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A Balmain

Publications and source records attributed to A Balmain.

At least 37 records · Page 2Linked to original sources
PubMed1998

Epithelial carcinogenesis in the mouse: correlating the genetics and the biology.

Tumour formation relies on a complex combination of genetic and environmental factors. In particular, the contributions from inherited predisposition genes as well as carcinogens, for example from cigarettes or in the diet, are amongst the major contributors to tumorigenesis. Since the study of such processes in particularly difficult in human cancers, the availability of a well-defined model system is of obvious benefit. The mouse skin model of multistage carcinogenesis offers an excellent tool for the study of the target cells, the target genes and the biological events associated with neoplasia. In this system, tumorigenesis occurs in a series of defined stages, each of which is characterized by specific and reproducible alterations in genes such as H-ras, cyclin D1, p53 and p16INK4A. Additional changes occur in the production of, or response to, factors such as transforming growth factor beta (TGF beta). These genetic and biological alterations are mirrored in human tumours of epithelial origin. Hence, research into the general principles of tumour initiation, promotion and progression in the context of the mouse skin model is likely to prove valuable in the continual search for new methods for the diagnosis, prevention, and therapeutic treatment of human cancers.

Animals↗
PubMed1998

The malignant capacity of skin tumours induced by expression of a mutant H-ras transgene depends on the cell type targeted.

BACKGROUND: . Pinpointing the cells from which tumours arise is a major challenge n tumour biology. Previous work has shown that the targeted expression of a mutant ras gene within the interfollicular cell compartment of mouse skin induces the formation of benign papillomas, but these do not spontaneously progress to malignancy. We have investigated the carcinogenic effects of expressing the same oncogene in a different population of epidermal cells. RESULTS: Expression of mutant ras from a truncated keratin 5 gene promoter, which directs expression to the follicular and interfollicular cells of newborn mice and the hair follicle cells of adults, stimulated the development of acanthotic areas in newborn mice. Within one week of birth, the acanthotic skin developed areas of carcinoma in situ and adult mice developed papillomas and keratoacanthomas, the latter having a high frequency of spontaneous malignant transformation to squamous and occasionally spindle carcinomas. The benign tumours that arose had several hallmarks of tumours at a high risk of malignant progression, including suprabasal cell proliferation and heterogeneous expression of keratin 13. In contrast to tumours induced by expressing mutant ras under the control of the keratin 10 or keratin 1 gene promoters, the formation of these lesions was not dependent on wounding or a tumour promoter. CONCLUSIONS: Benign tumours that are at a risk of malignant conversion are primarily derived from cells located within the hair follicle, and the nature of the cell in which tumour initiation occurs is a major determinant of malignant potential.

Animals↗
PubMed1998

Cancer resistance genes in mice: models for the study of tumour modifiers.

Smokers have frequently been heard to defend their habit by recounting anecdotes about relatives or friends who have smoked heavily for many years without developing cancer. While individuals who have survived many years of repeated mutagen exposure are probably very rare, their existence suggests that some people are intrinsically resistant to the effects of carcinogens, probably because of their genetic background. This interpretation is supported by studies on mouse strains that are highly resistant to the development of tumours induced by treatment with exogenous carcinogens. In this review we discuss the advantages of the mouse as a model system for the isolation of cancer-resistance genes that have potentially important uses in diagnostics, prevention and tumour therapy.

Animals↗
PubMed1998

Stochastic modelling of tumorigenesis in p53 deficient mice.

Stochastic models of tumorigenesis have been developed to investigate the implications of experimental data on tumour induction in wild-type and p53-deficient mice for tumorigenesis mechanisms. Conventional multistage models in which inactivation of each p53 allele represents a distinct stage predict excessively large numbers of tumours in p53-deficient genotypes, allowing this category of model to be rejected. Multistage multipath models, in which a p53-mediated pathway co-exists with one or more p53-independent pathways, are consistent with the data, although these models require unknown pathways and do not enable age-specific curves of tumour appearance to be computed. An alternative model that fits the data is the 'multigate' model in which tumorigenesis results from a small number of gate-pass (enabling) events independently of p53 status. The role of p53 inactivation is as a rate modifier that accelerates the gate-pass events. This model implies that wild-type p53 acts as a 'caretaker' to maintain genetic uniformity in cell populations, and that p53 inactivation increases the probability of occurrence of a viable cellular mutant by a factor of about ten. The multigate model predicts a relationship between the time pattern of tumour occurrence and tumour genotype that should be experimentally testable. Stochastic modelling may help to distinguish 'gatekeeper' and 'caretaker' genes in other tumorigenic pathays.

