Uhrbom L, Nerio E, Holland ECDissecting tumor maintenance requirements using bioluminescence imaging of cell proliferation in a mouse glioma model. Nat Med 10: 1257-1260

Uppsala University, Department of Genetics and Pathology, Rudbeck Laboratory, SE-75185 Uppsala, Sweden.
Nature Medicine (Impact Factor: 27.36). 12/2004; 10(11):1257-60. DOI: 10.1038/nm1120
Source: PubMed


Bioluminescence imaging has previously been used to monitor the formation of grafted tumors in vivo and measure cell number during tumor progression and response to therapy. The development and optimization of successful cancer therapy strategies may well require detailed and specific assessment of biological processes in response to mechanistic intervention. Here, we use bioluminescence imaging to monitor the cell cycle in a genetically engineered, histologically accurate model of glioma in vivo. In these platelet-derived growth factor (PDGF)-driven oligodendrogliomas, G1 cell-cycle arrest is generated by blockade of either the PDGF receptor or mTOR using small-molecule inhibitors.

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    • "Reporter gene approaches are based on the use of specific regulatory sequences attached to genes that confer organisms a property that could be easily detected and quantified, typically light or fluorescence emission [4]. Different luciferase and fluorescent proteins-based strategies have been developed for monitoring signaling pathways involved in cancer and aging [5-11]. "
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    ABSTRACT: Background Monitoring activity of specific signaling pathways in vivo is challenging and requires highly sensitive methods to detect dynamic perturbations in whole organisms. Results In vivo gene delivery of a luciferase reporter followed by bioluminiscence imaging allows measuring NF-κB activity in mice liver and lungs. Conclusions This protocol allows a direct measure of NF-κB activity through quantification of bioluminescence signal, demonstrating its accuracy and sensitivity in different animal models and experimental conditions. Variants could be also applied for the analysis of NF-κB activity in different tissues or for studying other signaling pathways in vivo.
    Full-text · Article · Mar 2013 · Cell Communication and Signaling
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    • "It is also possible that chronic PDGF-A stimulation induces glioma-like lesions that are reversible upon removal of PDGF-A (31) only if there are no additional events occurring. One study has demonstrated how PTK787-mediated inhibition of PDGF signaling in PDGF-B-induced gliomas results in a markedly reduced proliferation without elimination of tumors, indicating that these tumors are dependent on PDGF signaling to maintain proliferative capacity while inhibition does not eliminate tumors (64). The mechanism by which PDGF-B induces glioma, and if it is reversible, has yet to be determined. "
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    ABSTRACT: Platelet-derived growth factor B (PDGF-B) is a growth factor promoting and regulating cell migration, proliferation, and differentiation, involved in both developmental processes and in maintaining tissue homeostasis under strict regulation. What are the implications of prolonged or uncontrolled growth factor signaling in vivo, and when does a growth factor such as PDGF-B become an oncogene? Under experimental conditions, PDGF-B induces proliferation and causes tumor induction. It is not known whether these tumors are strictly a PDGF-B-driven proliferation of cells or associated with secondary genetic events such as acquired mutations or methylation-mediated gene silencing promoting neoplasia. If PDGF-B-driven tumorigenesis was only cellular proliferation, associated changes in gene expression would thus be correlated with proliferation and not associated with secondary events involved in tumorigenesis and neoplastic transformation such as cycle delay, DNA damage response, and cell death. Changes in gene expression might be expected to be reversible, as is PDGF-B-driven proliferation under normal circumstances. Since PDGF signaling is involved in oligodendrocyte progenitor cell differentiation and maintenance, it is likely that PDGF-B stimulates proliferation of a pool of cells with that phenotype, and inhibition of PDGF-B signaling would result in reduced expression of oligodendrocyte-associated genes. More importantly, inhibition of PDGF signaling would be expected to result in reversion of genes induced by PDGF-B accompanied by a decrease in proliferation. However, if PDGF-B-driven tumorigenesis is more than simply a proliferation of cells, inhibition of PDGF signaling may not reverse gene expression or halt proliferation. These fundamental questions concerning PDGF-B as a potential oncogene have not been resolved.
    Full-text · Article · Feb 2012 · Upsala journal of medical sciences
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    • "In hPDGFb-induced gliomas, pharmacologic blockade by the PDGFR/VEGFR inhibitor PTK787 that crosses the blood-brain barrier results in cell cycle arrest of the tumor cells; thus, these gliomas retain their dependence on PDGFR signaling [39]. Since gliomas with large areas of recruited cells did not express PDGFRα, we investigated whether recruited cells became independent of hPDGFb signaling during glioma progression. "
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    ABSTRACT: Gliomas are thought to form by clonal expansion from a single cell-of-origin, and progression-associated mutations to occur in its progeny cells. Glioma progression is associated with elevated growth factor signaling and loss of function of tumor suppressors Ink4a, Arf and Pten. Yet, gliomas are cellularly heterogeneous; they recruit and trap normal cells during infiltration. We performed lineage tracing in a retrovirally mediated, molecularly and histologically accurate mouse model of hPDGFb-driven gliomagenesis. We were able to distinguish cells in the tumor that were derived from the cell-of-origin from those that were not. Phenotypic, tumorigenic and expression analyses were performed on both populations of these cells. Here we show that during progression of hPDGFb-induced murine gliomas, tumor suppressor loss can expand the recruited cell population not derived from the cell-of-origin within glioma microenvironment to dominate regions of the tumor, with essentially no contribution from the progeny of glioma cell-of-origin. Moreover, the recruited cells can give rise to gliomas upon transplantation and passaging, acquire polysomal expression profiles and genetic aberrations typically present in glioma cells rather than normal progenitors, aid progeny cells in glioma initiation upon transplantation, and become independent of PDGFR signaling. These results indicate that non-cell-of-origin derived cells within glioma environment in the mouse can be corrupted to become bona fide tumor, and deviate from the generally established view of gliomagenesis.
    Full-text · Article · Jul 2011 · PLoS ONE
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