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PubMed2007

Conditional mouse models of cancer.

The development of inducible and conditional technologies allowed us to generate transgenic mouse models that faithfully recapitulate human tumorigenesis. It is possible to control, in time and space, the development of tumors in almost every mouse tissue. The result is that now we have available mouse models for all major human cancers. Novel noninvasive approaches to tumor imaging will enable us to follow tumor development and metastasis in vivo, as well as the effects of candidate therapeutic drugs. Such new generation tumor 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 tumor development. In this review, we focus on the different mouse models for colon cancer.

Adenomatous Polyposis Coli↗
PubMed2003

Adhesion, invasion, and translocation characteristics of Listeria monocytogenes serotypes in Caco-2 cell and mouse models.

Adhesion is a crucial first step in Listeria monocytogenes pathogenesis. In this study, we examined how the adhesion properties of serotypes correlate with their invasion efficiencies in a cell culture model (Caco-2) and in a mouse model. Adhesion characteristics of all 13 serotypes of L. monocytogenes (25 strains) were analyzed, which yielded three distinct groups (P < 0.05) with high-, medium-, and low-level-adhesion profiles. The efficiency of these strains in invading the Caco-2 cell line was analyzed, which produced two groups; however, the overall correlation (R(2)) was only 0.1236. In the mouse bioassay, all selected strains, irrespective of their adhesion profiles, translocated to the liver and the spleen with almost equal frequencies that did not show any clear relationship with adhesion profiles. However, the serotypes with increased adhesion showed a slightly increased translocation to the brain (R(2) = 0.3371). Collectively, these results indicate that an in vitro adhesion profile might not be an accurate assessment of a strain's ability to invade a cultured cell line or organs or tissues in a mouse model.

Animals↗
PubMed2005

Development of a new mouse model (xeroderma pigmentosum a-deficient, stem cell factor-transgenic) of ultraviolet B-induced melanoma.

It is well established that exposure to sunlight or ultraviolet radiation (UVR) is the major environmental risk factor for the development of skin neoplasms. To date, however, there have been few appropriate mouse models available for studying the role of UVR in melanoma carcinogenesis, mainly because of the murine lack of the epidermal melanocyte, which is a major source of origin of human melanoma. In this study, we established xeroderma pigmentosum group A gene-deficient, stem cell factor-transgenic mice, which are defective in the repair of damaged DNA and do have epidermal melanocytes. The mice were exposed to UVR three times a week for 10 wk. More than 30% of the irradiated mice developed tumors of melanocyte origin that metastasized to the lymph nodes. Histologically, proliferated cells exhibited lentigo maligna melanoma or nodular melanoma. Immunohistochemistry confirmed that the tumor cells were characteristic of melanoma. Non-irradiated mice did not develop skin tumors spontaneously. The newly generated model mouse might be useful for studying the photobiological aspects of human melanoma, because the mice developed melanoma from epidermal melanocytes only after UVR exposures.

Animals↗
PubMed1996

Evaluation of a plasmid-based transgenic mouse model for detecting in vivo mutations.

