Epstein-Barr virus (EBV) infects cells in latent or lytic forms, but the role of lytic infection in EBV- DLBCL). Animals infected with the control virus developed tumors more frequently than Z-KO virus-infected animals. Specific immune responses against EBV-infected B cellswere generated in mice infected with either the control virus or the Z-KO virus. In both cases, forms of viral latency (type I and type IIB) were observed that are less immunogenic than the highly transforming form (type III) commonly found in tumors of immunocompromised hosts, suggesting that immune pressure contributed to the outcome of the infection. These results point to an important role for lytic EBV infection in the development of B cell lymphomas in the context of an active host immune response.

Animal models, particularly mouse models, play a central role in the study of the etiology, prevention and treatment of human prostate cancer (PCa). While tissue culture models are extremely useful in understanding the biology of PCa, they cannot recapitulate the complex cellular interactions within the tumor microenvironment that play a key role in cancer initiation and progression. The NCI Mouse Models of Human Cancers Consortium convened a group of human and veterinary pathologists to review the current animal models of PCa and make recommendations regarding the pathological analysis of these models. Over 40 different models with 439 samples were reviewed including genetically engineered mouse models, xenograft, rat and canine models. Numerous relevant models have been developed over the last 15 years and each approach has strengths and weaknesses. Analysis of multiple genetically engineered models has shown that reactive stroma formation is present in all the models developing invasive carcinomas. In addition, numerous models with multiple genetic alterations display aggressive phenotypes characterized by sarcomatoid carcinomas and metastases, which is presumably a histological manifestation of epithelial-mesenchymal transition. The significant progress in development of improved models of PCa has already accelerated our understanding the complex biology of PCa and promises to enhance development of new approaches to prevention, detection and treatment of this common malignancy.

Stearoyl-CoA desaturase-1 (SCD1) catalyzes the synthesis of monounsaturated fatty acids and is an important regulator of whole body energy homeostasis. Severe cutaneous changes in mice globally deficient in SCD1 also indicate a role for SCD1 in maintaining skin lipids. We have generated mice with a skinspecific deletion of SCD1 (SKO) and report here that SKO mice display marked sebaceous gland hypoplasia and depletion of sebaceous lipids. In addition, SKO mice have significantly increased energy expenditure and are protected from high fat diet-induced obesity, thereby recapitulating the hypermetabolic phenotype of global SCD1 deficiency. Genes of fat oxidation, lipolysis, and thermogenesis, including uncoupling proteins and peroxisome proliferator-activated receptor-␥ co-activator-1␣, are up-regulated in peripheral tissues of SKO mice. However, unlike mice globally deficient in SCD1, SKO mice have an intact hepatic lipogenic response to acute high carbohydrate feeding. Despite increased basal thermogenesis, SKO mice display severe cold intolerance because of rapid depletion of fuel substrates, including hepatic glycogen, to maintain core body temperature. These data collectively indicate that SKO mice have increased cold perception because of loss of insulating factors in the skin. This results in up-regulation of thermogenic processes for temperature maintenance at the expense of fuel economy, illustrating cross-talk between the skin and peripheral tissues in maintaining energy homeostasis.Obesity is a multifactorial disease stemming from a combination of genetic, dietary, and lifestyle factors and the interaction between these components (1-3). The microsomal enzyme, stearoyl-CoA desaturase-1 (SCD1), 3 is a critical control point in the development of metabolic diseases, including obesity and insulin resistance. SCD1 catalyzes the conversion of saturated fatty acids, such as palmitate (16:0) and stearate (18: 0), into their ⌬-9 monounsaturated products, palmitoleate (16:1 n-7) and oleate (18:1 n-9), respectively. Mice lacking the SCD1 enzyme because of a global deletion of the Scd1 gene (GKO) are lean and protected from diet-induced and leptin deficiency-induced obesity. These mice have a marked increase in energy expenditure and almost complete protection from high fat diet-induced weight gain and glucose intolerance (4 -10). Because SCD1 is expressed in multiple tissues, including liver, brown and white adipose tissue, skeletal muscle, and skin, it has been difficult to determine the relative contributions of these tissues to the dramatically altered metabolic phenotypes of GKO mice. Studies using antisense oligonucleotide-mediated approaches to knock down Scd1 expression have reported protection from diet-induced weight gain and hepatic insulin resistance upon hepatic SCD1 inhibition (11-13). However, whereas the liver is a major target of these antisense oligonucleotides, they have also been reported to affect expression of target genes in adipose tissue (13,14) and possibly other organs (15). Using Cre re...