Animals↗
PubMed1998

Transforming growth factor beta is essential for spindle cell conversion of mouse skin carcinoma in vivo: implications for tumor invasion.

Transforming growth factor beta1 (TGF-beta1) regulates both cell growth and cellular plasticity and is therefore important in the molecular control of both the developmental and neoplastic processes. It has been suggested that TGF-beta1 may be a positive or negative regulator of tumorigenesis. Stimulation of tumorigenesis could be due to its action as an immunosuppressor or as an inducer of angiogenesis, or by its direct action on the cell in promoting cellular plasticity. In the current study, we provide evidence that TGF-beta1 can act directly on keratinocytes in vivo to induce the reversible epithelial-mesenchymal conversion of a malignant metastatic keratinocyte cell line. Two squamous clones from the cell line were shown to undergo a reversible conversion to a fibroblastoid phenotype after culture in 1 ng/ml TGF-beta1. The morphological conversion became apparent at 24 h post-TGF-beta treatment and was complete after another 24 h. The conversion was characterized by a rapid delocalization of E-cadherin within 6-12 h posttreatment, followed by down-regulation of E-cadherin levels by 72 h. These squamous clones spontaneously converted to a fibroblastoid phenotype after s.c. injection in nude mice. Importantly, four of four clones that had been stably transfected with a dominant negative TGF-beta type II receptor were unable to undergo this mesenchymal switch in vivo, despite the fact that all clones stably transfected with neomyocin resistance alone retained their spindle characteristics in vivo. This demonstrates that the epithelial-mesenchymal conversion event is mediated directly via the TGF-beta signaling pathway of the tumor cell per se, and that it is sufficient to significantly enhance tumorigenicity and the malignant and invasive characteristics of the tumor in vivo.

Animals↗
PubMed1997

Chromosomal and genetic alterations of 7,12-dimethylbenz[a]anthracene-induced melanoma from TP-ras transgenic mice.

The TP-ras transgenic mouse line expresses an activated human T24 Ha-ras gene with a mutation in codon 12, regulated by a mouse tyrosinase promoter. The transgene is expressed in melanocytes of the skin, eyes, and brain. The mice develop cutaneous melanoma when treated with 7,12-dimethylbenz[a]anthracene. Cell lines have been generated from the cutaneous tumors and metastatic lesions. By using fluorescence in situ hybridization with mouse whole chromosome paints, the cell lines were characterized for chromosomal abnormalities. Key findings in the tumor cells included translocations of chromosome 4 and alterations in chromosome 6. One tumor cell line contained a double translocation involving chromosomes 3 and 6. To extend the results of the chromosome 4 painting, Southern analysis of the p15INK4B, p16INK4A, and p19INK4D genes was performed. Our data indicated that there were homozygous and partial allelic deletions and polymorphisms in the region of chromosome 4 containing these genes, resulting in the absence or reduced expression of the p16 product. These findings are similar to those reported for human melanoma, and the TP-ras transgenic mouse may therefore be a valuable model for studying novel strategies for melanoma prevention and treatment.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1997

Changes in gap junctional intercellular communication in mouse skin carcinogenesis.

