The use of mouse models for human cancer in preclinical trials requires the identification of mice with tumors and quantitation of their tumor size for stratification, measurements of growth rate, and treatment response. In the case of mouse models for brain tumors, the identification of mice with tumors is complicated because of the inability to detect their presence because of their location within the cranial cavity. The development of noninvasive imaging techniques is necessary for maximizing the information available from these novel models.
In humans, low-grade gliomas are typically seen as areas of hypointense signal on T1 (spin-lattice relaxation time)-weighted scans and hyperintense signal on T2 (spin-spin relaxation time)-weighted scans, and do not enhance with gadolinium diethylenetriamine pentaacetic acid (Gd-DTPA) [1–3
]. The biological properties that correlate with these imaging characteristics are proposed to be an intact blood-brain barrier and edema surrounding the tumor cells. In contrast, glioblastomas reveal marked contrast enhancement indicating a disrupted blood-brain barrier, and nonenhancing regions within the tumor that correlate with foci of necrosis [1–3
]. Therefore, magnetic resonance imaging (MRI) is used to identify the presence of these tumors, to follow their response to therapy, and to provide evidence of residual or recurrence of disease.
MRI has been used to examine experimental brain tumors in rodents in diverse models [4–10
]. Many of these studies utilized T1- and T2-weighted imaging techniques [4–6,8
], which were found to be quantitative based upon phantom studies [6
]. More recently, diffusion-weighted imaging has been added in brain tumor studies [9,10
]. Chenevert et al. [5,9
] suggested that diffusion-weighted imaging could provide a surrogate marker for treatment response in patients based upon rodent tumor studies. MRI and magnetic resonance spectroscopy (MRS) have also been used to study other tumor models and to provide metabolic and anatomic information [11–15
]. Other imaging modalities including optical imaging [16–20
], computed tomography [21
], and radionuclide imaging have also been used to study rodent tumors [22–25
MRI can be utilized to screen and identify mice harboring brain tumors, and the imaging characteristics of the tumors could potentially be used as one criterion of efficacy for strategies being developed and tested. In order to use such technology in this manner, baseline investigations correlating the imaging properties of brain tumors in mice with their histologic properties are necessary. Subsequent studies to determine how the tumor and its physiological parameters have changed in response to treatment need to be done noninvasively. In order to perform such studies, mouse modeling systems that generate tumors with defined histologies mimicking human gliomas are required.
The RCAS/tv-a system has been used to generate several glioma types that are similar both in histology and genetics to that found in humans. This system utilizes avian RCAS retroviral vectors that transfer genes to mammalian cells only if they express the receptor for RCAS known as TVA [26
]. TVA is not normally expressed in mammals but can be expressed as a transgene from tissue-specific promoters in transgenic mice. Two transgenic mouse lines that express tv-a from the nestin promoter (Ntv-a) [27
] and the GFAP promoter (Gtv-a) [28
] to support gene transfer into glial progenitors and astrocytes, respectively, have been used.
Oligodendrogliomas in this model are generated by transfer of platelet-derived growth factor (PDGF) to glial progenitors, generating an autocrine loop [29
]. These PDGFinduced gliomas are predominantly low grade and show all the histological characteristics of oligodendrogliomas in humans including the classic “chicken wire vasculature” and invasion of adjacent normal brain structures. In contrast, the simultaneous activation of Ras and Akt signaling pathways in these same glial progenitors leads to the formation of tumors with histologic appearance of glioblastoma multiforme (GBM) [30
]. These tumors reveal regions of nuclear pleomorphism, pseudopalisading necrosis, and microvascular proliferation.
The object of this study is to demonstrate that the MRI characteristics of the low- and high-grade gliomas in mice are similar to the equivalent human gliomas. Furthermore, the ability of MRI to identify mice with large gliomas for inclusion in preclinical trials is demonstrated.