To study in vivo somatic mutations a C57BL/6 transgenic mouse model was constructed harboring multiple chromosomally integrated copies of the plasmid pUR288, which carried the lacZ reporter gene as the mutational target. We previously demonstrated that lacZ-containing plasmids could be rescued from their integrated state efficient enough to detect mutations in lacZ by positive selection. The smaller size of the plasmid vector, as compared with our earlier transgenic mouse model based on bacteriophage lambda vectors, should offer considerable advantages in terms of rescue efficiency and sensitivity to large size alterations in the lacZ gene. To evaluate the plasmid-based mouse model for its suitability to detect in vivo mutations, we determined mutant frequencies in different organs of untreated and ethyl nitrosourea (ENU)-treated animals using a new, improved protocol. The rescue efficiencies obtained were as high as 200,000/micrograms genomic DNA; millions of transformants could be obtained in one single experiment. The average spontaneous mutant frequency in four different organs of 4- to 8-week-old mice ranged from 4.41 to 6.82 x 10(-5), compared with a mutant frequency of the same plasmid grown in Escherichia coli of approximately 1 x 10(-5) or less. Single treatments with 100 and 250 mg ENU/kg body wt resulted in a 7- and 14-fold increase, respectively, in spleen mutant frequency at 14 days after i.p. administration of the alkylating agent. Restriction enzyme analysis showed that a considerable portion of spontaneous mutants were size changes varying from approximately 100 to 3000 bp. Some mutant plasmids contained mouse genomic sequences, which is indicative of large genetic rearrangement events involving the 3' flanking regions of the transgene cluster. Among the ENU-induced mutants, size changes comprised only a minor fraction of the total, which is in keeping with the known ENU mutation spectra in vitro and in vivo. The high rescue efficiency of this plasmid-based model, in combination with its sensitivity to a broad spectrum of mutations, including large deletions, makes it very suitable as a general in vivo mutagenicity test system.

Animals↗
PubMed2006

Regenerative capacity of individual liver lobes in the microsurgical mouse model.

In the development of microsurgical mouse models of hepatic regeneration and repair, lobe-specific regenerative responses were observed. We therefore determined the hepatic regenerative capacity of individual mouse liver lobes. In mice, 26, 60, 75, and 83% of total liver mass was resected. Bromo-deoxyuridine (BrdU) was injected prior to liver harvest and the BrdU labeling index determined in all remaining individual liver lobes. BrdU-positive nuclei were seen in all liver lobes after the 26 and 60% resection, but significantly fewer were detected in the caudate lobe. In the 75% group, equally distributed positive nuclei were found. However, BrdU labeling was scant in the 83% group. In microsurgical mouse liver-regeneration models, the average hepatic response depends on amount of liver tissue resected and on the remaining liver lobe. BrdU incorporation can vary significantly among individual lobes. The lobe-specific differences observed may prove valuable in further investigations of hepatic regeneration and repair.

Animals↗
PubMed2005

Mouse models for human lung cancer.

In recent years several new mouse models for lung cancer have been described. These include models for both non-small-cell lung cancer (NSCLC) and small-cell lung cancer (SCLC). Tumorigenesis in these conditional mouse tumor models can be initiated in adult mice through Cre-recombinase-induced activation of oncogenic mutations in a subset of the cells. They present a marked improvement over mouse models that depend on carcinogen induction of tumors. These models permit us to study the consecutive steps involved in initiation and progression and allow us to address questions like the cell of origin, and the role of cancer stem cells in the maintenance of these tumors. They now need to be validated as suitable preclinical models for intervention studies in which questions with respect to therapy response and resistance can be addressed.

Animals↗
PubMed1998

Transgenic mouse models for gonadal tumorigenesis.

The versatile transgenic (TG) techniques allow the production of in vivo animal models for a variety of diseases, including malignant tumors, through tissue-specific expression of oncogenes. We have created a TG mouse model for gonadal somatic cell tumors by expressing the powerful viral oncogene, Simian virus 40 T-antigen (Tag) under regulation of the murine inhibin alpha-subunit promoter (inh alpha). Ovarian granulosa and theca cell tumors were formed in the female, and those of testicular Leydig cells, in the male TG mice at the age of 5-6 months, with 100% penetrance. The tumors produced high levels of inhibin peptides, especially the alpha-subunit, and were steroidogenically active, mainly producing progesterone. The gonadal tumorigenesis was gonadotropin-dependent, since TG mice rendered gonadotropin-deficient by crossbreeding them into the hypogonadotropic hpg genetic background, or by treating them with a gonadotropin-releasing hormone (GnRH) antagonist, did not develop tumors. In order to study the possibility of using the tumor mouse model for testing gene therapy, we created another TG mouse model expressing under the same inhibin-alpha promoter the Herpes Simplex virus (HSV) thymidine kinase (TK) transgene. The inh alpha/HSV-TK mice were crossbred with the inh alpha/Tag mice and the double mutant mice also developed gonadal tumors. When they were treated with antiherpes drugs (acyclovir or gancyclovir), further growth of the tumors was blocked. These preliminary findings prove the principle that tumor ablation in our TG mouse model can be achieved by transduction of the HSV-TK gene into the tumor cells. Besides studies of formation, regulation and therapy of the tumors in vivo, immortalized cell lines derived from them provide models for studies of gonadal somatic cell functions in vitro.

