Abstract
Human platelet-derived growth factor B (hPDGFB) has been characterized in vitro and shown to mediate numerous cellular responses including glial proliferation and differentiation. Expression of PDGFB is thought to be important in the pathogenesis of glioma and several animal models of cerebral glioma based on PDGF expression have been described. To examine whether PDGF could contribute to the pathogenesis of spinal cord glioma, we developed transgenic mice that express hPDGFB under the control of a tetracycline-responsive element (TRE/hPDGFB). These TRE/hPDGFB mice were mated with transgenic mice expressing the tetracycline transcriptional activator (tet-off), tTA, regulated by the human glial fibrillary acidic protein (GFAP) promoter and exhibiting uniquely strong promoter activity in the spinal cord. These transgenic mice (GFAP/tTA:TRE/hPDGFB) expressed hPDGFB in GFAP-expressing glia in a manner responsive to doxycycline administration. Without doxycycline, almost all GFAP/tTA:TRE/hPDGFB mice developed spinal cord neoplasms resembling human mixed oligoastrocytoma. Tumorigenesis in these animals was suppressed by doxycycline. To further examine the importance of PDGFB in mouse primary intramedullary spinal cord tumors, we also created transgenic mice expressing hPDGFB under the control of the human GFAP promoter (GFAP/hPDGFB). These GFAP/hPDGFB mice also developed spinal oligoastrocytoma. PDGFB can mediate the development of mouse spinal tumors that are histologically and pathologically indistinguishable from primary intramedullary spinal tumors of humans and may provide opportunities for both novel insights into the pathogenesis of these tumors and the development of new therapeutics.
Highlights
Glial tumors are the most common tumors of the central nervous system (CNS)
To evaluate platelet-derived growth factor (PDGF) in the development of mouse spinal cord tumors, we developed an animal model of spinal tumorigenesis building on two important observations: aberrant PDGF CNS expression leads to the development of cerebral glioma [13, 14, 16] and enhanced expression of a transgene in the spinal cord could be facilitated by a regulatory element mediating spinal cord expression
The proliferative index varied somewhat from animal to animal and within individual tumor areas but was estimated to be f13% in grade 3 tumors, we could identify indices of 25% in the most proliferative areas (Fig. 2B). These findings indicated that the spinal tumors that develop in glial fibrillary acidic protein (GFAP)/tTA embryo (tTA):tetracycline-responsive element (TRE)/ Human platelet-derived growth factor B (hPDGFB) mice were similar to spinal gliomas seen in humans, which can range from low-grade to high-grade and can exhibit evidence of either oligodendroglial or astrocytic features or both
Summary
Spinal gliomas represent only a small fraction of these tumors, the morbidity that such tumors cause is dramatic, and their prognosis is poor. These tumors may occur at any location along the spine, and their clinical presentation typically reflects both their location and grade [1,2,3,4,5,6]. Little is known of the molecular pathology that underlies spinal glioma, and there are no animal models of these tumors. Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/). Doi:10.1158/0008-5472.CAN-08-1063 molecular pathogenesis of glioma arising within the cerebrum. The pathogenesis of these tumors often involves members of the platelet-derived growth factor (PDGF) family
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