The Shope Papilloma-Carcinoma Complex of Rabbits: A Model System of Neoplastic Progression and Spontaneous Regression

Kreider, John W.; Bartlett, Gerald L.

doi:10.1016/s0065-230x(08)60909-4

Cited by 106 publications

(47 citation statements)

References 72 publications

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“…HPV16 infections vary greatly in duration (57,99) and also show variation in the timing of their late gene expression. Persistent infections caused by HPV16 (at cervical epithelial sites) and CRPV (in New Zealand White rabbits) are associated with an increased risk of malignant progression (31,62,101). Although there is as yet no firm evidence to link the duration of infection with the extent of virus synthesis, many reports have revealed the importance of the host immune system in restricting papilloma growth and in stimulating regression (reviewed in references 56 and 89).…”

Section: Discussionmentioning

confidence: 99%

Life Cycle Heterogeneity in Animal Models of Human Papillomavirus-Associated Disease

Peh

Middleton

Christensen

et al. 2002

J Virol

152

171

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Animal papillomaviruses are widely used as models to study papillomavirus infection in humans despite differences in genome organization and tissue tropism. Here, we have investigated the extent to which animal models of papillomavirus infection resemble human disease by comparing the life cycles of 10 different papillomavirus types. Three phases in the life cycles of all viruses were apparent using antibodies that distinguish between early events, the onset of viral genome amplification, and the expression of capsid proteins. The initiation of these phases follows a highly ordered pattern that appears important for the production of virus particles. The viruses examined included canine oral papillomavirus, rabbit oral papillomavirus (ROPV), cottontail rabbit papillomavirus (CRPV), bovine papillomavirus type 1, and human papillomavirus types 1, 2, 11, and 16. Each papillomavirus type showed a distinctive gene expression pattern that could be explained in part by differences in tissue tropism, transmission route, and persistence. As the timing of life cycle events affects the accessibility of viral antigens to the immune system, the ideal model system should resemble human mucosal infection if vaccine design is to be effective. Of the model systems examined here, only ROPV had a tissue tropism and a life cycle organization that resembled those of the human mucosal types. ROPV appears most appropriate for studies of the life cycles of mucosal papillomavirus types and for the development of prophylactic vaccines. The persistence of abortive infections caused by CRPV offers advantages for the development of therapeutic vaccines.

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Section: Discussionmentioning

confidence: 99%

Life Cycle Heterogeneity in Animal Models of Human Papillomavirus-Associated Disease

Peh

Middleton

Christensen

et al. 2002

J Virol

152

171

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“…Cottontail rabbit papillomavirus (CRPV) is a strict species-and tissuespecific virus that infects the skin of cottontail and domestic rabbits and induces papillomas that may progress to carcinomas in the infected skin. 38 Previous studies suggest that this specificity is determined by regulatory elements within the upstream regulatory region (URR) of the virus genome. 29,30 The tissue specificity of CRPV URR is further confirmed in our novel transgenic rabbits.…”

Section: Discussionmentioning

confidence: 99%

Development of Keratoacanthomas and Squamous Cell Carcinomas in Transgenic Rabbits with Targeted Expression of EJras. Oncogene in Epidermis

Peng

Griffith

Han

et al. 1999

The American Journal of Pathology

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Activated ras genes have been frequently identified in both benign and malignant human tumors , including keratoacanthoma and squamous cell carcinoma. In this study , we developed two lines of transgenic rabbits in which the expression of EJras has been specifically targeted to the rabbit epidermal keratinocytes , using the upstream regulatory region of cottontail rabbit papillomavirus. All of the F1 transgenic progenies developed multiple keratoacanthomas at about 3 days after birth. The rabbits developed an average of 20 tumors , which usually reached the size of approximately 1 cm in diameter and then spontaneously regressed in about 2 months , similar to keratoacanthoma regression in humans. In addition , up to 18% of the rabbits then developed squamous cell carcinoma at about 5 months of age. The expression of EJras was detectable in all of the keratoacanthomas and squamous cell carcinomas. These results strongly support the involvement of the ras oncogene in both the initiation and regression of keratoacanthoma , and in the development of squamous cell carcinomas. These novel transgenic rabbits , with their consistent tumorigenic phenotype at an early age , high similarity to the human lesions, and easy accessibility for examination , manipulation, biopsy , and treatment , should provide a unique model system for studying ras activation-related tumor initiation , regression , and progression , and for evaluating antitumor therapies. (Am J Pathol 1999, 155:315-324)Ras genes encode a family of plasma membrane-bound proteins (p21ras) that function as intermediates in cell signal transduction pathways. These proteins play a pivotal role in regulating cell growth and differentiation in nearly all studied eukaryotic cell types. 1 The activity of ras proteins as regulating switches is strictly controlled by cycling between active GTP-bound and inactive GDPbound states. 2 The active and inactive cycling of the p21ras proteins may be broken because of a point mutation at position 12, 13, or 61 of the proteins, which has been found in both experimental and spontaneous tumors. This cellular transformation property is considered to be due to the extended life and resultant accumulation of p21ras proteins in the active GTP state, 3 which leads to tumorigenesis due to loss of regulatory control of cell proliferation and differentiation. However, many aspects of ras mutation-related neoplasia still remain to be elucidated, especially the dual roles of activated ras genes in cell growth stimulation or differentiation, and its correlation with tumor initiation, regression, and progression.It is well known that carcinogenesis is a complex multistep process that usually involves mutation and/or inappropriate expression of certain cellular genes, such as the mutational activation of proto-oncogenes and the inactivation of tumor suppressor genes. Among the oncogenes, activated ras genes have been found in a wide variety of human tumors, and ranges from 10 -20% Haras activation in bladder carcinomas to 85-100% Ki-ras in colorec...