Animals↗
PubMed2006

Knockout mouse models of sperm flagellum anomalies.

To date, 21 knockout mouse models are known to bear specific anomalies of the sperm flagellum structures leading to motility disorders. In addition, genes responsible for flagellar defects of two well-known spontaneous mutant mice have recently been identified. These models reveal genetic factors, which are required for the proper assembly of the axoneme, the annulus, the mitochondrial sheath and the fibrous sheath. Many of these genetic factors follow unexpected cellular pathways to act on sperm flagellum morphogenesis. These mouse models may bear anomalies which are restricted to the spermatozoa or display more complex phenotypes that often include neuropathies and/or cilia-related diseases. In human, several structural disorders of the sperm flagellum found in brothers or consanguineous men probably have a genetic origin, but the genes involved have not yet been identified. The mutant mice we present in this review are invaluable models, which can be used to identify potential candidate genes for infertile men with specific sperm flagellum anomalies.

Animals↗
PubMed2006

Mouse models of BRCA1 and BRCA2 deficiency: past lessons, current understanding and future prospects.

Germline mutations in BRCA1 and BRCA2 are responsible for a large proportion of hereditary breast and ovarian cancers. Soon after the identification of both genes in the mid-1990s, investigators set out to develop mouse models for the associated disease. Whereas conventional Brca1 and Brca2 mouse mutants did not reveal a strong phenotype in a heterozygous setting, most homozygous mutations caused embryonic lethality. Consequently, development of mouse models for BRCA-associated tumorigenesis required the generation of tissue-specific conditional knockout animals. In this review, we give an overview of the conventional and the conditional mouse models of BRCA1 and BRCA2 deficiency generated over the last decade, as well as the contribution of these models to our understanding of the biological and molecular functions of BRCA1 and BRCA2. The most advanced mouse models for BRCA1- and BRCA2-associated tumorigenesis mimic human disease to the extent that they can be used in studies addressing clinically relevant questions. These models will help to resolve yet unanswered questions and to translate our increasing knowledge of BRCA1 and BRCA2 biology into clinical practice.

Animals↗
PubMed2006

Mouse models of neointimal hyperplasia: techniques and applications.

Neointimal hyperplasia is a major cause of the failure in vascular reconstructive procedures such as angioplasty, vascular stenting, small caliber vascular graft, and vein graft. However, the underlying molecular mechanisms are not yet fully understood. The study of neointimal hyperplasia has relied heavily on the use of experimental animal models. Recent development in gene manipulation techniques in mice offers a unique opportunity to unravel the molecular basis of the neointimal response at the genetic level, which is critical to develop new strategies to prevent human neointimal hyperplasia. Several mouse models for studying neointimal hyperplasia have recently been established including blood-flow cessation, mechanical injury, and vein bypass graft. In an attempt to elaborate these models, this review highlights the characteristics, advantages, disadvantages, and applications of these mouse models in vascular disease. In addition, the difference between mouse models and human lesions is discussed. Thus, this review provides updated information and helps vascular surgeons and other vascular biologists in selecting appropriate mouse models for their research on neointimal hyperplasia.

Animals↗
PubMed1991

Use of a mouse model to examine anti-Helicobacter pylori agents.

