Sipa1 is a candidate for underlying the metastasis efficiency modifier locus Mtes1.

We previously identified loci in the mouse genome that substantially influence the metastatic efficiency of mammary tumors. Here, we present data supporting the idea that the signal transduction molecule, Sipa1, is a candidate for underlying the metastasis efficiency modifier locus Mtes1. Analysis of candidate genes identified a nonsynonymous amino acid polymorphism in Sipa1 that affects the Sipa1 Rap-GAP function. Spontaneous metastasis assays using cells ectopically expressing Sipa1 or cells with knocked-down Sipa1 expression showed that metastatic capacity was correlated with cellular Sipa1 levels. We examined human expression data and found that they were consistent with the idea that Sipa1 concentration has a role in metastasis. Taken together, these data suggest that the Sipa1 polymorphism is one of the genetic polymorphisms underlying the Mtes1 locus. This report is also the first demonstration, to our knowledge, of a constitutional genetic polymorphism affecting tumor metastasis.

Caffeine suppresses metastasis in a transgenic mouse model: a prototype molecule for prophylaxis of metastasis.

A significant fraction of cancer patients have occult disseminated tumors at the time of primary diagnosis, which usually progress to become clinically relevant lesions. Since the majority of cancer mortality is associated with metastatic disease, the ability to inhibit the growth of the secondary tumors would significantly reduce cancer-related morbidity and mortality. We have investigated whether caffeine, which has been shown to suppress tumor cell invasiveness and experimental metastasis, can suppress metastasis in a spontaneous transgene-induced mammary tumor model. Chronic exposure to caffeine prior to the appearance of palpable mammary tumors significantly reduced both tumor burden and metastatic colonization. However, when caffeine exposure began after the appearance of frank tumors, caffeine suppressed metastasis without changing primary tumor burden. The means by which caffeine suppressed metastatic activity may be associated with inhibition of malignant transformation of mammary epithelial cells, inhibition of conversion of dormant tumor cells to micrometastases, micrometastases to macrometastases, or inhibition of tumor cell adhesion and motility. Gene and protein expression patterns resulting from caffeine treatment showed that metastasis suppression may be associated with up-regulation the mRNA expression of multiple extracellular matrix genes, including Fbln1, Bgn, Sparc, Fbn1, Loxl1, Colla1, Col3a1, Col5a1, ColS5a2, ColSa3, Col6a1, Col6a2, and Col6a3. These data suggested that caffeine or other methyl xanthine derivatives may improve the clinical outcome in patients prior to and following the diagnosis of metastatic disease, and could potentially reduce the morbidity and mortality associated with disseminated tumors.

Putative tumor-suppressor gene regions responsible for radiation lymphomagenesis in F1 mice with different p53 status.

Regions of allelic loss on chromosomes in many tumors of human and some experimental animals are generally considered to harbor tumor-suppressor genes involved in tumorigenesis. Allelotype analyses have greatly improved our understanding of the molecular mechanism of radiation lymphomagenesis. Previously, we and others found frequent loss of heterozygosity (LOH) on chromosomes 4, 11, 12, 16 and 19 in radiation-induced lymphomas from several F1 hybrid mice. To examine possible contributions of individual tumor-suppressor genes to tumorigenesis in p53 heterozygous deficiency, we investigated the genome-wide distribution and status of LOH in radiation-induced lymphomas from F1 mice with different p53 status. In this study, we found frequent LOH (more than 20%) on chromosomes 4 and 12 and on chromosomes 11, 12, 16 and 19 in radiation-induced lymphomas from (STS/A X MSM/Ms)F1 mice and (STS/A X MSM/Ms)F1-p53KO/+ mice, respectively. Low incidences of LOH (10-20%) were also observed on chromosomes 11 in mice with wild-type p53, and chromosomes 1, 2, 9, 17 and X in p53 heterozygous-deficient mice. The frequency of LOH on chromosomes 9 and 11 increased in the (STS/A X MSM/Ms)F1-p53KO/+ mice. Preferential losses of the STS-derived allele on chromosome 9 and wild-type p53 allele on chromosome 11 were also found in the p53 heterozygous-deficient mice. Thus, the putative tumor-suppressor gene regions responsible for lymphomaganesis might considerably differ due to the p53 status.

Mapping of putative ether-anesthesia resistance gene using C57BL/6J and MSM/Ms mouse strains.

PURPOSE: We attempted to identify the locations of major mouse genes responsible for sensitivity to diethylether (ether) anesthesia, using microsatellite linkage analyses including Quantitative Trait Locus (QTL) analysis. METHODS: To determine the locations of ether anesthesia resistance genes on chromosomes, an ether anesthesia-resistant mouse strain, C57BL/6J (C57BL), and an ether anesthesia-sensitive mouse strain, MSM/Ms (MSM), were used. The sensitivity of mice to ether anesthesia was determined from the latency time required to lose the righting reflex during exposure to 4% ether vapor in air. The (C57BL x MSM) F(1) mice were found to be resistant to ether, showing that the resistant phenotype is genetically dominant. Twelve resistant and 12 sensitive mice were then selected from the 196 backcrossed F(2) mice (F(1) x MSM) at 11-16 weeks of age. Genomic DNA samples were extracted from the tails for mapping ether anesthesia-related genes using microsatellite linkage analyses. RESULTS: One major putative gene related to resistance to ether anesthesia was restricted in the region 23 to 37 cM from the centromere in chromosome 7 by primary and secondary linkage analyses. The QTL analysis narrowed the position of the gene to 29.0 cM, with a maximum logarithm of odds (LOD) score of 3.03, and it was termed Etan1 ( ether-anesthesia 1). CONCLUSION: Microsatellite linkage analyses, including QTL analysis, determined the location of the ether-resistance gene, Etan1, within a narrow range. Our findings should be helpful for further experiments, such as cloning of the gene governing the sensitivity to ether anesthesia in mice.