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“…They are strictly epitheliotrophic viruses and have evolved a remarkable replication strategy which depends upon the complete expression of the keratinocyte differentiation programme from stem cell to squame. This absolute dependence upon the squamous epithelial microenvironment was shown first for the cottontail rabbit papillomavirus (CRPVj Kreider & Bartlett, 1981). In papillomas induced by infection with CRPV; the basal epithelial layers are hyperplastic but viral DNA is difficult to detect.…”

Section: Infectious Cycle Of the Papillomavirusesmentioning

confidence: 99%

“…If the target cell for infection is indeed a stem cell this does offer an explanation for some aspects of the papillomavirus infectious cycle. There is the interesting phenomenon of the lag phase (which can be weeks or months) between infection and the first evidence of viral gene expression, seen both in the rabbit (Kreider & Bartlett, 1981;Schmitt et al, 1996) and nude mouse xenograft models (Stoler etal., 1990;Sterling etal., 1990), with anecdotal evidence in man (Oriel, 1971). An attractive explanation for this is that the virus infects the stem cell, which is out of cycle in Go' and the 3-4 week delay before viral gene expression is detectable reflects the time required for the stem cell to be recruited into the cycle and for the committed daughter cells to enter the transit cycling population of the epithelium (which includes the basal and parabasal cells), permissive for immediate early viral gene expression.…”

Section: Infectious Cycle Of the Papillomavirusesmentioning

confidence: 99%

In vitroand Animal Models for Antiviral Therapy in Papillomavirus Infections

Stanley

Masterson

Nicholls

1997

Antivir Chem Chemother

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SummaryThe need for antiviral therapies for papillomavirus infections is well recognized but the difficulties of reproducing the infectious cycle of papillomaviruses in vitro has hindered our understanding of virus-cell interactions and the regulation of viral gene expression during permissive growth. Recent advances in understanding the temporal expression and function of papillomavirus proteins. has enabled consideration of a targeted approach to papillomavirus chemotherapy and in particular the inhibition of viral replication by targeting the El and E2 proteins. There are in vitro culture systems available for the screening of new chemotherapeutic agents, since significant advances have been made with culture systems which promote epithelial differentiation in vitro. However, to date, there are no published data which show that virions generated in vitro can infect keratinocytes and initiate another round of replication in vitro. In vivo animal models are therefore necessary to assess the efficacy of antivirals in preventing and treating viral infection, particularly for the low-risk genital viruses which are on the whole refractory to culture in vitro. Although papillomaviruses affect a wide variety of hosts in a species-specific manner, the animals most useful for modelling papillomavirus infections include the rabbit, ox, mouse, dog, horse, primate and sheep. The ideal animal model should be widely available, easy to house and handle, be large enough to allow for adequate tissue sampling, develop lesions on anatomical sites comparable with those in human diseases and these lesions should be readily accessible for monitoring and ideally should yield large amounts of infectious virus particles for use in both in vivo and in vitro studies. The relative merits of the various papillomavirus animal models available in relation to these criteria are discussed.

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The Shope Papilloma-Carcinoma Complex of Rabbits: A Model System of Neoplastic Progression and Spontaneous Regression

Cited by 106 publications

References 72 publications

Life Cycle Heterogeneity in Animal Models of Human Papillomavirus-Associated Disease

Life Cycle Heterogeneity in Animal Models of Human Papillomavirus-Associated Disease

Development of Keratoacanthomas and Squamous Cell Carcinomas in Transgenic Rabbits with Targeted Expression of EJras. Oncogene in Epidermis

In vitroand Animal Models for Antiviral Therapy in Papillomavirus Infections

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