I↗
PubMed2000

High levels of phosphorylated c-Jun, Fra-1, Fra-2 and ATF-2 proteins correlate with malignant phenotypes in the multistage mouse skin carcinogenesis model.

Analysis of the functions of AP-1 transcription factor in cellular systems has shown its key role as a mediator of oncogenic signals. The employment of suitable animal model systems greatly facilitates the study of changes in the composition and activity of the AP-1 complex. Here, we have analysed the quantitative and qualitative changes of AP-1 at different stages of carcinogenesis in mouse skin cell lines, derived from tumours induced by chemical mutagens. The findings of this study suggest that elevated AP-1 DNA binding and transactivation activity characterize the carcinoma cell lines, most notably the highly malignant spindle carcinomas. In addition, increased amounts and post-translational modifications of c-Jun, Fra-1, Fra-2 and ATF-2 proteins account for a high percentage of the increased AP-1 activity. Remarkably, high levels of phosphorylated ATF-2 protein were detected in malignant cell lines, indicating a novel role of ATF-2 in tumour progression. c-Jun and ATF-2 proteins are phosphorylated by highly active JNK kinases present in tumour cells. Finally, our results indicate distinct functions for different AP-1 components in the promotion and progression of mouse skin tumours. Oncogene (2000) 19, 4011 - 4021.

Activating Transcription Factor 2↗
PubMed2000

Integration of positive and negative growth signals during ras pathway activation in vivo.

Expression of RAS proteins can have either positive or negative effects on cell growth, differentiation and death. New technologies are being developed for the generation of animal models to address the questions of where, when and how much Ras is expressed during tumorigenesis, and how these disparate signals are integrated during multistage carcinogenesis.

Animals↗
PubMed2000

Targeting gene expression to tumor cells with loss of wild-type p53 function.

The tumor suppressor protein p53 is a transcription factor that can positively regulate the expression of critical target genes involved in negative control of cell growth or induction of apoptosis; p53 is also able to suppress the transcription of other genes by virtue of its ability to bind components of the basal transcription machinery. Over 50% of human tumors are characterized by p53 mutations that result in a loss of wild-type p53 (wtp53) function in the transcriptional control of these target genes. We have exploited this loss of p53 function in the regulation of gene transcription to develop a novel gene therapy strategy that maximizes expression of the potential therapeutic gene in tumors while simultaneously down-regulating the same gene in normal cells. In one construct (unit I), the potential therapeutic gene (in this case represented by a luciferase reporter) is placed under the control of a promoter such as the heat shock protein 70 gene promoter, which is repressed by wtp53 but overexpressed in many tumor cells with defective p53 function. Residual expression of the reporter in normal cells is repressed by cotransfection of another construct (unit II) consisting of a repressor of unit I under the control of a promoter that is activated by wtp53 expression. Unit II contains a promoter with a consensus wtp53 binding site driving a transcriptional repressor or an antisense construct for the gene in unit I. Our results suggest that this dual control approach may represent a strategy with wide applications in the field of cancer gene therapy.

Feasibility Studies↗
PubMed2000

Carcinogenesis in mouse and human cells: parallels and paradoxes.

It has been known since the last century that genetic changes are important in carcinogenesis [Boveri,T. (1914) Zur Frage der Erstehung Maligner Tumoren. Gustav Fischer, Jena]. Observations of tumor cells growing in tissue culture led to the prediction, even before the true nature of the genetic material was known, that alterations at the chromosomal level were critically involved in the process of neoplastic development. The past 20 years have seen the transition of carcinogenesis studies from the purely observational to the molecular genetic level. Although much more needs to be done, it is nevertheless gratifying to be able to piece together the sequence of events from carcinogen exposure, metabolism of the carcinogen to the activated form, formation of specific carcinogen-DNA adducts, misrepair leading to the fixation of mutations in particular target genes, and the resulting selective outgrowth of neoplastic cells. The nature of many of these steps has been clarified only in the relatively recent past, and only for a small number of specific target genes, but the fact that we can say with confidence that such processes occur and are causal changes in tumorigenesis represents a tremendous advance over the situation pertaining 20 years ago. The purpose of this review is to summarize the advances over this time period in our understanding of some of the genetic alterations that contribute to neoplasia, with particular emphasis on chemical carcinogenesis in rodents and the parallels with transformation of human cells.

Animals↗
PubMed2000

Productive replication of human adenoviruses in mouse epidermal cells.

In contrast to most cells of mouse origin, cell lines derived from mouse epidermis are permissive for replication of human adenovirus type 5. The extent of epidermal cell differentiation correlated with the level of E1A expression and virus replication. Mouse epidermal cells may provide useful models for cancer therapy using replication-competent human adenoviruses.

3T3 Cells↗
PubMed1999

A subset of skin tumor modifier loci determines survival time of tumor-bearing mice.

Studies of mouse models of human cancer have established the existence of multiple tumor modifiers that influence parameters of cancer susceptibility such as tumor multiplicity, tumor size, or the probability of malignant progression. We have carried out an analysis of skin tumor susceptibility in interspecific Mus musculus/Mus spretus hybrid mice and have identified another seven loci showing either significant (six loci) or suggestive (one locus) linkage to tumor susceptibility or resistance. A specific search was carried out for skin tumor modifier loci associated with time of survival after development of a malignant tumor. A combination of resistance alleles at three markers [D6Mit15 (Skts12), D7Mit12 (Skts2), and D17Mit7 (Skts10)], all of which are close to or the same as loci associated with carcinoma incidence and/or papilloma multiplicity, is significantly associated with increased survival of mice with carcinomas, whereas the reverse combination of susceptibility alleles is significantly linked to early mortality caused by rapid carcinoma growth (chi(2) = 25.22; P = 5.1 x 10(-8)). These data indicate that host genetic factors may be used to predict carcinoma growth rate and/or survival of individual backcross mice exposed to the same carcinogenic stimulus and suggest that mouse models may provide an approach to the identification of genetic modifiers of cancer survival in humans.

Animals↗
PubMed1999

Genetic events and the role of TGF beta in epithelial tumour progression.

The mouse skin model of chemical carcinogenesis has been very well characterized with respect to epigenetic changes, which occur during tumour cell initiation, promotion and progression. The use of transgenic and gene knock-out mice has contributed greatly to knowledge in this area. The H-ras genetic locus has been shown to undergo multiple genetic changes, including mutagenic activation, amplification of the mutant gene, and loss of the normal allele. These different genetic events lead to thresholds of ras activity which contribute to different stages along the pathway to neoplasia. The genetic and epigenetic events which lead to tumour invasion and metastasis have been less well characterized than studies on tumour initiation and promotion, despite the fact that it is metastases which ultimately kill the animal/patient. In the mouse skin model, loss of p53 contributes to malignant conversion. Gene deletion of the INK4 locus is associated with transformation to a highly invasive spindle cell tumor phenotype. This spindle cell transformation can also be induced in vitro or in vivo by TGF beta 1, possible by synergizing with mutant H-ras. TGF beta can have both positive and negative effects on tumourigenesis, acting early as a tumour suppresser, but later as a stimulator of tumour invasion. It is this latter effect which may be clinically more significant, since many human tumours overexpress TGF beta, yet the majority still retain the intracellular signaling systems necessary for the cell to respond to this growth factor.

Animals↗