Cat and Mouse (Ralph Williams story)
"Cat and Mouse" is a science fiction novelette by Ralph Williams. Originally published in the June 1959 issue of Astounding Science Fiction, it was nominated for, but did not win, the 1960 Hugo Award for Best Short Fiction.
A kangaroo mouse is either one of the two species of jumping mouse (genus Microdipodops) native to the deserts of the southwestern United States, predominantly found in the state of Nevada. The name "kangaroo mouse" refers to the species' extraordinary jumping ability, as well as its habit of bipedal locomotion. The two species are: Pale kangaroo mouse - Microdipodops pallidus Dark kangaroo mouse - Microdipodops megacephalusBoth species of kangaroo mouse live in sandy desert ecosystems, and forage for seeds and vegetation amongst the scrub brush of their native habitat. The dark kangaroo mouse is also known to feed occasionally on insects and carrion. The mouse rarely drinks water, instead deriving it metabolically from the foods it eats. The kangaroo mouse collects food and maintains large caches in their burrows, which are excavated to a length of between 3 and 8 feet (1 to 2.5 meters). The burrow, the entrance to which the mouse covers during daylight hours, is also used to raise litters of between 2 and 7 young. The pale kangaroo mouse burrows only in fine sand, while the dark kangaroo mouse prefers fine, gravelly soils but may also burrow in sand or sandy soil. Kangaroo mice are nocturnal, and are most active in the two hours following sunset. They are believed to hibernate during cold weather. Although mitochondrial data indicate that the clades appear to be in approximate genetic equilibrium and have not suffered any extreme bottlenecks over time, there is still concern for the survival of smaller and more vulnerable Microdipodops subpopulations due to impending habitat threats in the Great Basin Desert. The kangaroo mice are closely related to the kangaroo rats, which belong to the same subfamily, Dipodomyinae.
The ob/ob or obese mouse is a mutant mouse that eats excessively due to mutations in the gene responsible for the production of leptin and becomes profoundly obese. It is an animal model of type II diabetes. Identification of the gene mutated in ob led to the discovery of the hormone leptin, which is important in the control of appetite. The first ob/ob mouse arose by chance in a colony at the Jackson Laboratory in 1949. The mutation is recessive. Mutant mice are phenotypically indistinguishable from their unaffected littermates at birth, but gain weight rapidly throughout their lives, reaching a weight three times that of unaffected mice. ob/ob mice develop high blood sugar, despite an enlargement of the pancreatic islets and increased levels of insulin. The gene affected by the ob mutation was identified by positional cloning. The gene produces a hormone, called leptin, that is produced predominantly in adipose tissue. One role of leptin is to regulate appetite by signalling to the brain that the animal has had enough to eat. Since the ob/ob mouse cannot produce leptin, its food intake is uncontrolled by this mechanism.
Generating mouse models of breast cancer
Targeted expression of oncogenes in mouse mammary epithelial cells is a way of modeling human breast cancer. Mutation or over expression of oncogenes can be kept under controlled expression in a very specific cellular context rather than throughout the organism. Another way to model human breast cancer is done through the targeted inhibition of a tumor suppressor gene. Mice in genetic researchIn 1909, Clarence C. Little developed the first inbred strain, the DBA (Dilute, brown non-Agouti) mouse. In 1915, N.M Haldane identified first linkage in mouse between Albino mice and pink eye dilution on chromosome seven.
In 1921, C57BL became one of the most widely used mice in genetics and was the first strain to have its genome sequenced. In 1982, Palmiter and Brinster implanted a foreign gene into fertilized egg, finally generating the first transgenic mice genetically engineered to express dominant oncogenes. In 1982, the stimulation of expression from the MMTV-LTR (Mouse mammary tumor virus-Long terminal repeat) was done by multiple rounds of pregnancy and lactation to evaluate the relevance of a cellular proto-oncogene, c-myc. Human and mouse: a genomic comparisonGenetic studies of common diseases in humans suffer significant limitations for practical and ethical reasons. Human cell lines can be used to model disease but it is difficult to study processes at the tissue level, within an organ or across the entire body.
Mice can be a good representation of diseases in humans because:. There are close similarities of physiology, development and cell biology between mice and humans. Humans and mice both have around 30,000 protein-coding genes. The number of mouse genes without a corresponding human homologue is less than 1%. 90% of the human and mouse genomes are syntenic. 40% of both human and mouse genomes can be aligned at the nucleotide level. Mice have relatively short gestation periods. Mice take a brief time to reach sexual maturity. Mice have large litter sizes.
The availability of hundreds of mutations affecting almost every tissue and aspect of development. Mice may not be an ideal model for breast cancer. This is mainly due to the lack of precision in many of the models. When looking at metastasis, it is difficult to determine the precise location as well as its frequency. Another issue revolves around the epithelial sub types and the inability to specifically target them when targeting a mutation.
An example of this would be determining the development of tumors in K14-Cre BRCA2 mice. In a standard case, the excision of BRCA2 resulted in no tumorgenesis, but if p53 was mutated and inactivated, tumorgenesis would occur. Therefore, there is not a definitive answer in terms of the origin of the tumor, due to the extra mutation in p53. Metastatic mouse mammary carcinoma cell linesVarious mouse mammary carcinoma cell lines, like 4T1 and TS/A, are metastatic in syngeneic immunocompetent mice and can be used to identify genes and pathways involved in the metastatic process. Simple tumor transplantation modelsTransplantation of tumor cells into immunodeficient mice is a tool to study breast cancer and its metastatic effects. The transplantation occurs as either allotransplants or xenographic transplants.