Gap junction intercellular communication (GJIC) has been measured in cell lines that represent different stages of chemically induced mouse skin carcinogenesis. No significant difference in GJIC, as measured by dye spread, was found in cultures of normal keratinocyte, papilloma or squamous carcinoma cell lines. There was no correlation, in this system, between the presence of a mutant Ha-ras gene and down-regulation of communication. There was, however, a marked decrease in GJIC (80-90%) on progression from squamous to spindle carcinoma cells. Measurement of GJIC in somatic cell hybrids shows that the genetic defect responsible for this down-regulation is recessive and is common to two independently isolated spindle cell lines. No abnormalities were found in the spindle cells in expression of connexin 43, a cell component involved in gap junction formation and permeability. However, expression of E-cadherin, a cell-cell adhesion molecule implicated in the process of gap junction formation, was missing in the spindle carcinoma cells. Introduction of an E-cadherin cDNA into the spindle cells partially restored junctional communication without causing any noticeable alterations in cell morphology. During the study a non-tumourigenic keratinocyte line, a sub-clone of a normal keratinocyte line, was also found to have a low level of GJIC. However, the defect in this line was shown, by genetic complementation in somatic cell hybrids, to be different from that in the spindle carcinoma cell lines. Consistent with these data, analysis by immunofluorescence shows an abnormal distribution of connexin 43 in these cells.

Animals↗
PubMed1996

The p53 response to ionising radiation in adult and developing murine tissues.

The induction of the p53 response to ionising radiation has been studied during murine development and in the adult animal. The response has been assessed by precise quantitative assay of p53 protein levels in tissues and by immunohistochemistry. Newly developed transgenic mice in which a lacZ transgene is driven by a p53 response element have also been used to directly assess the transcriptional activity of the induced protein. There is striking developmental control of the p53 response so that in early development all tissues accumulate high levels of p53 following radiation and indeed p53 is present at elevated levels in some unirradiated tissues. Later in development clear heterogeneity of the p53 response becomes apparent, both in terms of the responses of individual tissues and of cell populations, within those tissues. The study of lacZ transgene expression and the occurrence of apoptosis in different tissues that accumulate p53 protein point to a further level of control regulating the nature and degree of the downstream response to elevated levels of p53 in cells. These findings have important implications for the susceptibility of different tissue types to carcinogenic and other insults. The early expression of the p53 response is consistent with novel models of p53 function that suggest it may have evolved principally as a defense against teratogenic insult that permits plasticity of development.

Age Factors↗
PubMed1996

TGFbeta1 inhibits the formation of benign skin tumors, but enhances progression to invasive spindle carcinomas in transgenic mice.

TGFbeta1 has been implicated in cell cycle control and carcinogenesis. To address the exact function of TGFbeta1 in skin carcinogenesis in vivo, mice with TGFbeta1 expression targeted to keratinocytes were subjected to long-term chemical carcinogenesis treatment. TGFbeta1 showed biphasic action during multistage skin carcinogenesis, acting early as a tumor suppressor but later enhancing the malignant phenotype. The transgenics were more resistant to induction of benign skin tumors than controls, but the malignant conversion rate was vastly increased. There was also a higher incidence of spindle cell carcinomas, which expressed high levels of endogenous TGFbeta3, suggesting that TGFbeta1 elicits an epithelial-mesenchymal transition in vivo and that TGFbeta3 might be involved in maintenance of the spindle cell phenotype. The action of TGFbeta1 in enhancing malignant progression may mimic its proposed function in modulating epithelial cell plasticity during embryonic development.

Animals↗
PubMed1996

Expression pattern of the cell adhesion molecules. E-cadherin, P-cadherin and alpha 6 beta 4 intergrin is altered in pre-malignant skin tumors of p53-deficient mice.

