Progress and applications of mouse models for human lung cancer.

The continued progress of modelling lung cancer in mice has led not only to new means of understanding the molecular pathways governing human lung cancer, but it has also created a vast reservoir of alternative tools to test treatments against this malignancy. More sophisticated somatic mouse models for nonsmall cell lung cancer, small cell lung cancer and pulmonary squamous cell carcinoma have been generated that closely mimic human lung cancer. These models enable us to identify the cells of origin and the role of stem cells in the maintenance of the various types of lung cancer. Moreover, results of lung cancer intervention studies are now starting to reveal the full potential of these somatic mouse models as powerful pre-clinical models.

Genotype-phenotype relationships in a mouse model for human small-cell lung cancer.

Lung tumors are usually classified into small-cell lung cancer (SCLC) or non-SCLC (NSCLC) depending on their pathological and histological characteristics. SCLC is defined not only by its characteristic neuroendocrine differentiation, aggressiveness, and metastatic potential, but also by a specific set of genetic aberrations, including the loss of the tumor suppressor genes p53 and Rb1 and the amplification of any member of the Myc family of oncogenes. We have previously described a mouse model of SCLC by somatic conditional disruption of Trp53 and Rb1 genes that closely resembles the human condition. Based on the possibility to study early tumor lesions and to culture and subclone progressed tumors and metastases, we discuss here a strategy to define genotype-phenotype relationships that can explain the underlying biology of lung neuroendocrine tumors. We have found that tumors may be constituted by genetically variant cell populations, which might represent different progression stages. Interestingly, we observed L-myc amplification and Ascl-1 expression in those populations showing neuroendocrine differentiation. Non-neuroendocrine cell populations from the same tumors did not show L-myc amplification nor Ascl-1 expression. We propose that this genetic divergence can play a relevant role in the definition of some phenotypic characteristics like metastasis potential or chemoresistance.

Synergistic tumor suppressor activity of BRCA2 and p53 in a conditional mouse model for breast cancer.

Inheritance of one defective BRCA2 allele predisposes humans to breast cancer. To establish a mouse model for BRCA2-associated breast cancer, we generated mouse conditional mutants with BRCA2 and/or p53 inactivated in various epithelial tissues, including mammary-gland epithelium. Although no tumors arose in mice carrying conditional Brca2 alleles, mammary and skin tumors developed frequently in females carrying conditional Brca2 and Trp53 alleles. The presence of one wildtype Brca2 allele resulted in a markedly delayed tumor formation; loss of the wildtype Brca2 allele occurred in a subset of these tumors. Our results show that inactivation of BRCA2 and of p53 combine to mediate mammary tumorigenesis, and indicate that disruption of the p53 pathway is pivotal in BRCA2-associated breast cancer.

Mouse model for lung tumorigenesis through Cre/lox controlled sporadic activation of the K-Ras oncogene.

The onset of human lung cancer occurs through sequential mutations in oncogenes and tumor suppressor genes. Mutations in K-Ras play a prominent role in human non-small cell lung cancer. We have developed a mouse lung tumor model in which K-Ras can be sporadically activated through Cre-lox mediated somatic recombination. Adenoviral mediated delivery of Cre recombinase in lung epithelial cells gave rise to rapid onset of tumorigenesis, yielding pulmonary adenocarcinomas with 100% incidence after a short latency. The lung tumor lesions shared many features with human non-small cell lung cancer. Our data show that sporadic expression of the K-Ras oncogene is sufficient to elicit lung tumorigenesis. Therefore this model has many advantages over conventional transgenic models used thus far.

Mouse models for sporadic cancer.

Much of the advancement in mouse models for cancer during the past 2 decades can be attributed to our increasing capacity to specifically modify the mouse germ line. The first generations of oncomice and tumor-suppressor gene knockouts are now being succeeded by regulatable or conditional mouse tumor models, which can be utilized more effectively to establish correlations between distinct genetic lesions and specific tumor characteristics and to design and improve therapeutic intervention strategies. In this review we try to give the reader a flavor of how the latest reagents can be utilized.

Temporal and spatial control of the Sycp1 gene transcription in the mouse meiosis: regulatory elements active in the male are not sufficient for expression in the female gonad.

Transcription controls active at the initial stages of meiosis are clearly key elements in the regulation of germinal differentiation. Transcription of the Sycp1 gene (synaptonemal complex protein 1) starts as early as the leptotene and zygotene stages. Constructs with Sycp1 5' upstream sequences directed the expression of reporter genes to pachytene spermatocytes in transgenic mice. A short fragment encompassing the transcription start (n.t. -54 to +102) was sufficient for stage-specific expression in the adult male and for temporal regulation during development. Upstream enhancer element(s) quantitatively regulating expression were localized in the region between -54 and -260. The gene is normally expressed both in the male and female gonads, but none of the promoter sequences active in the testis allowed the expression of reporter genes during meiosis in the ovary.

Constitutive expression of pathogenesis-related proteins PR-1, GRP, and PR-S in tobacco has no effect on virus infection.

Samsun NN tobacco cells were transformed with chimeric genes for pathogenesis-related (PR) proteins derived from genomic (PR-1a, GRP) or cDNA (PR-S) clones under the transcriptional control of the cauliflower mosaic virus 35S promoter. Regenerated plants were assayed by RNA and protein gel blotting, and plants showing high specific expression of the inserted genes were selected for self-pollination and seed formation. Inspection of second generation transformants showed that constitutive expression of PR-1a, GRP, and PR-S in tobacco in general does not have an effect on the phenotypic appearance of the plants or the expression of other endogenous PR genes. Furthermore, constitutive expression of the above genes does not affect the susceptibility of the plants to infection with tobacco mosaic virus or alfalfa mosaic virus.