Commonly, human cells are inoculated in an immunocompromised murine recipient. Inoculating cells through intra ductal transplantations, by cleared mammary fat pad injections or by transplantations into the tail vein. Different organs can be seeded with breast cancer cells depending on the route of injection Cardiac injection: Bone Tail vein injection: Lung Splenic injection: Liver Carotid artery Injection: BrainTumor tissue transplant modelsThe specific immunodeficient mice that were used were the NOD/SCID mouse (non-obese diabetic/severe conditional immunodeficient). These mutations allow for the integration of new xenograft tissue. The mouse must first have their mammary fat pads humanized by injecting human telemorase-immortalized human mammary stromal fibroblasts(RMF/EG fibroblasts) into the mammary fat pads. Without this injection, the human mammary epithelial cells en-grafted onto the pad are unable to colonize and grow.
The RMF/EG fibroblast must then be irradiated to allow the expression of key proteins and growth factors. After 4 weeks of development, the newly en-grafted human mammary epithelial cells expanded within the fat pad. Genetically engineered mice to study metastasisGenetically engineered mice are constructed to model human phenotypes and pathologies. Mutant mice may include transgenes using different delivery methods: The use of bacteria-derived tetracycline-inducible system permitting the switching on or off (Tet-On/Tet-Off system) Targeted mutations by knock in gene and knock out sequence by using Cre-Lox recombination system Introduction of retro viral mutations Introduction of chemically induced mutationsTransgenic mouse models of breast cancerThe mice undergoing the process of transgenesis are known as transgenic mice. A basic transgene has a promoter region, Protein coding sequence, Intron and a stop codon.
Mouse mammary tumor virus (MMTV), is a retro virus that has been a known promoter to cause breast tumors once activated. MMTV is a heritable somatic mutagen whose target range is limited. It harbors a regulatory DNA sequence called the long terminal repeat (LTR), which promotes steroid-hormone-inducible transcription. Tumorgenesis that was induced by the mouse mammary tumor virus can also be done by integration of the viral genome. The sites of integration have been known to be critical genes for cellular regulation.
Whey acidic protein (WAP), is another common promoter used to generate mouse mammary cancer models. For a list of other mammary gland specific promoters and mouse models see. MMTV-PyMTMMTV-PyMT is the model of breast cancer metastasis, in which MMTV-LTR is used to drive the expression of mammary gland specific polyomavirus middle T-antigen, leading to a rapid development of highly metastatic tumors. MMTV-PyMT is the most commonly used model for the study of mammary tumor progression and metastasis. MMTV-PyMT mice are then crossed bred with other genetically modified mice to generate various types of breast cancer models, including: PI3K/Akt signalling in metastasis can be demonstrated in MMTV-PyMT; Akt1/ mice.
Chemoattractive paracrine loop of colony-stimulating factor-1 (CSF-1) and EGF ligands between tumor-associated macrophages (TAMs) and tumor cells, and the lung metastasis can be studied by crossing MMTV-PyMT mice with Csf-1/ mice. The role of an innate and adaptive immune response to assist metastasis can be studied in MMTV-PyMT; Rag1/ mice in which CD4 T cells are selectively lost. Interleukin-4 (IL4) lacking model of MMTV-PyMT; IL4/ mice. Role of the adhesion molecule CD44 in lung metastasis. Conditional ablation in MMTV-PyMT breast cancer cells has been done to reveal pro-metastatic actions of the angiogenic factors, Vascular endothelial growth factor A (VEGF-A). The role of autocrine transforming growth factor beta 1(TGF-1) signaling on motility and survival in PymT cells derived from an MMTV-PymT mouse mammary cancer.
Others are MMTV-PyMT; uPA-/- and MMTV-PyMT; MEKK1-/-.MMTV-HER2/neuThe MMTV-LTR can also be used to promote receptor tyrosine-protein kinase ErbB2 to transform the mouse mammary epithelium. ErbB2 is an oncogene amplified and overexpressed in around 20% of human breast cancers. The mice harbouring this oncogene develop multifocal adenocarcinomas with lung metastases at about 15 weeks after pregnancy. To create a more accurate representation of HER2 gene mutations, researchers have fused the mouse gene containing neu and a rat gene containing neu. This addresses the issue in terms of modeling the amplification of HER2 in mice development.
In the non-fused mouse, the mammary gland would revert to a near virgin, but with this addition the mammary gland maintained the developed function. Bi-transgenic modelsMouse models having two transgenes are called bi transgenic. To check the cooperation of two oncogenes, Tim Stewert and group made the first bi-transgenic mouse models in 1987, MMTV-Myc and MMTV- Ras mice were crossed with a resulting acceleration in tumorigenesis. Expression of TGF in the breast cancer cells of MMTV-ErbB2; MMTV-TGF double-transgenic mice can induce higher levels of circulating tumor cells and lung metastasis. Ras gene can be combined with rtTA (reverse tetracycline transactivator) to generate bi-transgenic inducible mouse model through tetracycline-controlled transcriptional activation e.g. mice carrying TetO-KrasG12D (TOR) and MMTV-rtTA (MTB), comes with the transgene expressing the reverse tetracycline transactivator (rtTA) in mammary epithelial cells.
Tri-transgenic modelsTri-transgenic mouse models constitute of more than two genes. Multiple combinations and genetic modifications are made in such a way that either one or all the genes are put into a continuously expressed status, or in a controlled fashion to activate them at different time points. For example, TOM( TetO-myc); TOR; MTB mice, where both the myc (M) and ras (R) genes are under the control of tetracycline operators. They can also both be activated or deactivated by adding doxycycline. Other combinations in this respect are TOM; Kras; MTB, where myc can be induced and uninduced at various time points while Kras is in continuous expressed state, and myc; TOR; MTB model is vice versa.