Expression of the cell adhesion molecules E-cadherin, P-cadherin and alpha 6 beta 4 integrin and of the keratin K13 has been analyzed in chemically induced benign skin papillomas with genetically pre-determined risks for malignant conversion. It has been previously shown that papillomas induced in mice lacking both alleles of the p53 gene have a much higher rate of malignant conversion than those induced in wild-type and heterozygous p53 mice. Alterations in the expression pattern of the E-cadherin molecule, including focal loss at cell-cell contacts and heterogeneous distribution in the differentiated layers, were found in about 70% of the p53 null papillomas. In contrast, all of the wild-type and over 85% of the heterozygous p53 papillomas exhibited an expression pattern of E-cadherin indistinguishable from that of normal epidermis. Alterations in P-cadherin expression were also detected in the p53 null papillomas: aberrant suprabasal localization and heterogeneous distribution were observed more frequently than in heterozygous and wild-type p53 papillomas. The alpha 6 beta 4 integrin showed suprabasal expression in more than 70% of the papillomas derived from either wild-type, heterozygous or homozygous p53 null mice. Surprisingly, the extent of the suprabasal localization of alpha 6 beta 4 decreased in the p53 null papillomas. Aberrant keratin K13 expression was also detected in the majority of cases of all p53 genotypes, but again there was a clear decrease in expression levels in the p53 null papillomas. These alterations were also associated with keratinocytic atypia, which increased significantly in the p53 null papillomas. Changes in these parameters were particularly evident during malignant conversion in invasive regions of one progressing p53 null papilloma. Our results indicate the existence of dynamic changes in the expression pattern of the 3 cell adhesion molecules analyzed and identify down-regulation of E-cadherin as an early step in malignant conversion.

Animals↗
PubMed1996

Multigenic control of skin tumour development in mice.

Different inbred mouse strains vary greatly in their susceptibility to tumour development in a variety of tissues. Intraspecific and interspecific crosses can, therefore, be used to map the loci that control this predisposition. Crosses of Mus musculus with Mus spretus are highly resistant to tumour development in the skin, liver, lung and lymphoid system. M. spretus, therefore, has dominantly acting resistance loci, which we have attempted to map. More than 350 interspecific backcross mice were followed for 18 months to assess susceptibility to development of chemically induced papillomas and carcinomas. The results were analysed using a combination of MAPMAKER/QTL analysis and multiple regression analysis for the determination of linkage in multigenic quantitative traits. The results showed clearly that at least three genes on chromosomes 5 and 7 control resistance to tumour development. Importantly, some genes confer resistance to benign tumours but they have relatively little effect on malignant progression. This suggests the existence of different classes of benign tumours: those that are capable of tumour progression and those that have only a very low probability of becoming malignant. Identification of these genes will improve our understanding of mechanisms of carcinogenesis and may provide a novel route to the identification of "low-penetrance' human tumour susceptibility genes.

Animals↗
PubMed1996

Altered epidermal cell growth control in vivo by inducible expression of transforming growth factor beta 1 in the skin of transgenic mice.

An inducible bovine KIV* keratin gene promoter was used to target expression of latent or activated transforming growth factor beta 1 (TGF beta 1) to keratinocytes in transgenic mice. This short (2.2-kb) keratin 6 (K6) promoter element was generally silent in untreated animals but was induced in keratinocytes when placed in culture or, in vivo, in response to hyperplasia that follows topical application of the tumor promoter, 12-O-tetradecanoylphorbol-13-acetate. All of the K6-TGF beta 1 transgenic lines studied showed attenuation of the basal keratinocyte proliferative response to 12-O-tetradecanoylphorbol-13-acetate as a consequence of inducible TGF beta 1 gene expression. One of the six lines studied showed constitutive transgene expression at low levels in the skin, and this line had a 2- to 3-fold increase in epidermal DNA labeling index over control mice. Although in vitro TGF beta 1 is known to be a potent negative regulator of epithelial cell proliferation, in vivo TGF beta 1 has complex biological activities and can act as either a positive or negative regulator of keratinocyte proliferation.

Animals↗
PubMed1995

Deletion and altered regulation of p16INK4a and p15INK4b in undifferentiated mouse skin tumors.

p16INK4a and p15INK4b are cell cycle regulators that specifically bind to and inhibit the cyclin D-dependent kinases, cdk4 and cdk6. Because these genes undergo frequent deletions and/or mutations in various human cancers, we examined the status and expression of the cognate mouse cdk inhibitors in a panel of 29 cell lines, as well as in 12 primary tumors, representing different stages of mouse skin carcinogenesis. Deletion of p16INK4a and/or p15INK4b was seen in 8 of 10 cell lines derived from spindle carcinomas, the most advanced stage of skin carcinogenesis. Five showed deletion of both genes, and three had independent deletions of p16INK4a or p15INK4b, but in those retaining p16INK4a, expression of the protein was not detected. By contrast, none of 19 more differentiated squamous cell lines exhibited such deletions. In several cases, primary tumor DNA was available, and two spindle tumors showed the same deletion pattern as observed in the corresponding cell lines. In apparent contrast, comparison of two clonally related squamous and spindle cell lines derived from a single carcinoma showed unusually high levels of p16INK4a and p15INK4b only in the invasive spindle cells. Therefore, deletion or altered regulation of p16INK4a and p15INK4b occur concomitantly with the loss of differentiation associated with the late spindle stage of tumor progression in mouse skin.