A mouse model of Helicobacter infection of the gastric mucosa was evaluated for in vivo screening of new anti-Helicobacter pylori therapies. The aim of the study was to test antimicrobial agents with known anti-H. pylori effects in humans to validate that similar results were obtained in the mouse model. Specific pathogen-free mice were colonized with H. felis, a cat stomach isolate that has been shown to induce chronic gastritis in gnotobiotic mice. In H. felis-inoculated mice 4 weeks after treatment, only 25% were cleared with erythromycin, 47% with metronidazole, 0% with tetracycline, 70% with amoxycillin, and 25% with bismuth subcitrate. In contrast, triple therapy with metronidazole, amoxycillin, and bismuth subcitrate resulted in 80% eradication, whereas triple therapy with metronidazole, tetracycline, and bismuth subcitrate eradicated the Helicobacter from all the animals. We believe the similarities of these treatments to those reported in the literature for humans warrant the use of this model for the early screening of possible anti-H. pylori therapies, especially as in vitro testing has been found to be so non-predictive of therapeutic success.

Animals↗
PubMed1997

Intestinal physiology and pathology in gene-targeted mouse models of cystic fibrosis.

Cystic fibrosis (CF) is a fatal genetic disorder that affects approximately 1 in 2,500 live Caucasian births. The disease can be described as a generalized exocrine disease affecting a variety of epithelial tissues, with early manifestation as meconium ileus in a significant number of neonates. Cloning of the gene causing CF was accomplished in 1989, and the protein product, cystic fibrosis transmembrane conductance regulator (CFTR), has been conclusively shown to be an adenosine 3',5'-cyclic monophosphate (cAMP)-regulated Cl- channel. Subsequently, several mouse models of CF were generated by gene-targeting approaches in an attempt to further understand this disease. The initial excitement generated by the emergence of these mouse models was somewhat tempered by the finding that none of the models developed airway disease, which is currently responsible for most of the morbidity and mortality in the human CF population. However, the various CF mouse models, of which there are now 10, are remarkably similar to their human counterparts with respect to intestinal pathophysiology. Most importantly, the intestinal tract of the CF mouse models demonstrates the absence of cAMP-mediated Cl- transport, which is a hallmark of CF disease. Furthermore, the murine CF intestinal tract also shows an inability to secrete HCO3-, defective cAMP regulation of electroneutral NaCl absorption, and elevated electrogenic Na+ transport in the distal colon, as well as other ion transport perturbations. Besides the fundamental mechanisms of ion transport studied in the murine CF intestinal tract, these models have also been important in understanding other tissues with regard to CF. Mice heterozygous for the CFTR knockout gene have a reduced ability to secret Cl- and fluid and therefore provide further support for the CF "heterozygote advantage" hypothesis. Some CF mouse models maintain a limited ability to secrete Cl-, which may be due to accessory genes that are hypothesized to ameliorate disease severity in the intestines of these mice. This review describes the CF models generated and compares the murine defects in ion transport with observed abnormalities in the human CF intestine.

Animals↗
PubMed1986

Establishment of a mouse model for human rhinovirus infection.

We describe here a mouse model for rhinovirus infection using a variant of human rhinovirus type 2 (HRV2/H) which replicated 50- to 300-fold in the lungs of BALB/c mice. The variant virus differed only marginally from HRV2/H according to various biochemical parameters. Use of a photosensitive inoculum and pretreatment of the animals with actinomycin D were necessary for detection of reproducible and significant levels of virus replication. This mouse model of rhinovirus infection is the first example of human rhinovirus replication in a non-primate mammal, and provides an important link for the development of rhinovirus therapy or prophylaxis.

Animals↗
PubMed1984

A new mouse model for prostatic hyperplasia: induction of adult prostatic overgrowth by fetal urogenital sinus implants.