Mre11, Rad50, and Nbs1 function in a protein complex that is central to the metabolism of chromosome breaks. Null mutants of each are inviable. We demonstrate here that hypomorphic Rad50 mutant mice (Rad50 S/S mice) exhibited growth defects and cancer predisposition. Rad50 S/S mice died with complete bone marrow depletion as a result of progressive hematopoietic stem cell failure. Similar attrition occurred in spermatogenic cells. In both contexts, attrition was substantially mitigated by p53 deficiency, whereas the tumor latency of p53 −/− and p53 +/− animals was reduced by Rad50 S/S . Indices of genotoxic stress and chromosomal rearrangements were evident in Rad50 S/S cultured cells, as well as in Rad50 S/S and p53 −/− Rad50 S/S lymphomas, suggesting that the Rad50 S/S phenotype was attributable to chromosomal instability. These outcomes were not associated with overt defects in the Mre11 complex's previously established double strand break repair and cell cycle checkpoint regulation functions. The data indicate that even subtle perturbation of Mre11 complex functions results in severe genotoxic stress, and that the complex is critically important for homeostasis of proliferative tissues.

Disruption of the murine Mop3 (also known as Bmal1 or Arntl) locus results in a loss of behavioral and molecular circadian rhythms. Although Mop3 null mice do not display anomalies in early development, they do display reduced activity as they age. In an effort to explain this decreased activity, we characterized the physiological and anatomical changes that occurred with age. We observed that Mop3 null mice display an increased mortality after 26 weeks of age and a phenotype best described as a progressive noninflammatory arthropathy. Although little pathology is observed prior to 11 weeks of age, by 35 weeks of age essentially all Mop3 null animals develop joint ankylosis due to flowing ossification of ligaments and tendons and almost complete immobilization of weight-bearing and nonweight-bearing joints. This pathology appears to explain the decreased activity of Mop3 null mice and suggests that MOP3 is an inhibitor of ligament and tendon ossification.

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In October 2010, a pathology review of rodent models of intestinal neoplasia was held at The Jackson Laboratory. This review complemented 2 other concurrent events: a workshop on methods of modeling colon cancer in rodents and a conference on current issues in murine and human colon cancer. We summarize the results of the pathology review and the committee’s recommendations for tumor nomenclature. A virtual high-resolution image slide box of these models has been developed. This report discusses significant recent developments in rodent modeling of intestinal neoplasia, including the role of stem cells in cancer and the creation of models of metastatic intestinal cancer.

Alterations of the Wnt/B-catenin signaling pathway are positively associated with the development and progression of human cancer, including carcinoma of the prostate. To determine the role of activated Wnt/B-catenin signaling in mouse prostate carcinogenesis, we created a mouse prostate tumor model using probasin-Cre-mediated deletion of Apc. Prostate tumors induced by the deletion of Apc have elevated levels of B-catenin protein and are highly proliferative. Tumor formation is fully penetrant and follows a consistent pattern of progression. Hyperplasia is observed as early as 4.5 weeks of age, and adenocarcinoma is observed by 7 months. Continued tumor growth usually necessitated sacrifice between 12 and 15 months of age. Despite the high proliferation rate, we have not observed metastasis of these tumors to the lymph nodes or other organs. Surgical castration of 6-week-old mice inhibited tumor formation, and castration of mice with more advanced tumors resulted in the partial regression of specific prostate glands. However, significant areas of carcinoma remained 2 months postcastration, suggesting that tumors induced by Apc loss of function are capable of growth under conditions of androgen depletion. We conclude that the prostate-specific deletion of Apc and the increased expression of B-catenin associated with prostate carcinoma suggests a role for B-catenin in prostate cancer and offers an appropriate animal model to investigate the interaction of Wnt signaling with other genetic and epigenetic signals in prostate carcinogenesis.