Clinical and pathological features of the murine AT‐84 orthotopic model of oral cancer

Lou, Emil; Kellman, RM; Hutchison, Robert; Ej, Shillitoe

doi:10.1034/j.1601-0825.2003.00968.x

Cited by 20 publications

(21 citation statements)

References 14 publications

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“…120 Since its recent first description, this technique has been utilized for studying the interaction between head and neck tumor tissue and its clinically relevant local environment in immunocompetent animals (Table II). Recently, two alternative orthotopic syngeneic models of head and neck cancer using AT-84 cells injected into the tongue base, 58 and floor of mouth 128 of C3H/HeJ mice have shown reliable rates of tumorigenesis.…”

Section: Orthotopic Models Of Syngeneic Hnsccmentioning

confidence: 99%

Animal models for the study of squamous cell carcinoma of the upper aerodigestive tract: A historical perspective with review of their utility and limitations. Part A. Chemically‐induced de novo cancer, syngeneic animal models of HNSCC, animal models of transplanted xenogeneic human tumors

Smith

Thomas

2005

Intl Journal of Cancer

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Understanding the complex histological, genetic and molecular changes that lead to malignant transformation of squamous epithelia of the head and neck will likely guide the development of methods for improved diagnosis, monitoring and treatment of head and neck squamous cell carcinoma (HNSCC). The development and use of animal models that closely mimic the histopathology and molecular pathogenesis of HNSCC in humans would greatly expand the research possibilities and provide a means of testing potential therapeutic agents. However, many available animal models of HNSCC fall short of this objective. In order for investigators to select the appropriate model to answer scientific questions, it is important to understand the benefits and limitations of available animal models for the study of HNSCC. The purpose of this work is to give an overview of the most pertinent animal models of HNSCC, and to discuss future directions of research in this field. ' 2005 Wiley-Liss, Inc.Head and neck squamous cell carcinoma (HNSCC) involves the upper aerodigestive tract and can destroy the structure and function of organs involved in voice, speech, taste, smell and hearing, as well as vital structures necessary for survival. Approximately half of all patients with HNSCC have advanced stage disease at the time of diagnosis, with an expected 5-year survival rate between 10 and 40%.1 Despite treatments that may consist of mutilating surgery, radiotherapy and/or chemotherapy, overall long-term survival remains low due to uncontrollable persistent or recurrent disease. The survival rate of patients with locoregional and distant recurrences has highlighted the need for new approaches for diagnosis and treatment. To this end, a better understanding of the genetic, molecular and immunoregulatory processes leading to neoplastic transformation and progression of HNSCC is needed, so that novel and more effective diagnostic and therapeutic approaches can be designed.Although in vitro study systems are useful for studying the interactions between different cell populations in culture and are convenient and simple to use, they do not reproduce the complexity of HNSCC. For this reason, the development of new therapies will require clinically relevant animal models of HNSCC. Adequate animal models are necessary to test the translational potential of preventive and therapeutic agents, as well as to understand the biological mechanisms of epithelial carcinogenesis and progression. The ideal experimental animal tumor model for HNSCC must reproduce the characteristic features of the disease, including the complicated patterns of tumor-host interactions such as immune response, angiogenesis, invasion and metastasis. In the ideal model, clinical symptoms and laboratory abnormalities should be similar to the human disease and therapeutic agents should be as effective in both systems. The ideal model must also be easy to use, accessible to genetic and immunologic manipulations, reproducible and progress rapidly to allow timely investigations.Animal mod...

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Section: Orthotopic Models Of Syngeneic Hnsccmentioning

confidence: 99%

Animal models for the study of squamous cell carcinoma of the upper aerodigestive tract: A historical perspective with review of their utility and limitations. Part A. Chemically‐induced de novo cancer, syngeneic animal models of HNSCC, animal models of transplanted xenogeneic human tumors

Smith

Thomas

2005

Intl Journal of Cancer

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“…1, would be NK cells, and functional studies of lymphoid cells taken from the tumors could be done to test this. However, the inflammatory infiltrate to the tumors is sparse whether they are infected with HSV-1 (2) or are not infected (1). It would be difficult to obtain enough cells to study and for this reason and because the therapeutic effect was small, the question was not pursued further.…”

Section: Limitations Of Hsv-1 As An Oncolytic Virusmentioning

confidence: 99%

“…The murine oral cancer cell line, AT-84, was obtained from Dr. S. Karp (Medical College of Virginia, Richmond, VA) and was maintained and used to induce oral cancers in mice as described previously (1,2). The proportion of cells that were in the S phase was measured by staining with 40 Ag/mL propidium iodide followed by flow cytometry using a Becton Dickinson BDLSRII Flow Cytometer with fluorescence-activated cell sorting DiVa acquisition software and ModFit LT analysis software (Verity Software House, Inc., Topsham, ME).…”