A new mouse model for human BPH has been established. This model was developed on the basis that fetal and adult prostatic cells interact to induce the proliferation of adult prostatic cells. A 10- to 20-fold overgrowth of the adult mouse prostate gland can be induced by implantation of fetal UGS into the adult prostate gland. Components of UGS, fetal UGM, and fetal UGE may be involved in the regulation of adult prostatic overgrowth. The androgen dependency and the specificity (donor tissue, site of implantation, and strain and species) of UGS-induced adult prostatic overgrowth have also been established. The question remains whether the prostatic hyperplasia seen in this mouse model may be representative of human BPH. The observation that fetal UGS implants induce adult prostatic overgrowth in the complete absence of exogenous sex steroids support the hypothesis of McNeal that human BPH may develop as a result of the reactivation of fetal growth potential in the periurethral area of the adult prostate gland. The present mouse model may be used as a test system for the future development of anti-BPH drugs.

Androgens↗
PubMed2006

Altered distributions of nucleocytoplasmic transport-related proteins in the spinal cord of a mouse model of amyotrophic lateral sclerosis.

Recent investigations have indicated that the nucleocytoplasmic transport system is essential for maintaining cell viability and cellular functions and that its dysfunction could lead to certain disorders. To investigate the involvement of this system in the pathomechanisms of amyotrophic lateral sclerosis (ALS), we examined the immunohistochemical localization of proteins associated with nucleocytoplasmic transport in the lumbar spinal cord in a mutant SOD1 (G93A) transgenic mouse model of ALS. This model is widely used for ALS research, and the mutant mice are known to exhibit neuronal loss and Lewy body-like hyaline inclusions (LBHIs) in the anterior horns, similar to the pathology seen in familial ALS patients associated with an SOD1 mutation and in several other transgenic rodent models. Using antibodies against the importin beta family of proteins, the major carrier proteins of nucleocytoplasmic transport, and those against their adapter protein, importin alpha, we found that the immunoreactivities were decreased within the nuclei and increased within the cytoplasm of a subset of the surviving anterior horn cells of the transgenic mice. In addition, LBHIs were invariably reactive toward these antibodies. Furthermore, the immunoreactivities for histone H1 and beta-catenin, representative cargo proteins transported by importin beta-dependent and beta-independent nucleocytoplasmic transport pathways, respectively, showed distributions similar to those for importin beta family and importin alpha proteins. The altered distributions of these proteins were not associated with caspase-3 expression, suggesting that the findings are unlikely to be a manifestation of apoptotic processes. Chronological quantitative analysis of importin beta-immunostained sections from the transgenic mice revealed a statistically significant progressive decrease in the proportion of the anterior horn cells exhibiting a more intense reactivity for these proteins in the nucleus than in the cytoplasm. To the contrary, we found that the anterior horn cells with the immunoreactivity in their cytoplasm, being more pronounced than that in their nucleus, were significantly increased in number along with the disease progression. This is the first report investigating nucleocytoplasmic transport in the ALS model mouse, and our present results imply that its dysfunction could be involved in the pathomechanisms underlying ALS.

Amyotrophic Lateral Sclerosis↗
PubMed1999

Normal cochlear function in mdx and mdx(Cv3) Duchenne muscular dystrophy mouse models.

OBJECTIVES/HYPOTHESIS: Sensorineural hearing loss has been found in association with inherited muscular dystrophies in humans and in mouse models. An increased brainstem auditory evoked response threshold has been previously reported in the dystrophin-deficient mdx mouse model for Duchenne muscular dystrophy, suggesting that full-length dystrophin (Dp427) is involved in hearing. The objective of the present study was to confirm cochlear dysfunction with this gene defect and determine whether the shorter carboxyl terminus isoforms of dystrophin are also critical in maintaining normal hearing. STUDY DESIGN: Case controlled. Animal model. METHODS: Auditory brainstem response (ABR) audiometry to pure tones was used to evaluate cochlear function. Fourteen mdx, 4 mdx(Cv3), and 13 age-matched control (C57BL/6J and C57BL/10ScSn) male mice were tested at 5 weeks and 11 weeks of age. The ABR thresholds to tone-burst stimuli at 4, 8, 16, and 32 kHz were obtained for each ear and statistically compared (ANOVA) for potential group differences. RESULTS: Both mdx and mdx(Cv3) mice demonstrated normal ABR thresholds when compared with controls. CONCLUSIONS: Both mdx and mdx(Cv3) mouse models have normal hearing by ABR. The authors' data suggest that dystrophin and its carboxyl terminus isoforms do not play a critical role in hearing in the mouse. This was unexpected, as previous studies using the brainstem auditory evoked response method suggested that the mdx mouse has an increased threshold for hearing.

