Abstract
Simple retroviruses have gag (structural), pol (polymerase), and env (envelope) genes, but have no identified oncogenes and usually require long incubation times for tumor development since tumorigenesis in these instances is thought to occur by insertional mutagenesis. However, newborn lambs infected with jaagsiekte sheep retrovirus (JSRV), a simple retrovirus, rapidly (4–6 weeks) develop multiple lung tumors. Two recent papers have implicated the env gene of JSRV as being oncogenic. In the first, mouse NIH 3T3 fibroblast cells were transformed by transfection with JSRV DNA constructs. Transfection of JSRV DNA containing all active genes was transforming. Deletion of gag, pol, and an alternative open reading frame in pol did not abrogate transformation. The JSRV env gene alone was transforming, but a truncated env gene was not. In the second paper, the JSRV env protein is shown to bind HYAL2 and also that the env gene is able to transform rat embryo fibroblasts. HYAL2 is a hyaluronidase-related protein, but lacks hyaluronidase activity. It has features of a cell surface anchored signaling protein and mediated entry of JSRV into host cells. Although HYAL2 has unknown function in the host cell, the authors speculate that it may act as part of a cellular mitogenic signaling cascade, conferring part or all of the transforming capability of env. These papers describe a novel transforming agent, and presumably oncogenic agent, the envelope gene in a simple retrovirus.
Maeda N, Palmarini M, Murgia C, Fan H: Direct transformation of rodent fibroblasts by jaagsiekte sheep retrovirus DNA. Proc Natl Acad Sci USA
Contributed by Dr. K. A. Schafer, Wyeth-Ayerst Research, Chazy, NY
Great Britain is currently experiencing a major outbreak of foot-and-mouth disease, the first in 34 years. British epidemiologists have used a mathematical model to analyze the pattern of disease spread and to estimate the future disease incidence and the efficacy of different approaches to intervention. While slaughter of infected herds within the shortest possible time following diagnosis will probably slow the epidemic, more effective methods can be implemented, in particular ring culling or ring vaccination. These rely on rapidly slaughtering or vaccinating all susceptible animals within a certain radius of newly diagnosed infected animals. Ring vaccination requires a larger ring diameter, since vaccination does not remove the animals that are already infected with the disease. Extensive culling appears to be the most effective way to control the epidemic, although decay of the epidemic would still be expected to require several months.
Ferguson N, Donnelly C, Anderson R: The foot-and-mouth epidemic in Great Britain: pattern of spread and impact of interventions. Science, 2001 (published online April 12, 2001)
Ciliary neurotrophic factor (CNTF) was originally characterized as a growth factor for motor neurons. In human trials of CNTF in motor neuron diseases, patients had unexpected and substantial weight loss. The authors of a recent paper demonstrate that CNTF is able to cause weight loss via leptin-like hypothalamic pathways in diverse obesity animal models, such as in leptin deficient mice and rodent dietary models, including leptin-resistant models. In addition, because CNTF hypothalamic signaling does not trigger increased appetence in the presence of decreased food intake, withdrawal of CNTF does not result in overeating and increased weight gain, unlike food deprivation as a means of weight loss. CNTF binds receptors that are both related to leptin receptors and are distributed in the brain similarly to leptin receptors. Both leptin and CNTF appear to share JAKSTAT and other signaling pathways in the hypothalamus. However, independent CNTF pathways or divergent pathways, as yet unidentified, must exist for these differences in leptin and CNTF regulation of body fat to become apparent. Also, CNTF does not appear to produce a cachetic weight loss like that of other pleiotrophic cytokines, such as IL-1.
Lambert PD, Anderson KD, Sleeman MW, Wong V, Tan J, Hijarunguru A, Corcoran TL, Murray JD, Thabet KE, Yancopoulos GD, Wiegand SJ: Ciliary neurotrophic factor activates leptin-like pathways and reduces body fat, without cachexia or rebound weight gain, even in leptin-resistant obesity. Proc Natl Acad Sci USA
Contributed by Dr. K. A. Schafer, Wyeth-Ayerst Research, Chazy, NY
Aberrant crypt foci (ACF) arise during experimental colon carcinogenesis in rodents. In methylene blue-stained sections, these lesions appear as enlarged crypts with thickened epithelium and reduced lumina. ACF are regarded by some investigators as precursor lesions for colon cancer. A recent Japanese study showed that the number of ACF in rats given azoxymethane remained static during the 20-week course of the experiment and that ACF did not develop significant histologic atypia as measured by nuclear/cytoplasmic ratio, nuclear stratification, loss of nuclear polarity, or the development of other structural abnormalities. During this study, β-catenin was shown to accumulate in crypts that did not have the appearance of ACF. These “β-catenin-accumulated crypts” increased in size and number throughout the course of the study and the degree of histologic atypia in these lesions increased significantly over time. Based on these findings, the investigators have proposed that β-catenin-accumulated crypts are the true premalignant lesions for colon cancer in rodents.
Yanada Y, Yoshimi N, Hhirose Y, Matsunaga K, Katayama M, Sakata K, Shimizu M, Kuno T, Mori H: Sequential analysis of morphological annd biological properties of β-catenin-accumulated crypts, provable premalignant lesions independent of aberrant crypt foci in rat colon caricnogenesis. Cancer Res
Investigators in France and Canada characterized 27 human leiomyosarcomas by comparative genomic hybridization and by immunohistochemistry for the smooth muscle markers smooth muscle actin, common muscle actin, and desmin. Neither the pattern of genetic alterations observed nor the immunoreactivity of the tumors correlated in any way with tumor size or behavior. The most frequent genetic alteration was partial deletion of chromosome 13, with the region containing the retinoblastoma gene always being lost. An array of other genomic changes was seen that was very similar to the complex and unusual pattern of cytogenetic alterations seen in malignant fibrous histiocytoma (MFH). Based on this and other studies, the authors have suggested that the different subtypes of MFH may represent morphologic variants of other categories of soft tissue sarcoma. They further argued that MFH may not constitute a separate neoplastic entity but a final stage in the progression of diverse soft tissue sarcomas.
Derre J, Lagace R, Nicolas A, Mairal A, Chibon F, Coindre JM, Terrier P, Sastre X, Aurias A: Leiomyosarcomas and most malignant fibrous histiocytomas share very similar comparative genomic hybridization imbalances: an analysis of a series of 27 leiomyosarcomas. Lab Invest