Animals↗
PubMed1995

Cancer. Exploring the bowels of DNA methylation.

Recent studies of mice lacking methyltransferase, and of genes that modify cancer susceptibility, have shed light on the long-standing problem of how DNA methylation affects carcinogenesis.

Animals↗
PubMed1995

Spontaneous and ionizing radiation-induced chromosomal abnormalities in p53-deficient mice.

Chromosomal abnormalities have been assessed in p53-deficient mice. The in vivo frequency of spontaneous stable aberrations in bone marrow cells was elevated by approximately 20-fold in p53 nulls and 13-fold in p53 heterozygotes compared to wild-type. No excessive induction of stable aberrations by gamma-irradiation was observed, but p53 deficiency resulted in excess radiation-induced hyperploidy (> 10-fold wild-type frequency). No influence of p53 genotype on sister chromatid exchange or G2 chromatid damage was observed in mitogen-stimulated spleen cell cultures; however, a p53 effect on postirradiation mitotic entry was seen. Abnormalities in chromosome segregation and mitotic delay following irradiation in p53-deficient mice suggest a G2-M checkpoint role for p53 and are broadly consistent with data on tumorigenesis in these animals.

Aneuploidy↗
PubMed1995

Concerted action of TGF-beta 1 and its type II receptor in control of epidermal homeostasis in transgenic mice.

Transforming growth factor-beta 1 (TGF-beta 1) is a modulator of cellular proliferation, differentiation, and extracellular matrix deposition. It is a potent epithelial growth inhibitor and can alter the differentiative properties of keratinocytes, in vitro, but little is known about its normal physiological function in the epidermis in vivo. Transgenic mice were generated using a keratin 10 (K10) gene promoter to drive constitutive expression of TGF-beta 1 in the suprabasal keratinocyte compartment. Surprisingly, these mice showed a two- to threefold increase in epidermal DNA labeling index over control mice, in the absence of hyperplasia. The transgene, however, acted in the expected fashion, as a negative regulator of cell growth, when hyperplasia was induced by treatment by 12-tetradecanoyl-phorbol-13-acetate (TPA). Epidermal TGF-beta type I and II receptor (T beta RI and T beta RII) levels were examined in control and transgenic mice during induction of hyperplasia by TPA. Whereas T beta RI levels remained relatively constant, T beta RII expression was strongly induced in TPA-treated skins, prior to the induction of the growth inhibitory response to TGF-beta 1, and its level of expression correlated with growth sensitivity to TGF-beta 1 in vivo and in vitro. These results suggest that TGF-beta 1 and its type II receptor are part of the endogenous homeostatic regulatory machinery of the epidermis.

Activin Receptors, Type I↗
PubMed1995

Hyperpigmentation and melanocytic hyperplasia in transgenic mice expressing the human T24 Ha-ras gene regulated by a mouse tyrosinase promoter.

The tyrosinase promoter has been used to target expression of the mutated human T24 Ha-ras oncogene in pigment-producing cells of transgenic mice. Two independent founder mice carrying the transgene survived and showed the same distinct phenotype of mutated coat color, deeply pigmented skin with multiple nevi, and twirling behavior. The offspring of one of these founders were developed into a line that stably expressed the same phenotype. Histopathological analysis of the tissues revealed hyperpigmentation and/or melanocytic hyperplasia in the skin, eyes, inner ear, and meningeal membranes in the brain. Reverse transcriptase-polymerase chain reaction analysis revealed expression of the transgene in skin, brain, and spleen. We propose that these transgenic mice will be a model for studying the process of multistage melanoma carcinogenesis and a system for evaluating potential chemopreventive agents.

Animals↗