Animals↗
PubMed2002

Differential vulnerability of cranial motoneurons in mouse models with motor neuron degeneration.

Amyotrophic lateral sclerosis (ALS) is characterized by the progressive degeneration of selective motoneuron populations, yet it remains unclear why some groups of motoneurons are more vulnerable than others. Our aim was to compare the motoneuron loss in five cranial nuclei at different stages of the disease in three mouse models of ALS: two naturally occurring murine models (progressive motor neuronopathy (pmn) and wobbler) and a transgenic mouse model with a human G93A mutation in the superoxide dismutase-1 (SOD1) gene. By quantifying these different motoneuron populations we report that the degree of degeneration in the various cranial motoneuron nuclei depends on the mouse model and the stage of the disease. The biologically most significant difference between the mutations occurs in the oculomotor/trochlear nucleus which is affected in the pmn mouse but not in the wobbler and SOD G93A mice. These results suggest that there is a selective degeneration of cranial motoneurons in these mouse models as in ALS patients.

Amyotrophic Lateral Sclerosis↗
PubMed2006

Spontaneous rescue from cystic fibrosis in a mouse model.

BACKGROUND: From the original CftrTgH(neoim)Hgu mutant mouse model with a divergent genetic background (129P2, C57BL/6, MF1) we have generated two inbred CftrTgH(neoim)Hgu mutant strains named CF/1-CftrTgH(neoim)Hgu and CF/3-CftrTgH(neoim)Hgu, which are fertile and show normal growth and lifespan. Initial genome wide scan analysis with microsatellite markers indicated that the two inbred strains differed on the genetic level. In order to further investigate whether these genetic differences have an impact on the disease phenotype of cystic fibrosis we characterised the phenotype of the two inbred strains. RESULTS: Reduced amounts, compared to wild type control animals, of correctly spliced Cftr mRNA were detected in the nasal epithelia, lungs and the intestine of both inbred CftrTgH(neoim)Hgu strains, with higher residual amount observed for CF/1-CftrTgH(neoim)Hgu than CF/3-CftrTgH(neoim)Hgu for every investigated tissue. Accordingly the amounts of wild type Cftr protein in the intestine were 9% for CF/1-CftrTgH(neoim)Hgu and 4% for CF/3-CftrTgH(neoim)Hgu. Unlike the apparent strain and/or tissue specific regulation of Cftr mRNA splicing, short circuit current measurements in the respiratory and intestinal epithelium revealed that both strains have ameliorated the basic defect of cystic fibrosis with a presentation of a normal electrophysiology in both tissues. CONCLUSION: Unlike the outbred CftrTgH(neoim)Hgu insertional mouse model, which displayed the electrophysiological defect in the gastrointestinal and respiratory tracts characteristic of cystic fibrosis, both inbred CftrTgH(neoim)Hgu strains have ameliorated the electrophysiological defect. On the basis of these findings both CF/1-CftrTgH(neoim)Hgu and CF/3-CftrTgH(neoim)Hgu offer an excellent model whereby determination of the minimal levels of protein required for the restoration of the basic defect of cystic fibrosis can be studied, along with the modulating factors which may affect this outcome.

Animals↗