Rat brain tumor models in experimental neuro-oncology: the C6, 9L, T9, RG2, F98, BT4C, RT-2 and CNS-1 gliomas

Abstract

In this review we will describe eight commonly used rat brain tumor models and their application for the development of novel therapeutic and diagnostic modalities. The C6, 9L and T9 gliomas were induced by repeated injections of methylnitrosourea (MNU) to adult rats. The C6 glioma has been used extensively for a variety of studies, but since it arose in an outbred Wistar rat, it is not syngeneic to any inbred strain, and its potential to evoke an alloimmune response is a serious limitation. The 9L gliosarcoma has been used widely and has provided important information relating to brain tumor biology and therapy. The T9 glioma, although not generally recognized, was and probably still is the same as the 9L. Both of these tumors arose in Fischer rats and can be immunogenic in syngeneic hosts, a fact that must be taken into consideration when used in therapy studies, especially if survival is the endpoint. The RG2 and F98 gliomas were both chemically induced by administering ethylnitrosourea (ENU) to pregnant rats, the progeny of which developed brain tumors that subsequently were propagated in vitro and cloned. They are either weakly or non-immunogenic and have an invasive pattern of growth and uniform lethality, which make them particularly attractive models to test new therapeutic modalities. The CNS-1 glioma was induced by administering MNU to a Lewis rat. It has an infiltrative pattern of growth and is weakly immunogenic, which should make it useful in experimental neuro-oncology. Finally, the BT4C glioma was induced by administering ENU to a BD IX rat, following which brain cells were propagated in vitro until a tumorigenic clone was isolated. This tumor has been used for a variety of studies to evaluate new therapeutic modalities. The Avian Sarcoma Virus (ASV) induced tumors, and a continuous cell line derived from one of them designated RT-2, have been useful for studies in which de novo tumor induction is an important requirement. These tumors also are immunogenic and this limits their usefulness for therapy studies. It is essential to recognize the limitations of each of the models that have been described, and depending upon the nature of the study to be conducted, it is important that the appropriate model be selected.

A systematic review and meta‐analysis of gene therapy in animal models of cerebral glioma: why did promise not translate to human therapy?

“…We have observed a wide variety of glioma models used, but those most commonly selected (GL261, U87 and C6) tend to grow quickly and relatively non‐invasively into large discreet spheres,51, 52 contrasting sharply with irregularly shaped, poorly defined, infiltrative human glioblastoma multiforme tumours 1, 8. While each cell line has certain properties that do relate to human disease—for example extensive capillary networks in U87 models,53 white matter invasion and low immunogenicity in GL261,54, 55, 56 gene mutations in C6 that are comparable to human glioma57—these tumours are appropriate for the study of particular components of glioma biology (such as angiogenesis in U87 or immune therapies in GL261) but perhaps lack the robustness for survival studies preceding translation into clinical trial. The recent emergence of the glioma stem cell hypothesis (implicating a cell with stem‐like features in the aetiology and pathogenesis of human glioma) has influenced the design of novel preclinical models,58 but these, to our knowledge, have not yet been adopted into animal studies of gene therapy.…”

Concomitant treatment of F98 glioma cells with new liposomal platinum compounds and ionizing radiation

“…The rat F98 cell line was chosen because it represents a good model of human glioblastoma [18,19]. The F98 cell line was obtained from ATCC and tested negative for the MAP assay by Charles River Laboratories (Wilmington, MA, USA).…”

Optimization of the route of platinum drugs administration to optimize the concomitant treatment with radiotherapy for glioblastoma implanted in the Fischer rat brain

“…F98 model was also chosen because it is known to adequately reproduce the behaviour of human GBM, particularly in terms of its response/resistance to chemo-and radiotherapy. [13,14]. The F98 cell line was obtained from American Type Culture Collection (Manassas, VA, USA) and tested negative for the MAP assay by Charles River Laboratories (Wilmington, MA, USA).…”