Commonly used mouse models of osteosarcoma

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Abstract

Osteosarcoma is the commonest primary tumour of bone and the second highest cause of cancer-related death in the paediatric age group. Little is known of the aetiology of human osteosarcoma and lesser still of the various interactions that occur between host and tumour cells that govern growth and progression of osteosarcoma in vivo. Although numerous osteosarcoma cell lines have been established and characterized in vitro, some as far back as in the 1960s, there is a scarcity of reliable and reproducible in vivo animal models that mimics all aspects of the human condition at the temporal, physiological and histopathological level, hence, making the accurate testing of therapeutic strategies difficult. Given that osteosarcoma is a disease that affects young people and better disease management strategies are essential, development of a robust human osteosarcoma model is long overdue.

Introduction

Osteosarcoma, although a relatively uncommon malignancy, is the commonest primary tumour of bone and the second highest cause of cancer-related death in the paediatric age group. Children and adolescents are most commonly affected, with the peak incidence corresponding to the period of rapid skeletal growth. Although modern multimodality treatment has significantly improved tumour resectability and the long-term outcome of these patients, 25–50% of patients with initially non-metastatic disease, subsequently develop metastases, and this remains the major cause of death from this condition [1]. Greater than 30% of patients develop lung metastasis despite aggressive combination chemotherapy and surgery.

To date, relatively little is known as to the aetiology of human osteosarcoma. Even less is known of the various interactions that occur between host and tumour cells that govern growth and progression of osteosarcoma in vivo. The use of mouse models in science has now become an integral part of basic and clinical cancer research [2]. Mouse models of osteosarcoma can invariably provide greater insight into the complex mechanisms that underlie the development and pathogenesis of this aggressive tumour. Moreover, there is the potential to test various therapeutic agents and observe the in vivo response, not only at the primary site, but also in terms of the development of metastases.

Ideally, a mouse model should aim to replicate virtually all facets of the human disease, specifically with regards to tumour biology, genetics, aetiology and response to therapeutic agents. For osteosarcoma, the desired attributes would include an osteoblast-like cell line that would develop reliably after inoculation, within a short latent period, and allow for the analysis of tumour progression and spread within the relatively short lifespan of the mouse. Models should also demonstrate the expression of the several osteoblastic markers that are distinctive of osteosarcoma, such as alkaline phosphatase (ALP), pro-α1-collagen (COL), osteopontin (OPN), matrix Gla protein (MGP) and osteocalcin (OCN) [3]. Some of these biomarkers are not present in cultured cells but re-express when cells are inoculated in vivo [4]. In addition, it should display the characteristic production of an osteoid matrix. Furthermore, in order to be clinically relevant, an in vivo model of osteosarcoma should be able to spontaneously develop pulmonary metastases, which is the most common site of distant spread in the human condition.

However, the development of an “ideal” model of osteosarcoma has proven to be particularly difficult. Although numerous osteosarcoma cell lines have been established and characterized in vitro, there is a scarcity of reliable and reproducible in vivo animal models that closely recapitulates all aspects of the human condition at the temporal, physiological and histopathological level. In this review we will highlight the currently used mouse models for the study of osteosarcoma, and discuss the advantages and limitations of these models and also address recent advancements and remaining challenges in this field of cancer research.

Section snippets

Historical perspective

The first models of osteosarcoma in animals were developed as a result of scientists investigating the carcinogenic effects of radioactive substances or the administration of various chemicals. Several researchers, including Daels (1926), Sabin (1932) and Schurch (1935) were able to induce osteosarcoma de novo in the bones of experimental animals exposed to highly radioactive material [5]. However, it was in 1938 that Brunschwig et al. were able to generate osteosarcoma in the tibia of a mouse

Murine osteosarcoma cell lines

Murine (mouse or rat) osteosarcoma cell lines, such as UMR 106-01, K7M2 and K12, have been used successfully as metastatic models of osteosarcoma. One possible advantage of using this species of cells in a mouse is that murine osteosarcoma cells are grown in a murine microenvironment—a syngeneic model. Therefore, this potentially allows for a more physiological study of the interaction between tumour and host, and vice versa.

Human osteosarcoma cell lines

Although several human osteosarcoma cells lines have been studied in depth in vitro, there is still the need for an in vivo model of human osteosarcoma that can be used to more accurately study the key genetic aberrations contributing to tumour invasion and metastasis, and also to develop specific agents to target these.

Summary/future directions

Thus, there are only two murine osteosarcoma models available, both having been characterised to some extent regarding usage in vitro and in vivo. For human osteosarcoma, however, there is no one cell line that truly satisfies all requirements for procurement of a good clinically relevant osteosarcoma model, therefore, making the accurate testing of therapeutic strategies very difficult. Given that osteosarcoma is a disease that affects young people and better disease management strategies are

Reviewers

Dr. T.-C. He, Molecular Oncology Laboratory, The University of Chicago Center, 5841 South Maryland Avenue, MC 3078, Room J-611, Chicago, IL 60637, U.S.A.

Dr. N. Koshkina, Division of Pediatrics, University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston 77230, U.S.A.

Acknowledgements

The authors would like to acknowledge the generous support of the Australian Orthopaedic Association, the Victorian Orthopaedic Research Trust Grant and the Cancer Council of Victoria. Dr. Eugene T.H. Ek is supported by scholarships awarded by the Faculty of Medicine, University of Melbourne, the Royal Australasian College of Surgeons, and the National Health and Medical Research Council of Australia (NH&MRC).

Prof. Peter F.M. Choong Professor and Director of Orthopaedics, St. Vincent's Hospital, Melbourne. He is an esteemed orthopaedic surgeon and a world-renowned authority on musculoskeletal oncology.

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    Prof. Peter F.M. Choong Professor and Director of Orthopaedics, St. Vincent's Hospital, Melbourne. He is an esteemed orthopaedic surgeon and a world-renowned authority on musculoskeletal oncology.

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