Section: Tumor Cellsmentioning

confidence: 99%

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Factors That Limit the Effectiveness of Herpes Simplex Virus Type 1 for Treatment of Oral Cancer in Mice

Shillitoe

Pellenz²

2005

Clinical Cancer Research

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Although the growth of experimental oral cancers can be inhibited by infection with the herpes simplex virus type 1 (HSV-1), the effect is incomplete. To define factors that might limit the effectiveness of the virus, we examined the roles of the innate immune system and the replication status of the tumor cells. AT-84 tumors were induced in strains of mice that had specific immune defects and were treated with the virus. Explanted tumors and tumor cells in culture were also infected. No differences in viral replication or in the effect of virus on the tumor were seen between mice with a lack of Tor B lymphocytes, natural killer cells, phagocytic spleen cells, or complement. The virus did not replicate significantly more in tumors that were maintained as explants. Immediately after recovery of cells from a tumor the proportion of cells in the S phase was around 18%, and replication of virus in those cells was very limited. After 3 weeks in culture, the proportion in S had increased to 50% and both the recovery of virus from the cells and the toxic effect of the virus on the cells had increased significantly. The innate immune system thus seemed to have a minimal effect on replication of HSV-1when used as an oncolytic virus for oral cancers in mice. Instead, the fraction of cells in the S phase was important. Because human oral cancers, like mouse tumors, have a low fraction of cells in the S phase, it is likely that the in vivo use of HSV-1as cancer therapy will be limited by the replication of the virus.Several recent studies have evaluated the potential of replication-competent strains of herpes simplex virus type 1 (HSV-1) for therapy of cancer. Because the virus is able to multiply within tumor cells, it could be expected to proliferate throughout a tumor, thus eliminating it (1). One tumor type that might benefit from this is squamous cell cancer of the mouth, which arises from the mucous membrane that is the natural host for HSV-1. However, despite the attractiveness of oncolytic viral therapy for oral cancer, the results have yet to match the expectations. In a previous study with the AT-84 mouse model, we found that wild-type HSV-1 was rapidly eliminated from the tumors, and although the growth of the tumor was reduced while the virus was present, it resumed after the virus was lost (2). The injection of a second dose of virus gave greater inhibition of the tumor, which is consistent with the idea that the concentration of virus in the tumor is an important determinant of its antitumor effect. We thus concluded that replication of the virus within the tumor was essential for the optimal antitumor effect and that the limited results to date can be attributed to failure of the virus to multiply effectively.One possible explanation for failure of HSV-1 to replicate in tumors would be the effects of the immune response, either innate or acquired. In a rodent model of glioblastoma multiforme, it has been shown that replication of HSV-1 is inhibited by the animals' immunity. Complement and natural ant...

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“…23 The main goal of our study was the development of novel orthotopic models of HPV-associated HN cancer that may better predict clinical outcome of new immunotherapeutic approaches in a pre-clinical setting. A model of HPV-unrelated OSCC had been already developed by injecting AT-84 cell line, derived from a naturally-occurring OSCC of C3H mice, into the mouth pavement through an extra-oral route.…”

Section: Immunotherapy In New Pre-clinical Models Of Hpv-associated Omentioning

confidence: 99%

Immunotherapy in new pre-clinical models of HPV-associated oral cancers

Paolini

Massa

Manni

et al. 2013

Human Vaccines & Immunotherapeutics

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Clinical and pathological features of the murine AT‐84 orthotopic model of oral cancer

Abstract: The similarities to human oral cancer suggest that the model will be very useful in the evaluation of experimental therapies for oral cancer.

Cited by 20 publications

References 14 publications

Animal models for the study of squamous cell carcinoma of the upper aerodigestive tract: A historical perspective with review of their utility and limitations. Part A. Chemically‐induced de novo cancer, syngeneic animal models of HNSCC, animal models of transplanted xenogeneic human tumors

Animal models for the study of squamous cell carcinoma of the upper aerodigestive tract: A historical perspective with review of their utility and limitations. Part A. Chemically‐induced de novo cancer, syngeneic animal models of HNSCC, animal models of transplanted xenogeneic human tumors

Factors That Limit the Effectiveness of Herpes Simplex Virus Type 1 for Treatment of Oral Cancer in Mice

Immunotherapy in new pre-clinical models of HPV-associated oral cancers

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