Rodent Glioma Models: Intracranial Stereotactic Allografts and Xenografts

Abstract

Modeling human disease in small animals has been fundamental in advancing our scientific knowledge and for the development of novel therapeutic strategies. In the case of brain cancer, implantable tumor models, both intracranial and also in the periphery, have been widely used and extensively characterized. These models can be used to better understand certain aspects of tumor biology such as growth, neovascularization, response to potential therapies, and interaction with the immune system. Brain tumors from patients as well as rodents have been cultured in vitro, in an attempt to establish permanent cell lines. Human glioma tumors have also been maintained by serial passage in the flanks of immune-deficient animals, as it has been shown that it is not feasible to continuously passage them in culture. In this chapter, we describe various gliomas that have been isolated from mice, rats, and humans and subsequently used as syngeneic or xenograft tumor models in vivo. The majority of the models that we present in this chapter arose either spontaneously or by administration of chemical carcinogens. We compare and contrast the histopathological, genetic, and invasive features of the tumor lines as well as identify novel treatment modalities that have been developed. Finally, we present the procedures for intracranial implantation of tumor cells in rodents using stereotactic surgical techniques. The use of this technique enables the generation of large numbers of animals harboring intracranial tumors with relative ease and the survival of tumor-bearing animals is highly reproducible. These characteristics make the use of these in vivo models very attractive when aiming to develop and test the effectiveness of novel anticancer therapies.

Keywords: Allograft; Brain cancer; Glioma models; Neurosurgery in rodents; Stereotactic; Tumor implantation; Xenograft.

Fig. 1.

(a) Table with information relating to the biological features of syngeneic mouse GBM models including effective therapies. (b) Diagram depicting the stereotactic coordinates for injection of syngeneic mouse glioma cell lines as well as the cell number. (c) Kaplan–Meyer survival curve of mice bearing syngeneic intracranial brain tumors. C57BL/6 or VM/Dk mice implanted in the striatum with Gl26, SMA560, B16-f10, or GL261 cells.

Fig. 2.

(a) Table listing the biological features of human xenograft GBM models including effective therapies. (b) Diagram depicting the stereotactic coordinates for injection of human glioma cell lines as well as the cell number. (c) Kaplan–Meyer survival curve of mice bearing syngeneic intracranial brain tumors. Rag1-deficient mice were injected in the striatum with U87, U251, and GBM12 cells.

Fig. 3.

(a) Table with information about the biological features of syngeneic rat GBM models including effective therapies. (b) Diagram depicting the stereotactic coordinates for injection of human glioma cell lines as well as the cell number. (c) Kaplan–Meyer survival curve of rats bearing intracranial tumors. Lewis or Fisher rats were injected in the striatum with CNS-1, F98, 9L, and RG2 cells.

Fig. 4.

Schematic of a rat skull depicting the position of bregma relative to the frontal and parietal skull bones and the position for placing of the ear bars. Adapted from: The Rat Brain in Stereotaxic Coordinates, Academic Press, New York, 1998.

Fig. 5.

(a) Fisher rats were implanted in the striatum with 50,000 F98 cells or 500,000 9L cells, and Lewis rats were injected with 4,500 CNS-1 cells. Brains were harvested at the indicated time points. Microphotographs show the appearance of representative brain tumor sections stained with Nissl. (b) Nude mice were implanted with 1 × 10⁶ U251 human glioma cells. Animals were sacrificed at the specified time points. Microphotographs show the appearance of representative brain tumor sections stained with Nissl.