Loss of Arf causes tumor progression of PDGFB-induced oligodendroglioma

Tchougounova, Elena; Kastemar, Marianne; Bråsäter, Daniel; Holland, Eric C.; Westermark, Bengt; Uhrbom, Lene

doi:10.1038/sj.onc.1210455

Cited by 82 publications

(77 citation statements)

References 17 publications

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“…The proliferation index was 2-5%, determined by counting Ki67-positive cells (Figure 4b). Thus, the PDGF-B-induced tumors showed expression of many markers of early OPCs in line with previous result from PDGF-B-induced tumors in Ntv-a and Gtv-a mice (Dai et al, 2001;Tchougounova et al, 2007). To validate that induced tumors were caused by retroviral PDGF-B, we induced additional tumors using RCAS-PDGF-B-HA.…”

Section: Pdgf-b But Not Akt and K-ras Could Induce Tumors In Opcssupporting

confidence: 86%

“…If we put the result from the Ctv-a mice in the perspective of previous data using the RCAS/tv-a model (Dai et al, 2001;Tchougounova et al, 2007; Table 2) we can conclude that there are several cell types of the glial cell lineage that are sensitive to PDGF-B transformation and may serve as cell of origin for glioma. The fact that AKT and K-RAS could induce tumors only in Nestin-expressing stem cells and not in OPCs or astrocytes could imply that there are tumor suppressor pathways activated in these cells that can counteract the effects of AKT and K-RAS signaling.…”

Section: Discussionmentioning

confidence: 93%

“…The fact that AKT and K-RAS could induce tumors only in Nestin-expressing stem cells and not in OPCs or astrocytes could imply that there are tumor suppressor pathways activated in these cells that can counteract the effects of AKT and K-RAS signaling. In astrocytes, the expression of both p16INK4a and p19ARF is possible candidates as there is a prominent increase in PDGF-Binduced tumor incidence on loss of either of these oncogenes in Gtv-a mice (Tchougounova et al, 2007). The effect of Ink4a-Arf loss in OPCs in vivo remains to be elucidated.…”

Section: Discussionmentioning

confidence: 99%

“…The potential of platelet-derived growth factor B (PDGF-B), K-RAS and AKT oncogenes to induce tumors in neural/glial stem cells (Ntv-a mice) and astrocytes (Gtv-a mice) has already been thoroughly investigated using the RCAS/tv-a model (Holland et al, 2000a, b;Dai et al, 2001;Uhrbom et al, 2002Uhrbom et al, , 2005Tchougounova et al, 2007). We therefore selected these oncogenes in our initial tumor induction studies in the Ctv-a mice to compare the tumor-initiating capacity of the different cell types targeted.…”

Section: Pdgf-b But Not Akt and K-ras Could Induce Tumors In Opcsmentioning

confidence: 99%

“…In Gtv-a mice TV-A expression is driven by the glial fibrillary acidic protein (Gfap) promoter, which is active in astrocytes (Bignami et al, 1972) and neural stem cells of the SVZ (Doetsch et al, 1999). The effect by various oncogenes cloned into RCAS on gliomagenesis has been extensively studied in the Ntv-a and Gtv-a mice (Doetsch et al, 1999;Holland et al, 2000a, b;Dai et al, 2001;Fults et al, 2002;Rao et al, 2003;Rao et al, 2004;Shih et al, 2004;Uhrbom et al, 2005;Jackson et al, 2006;Dunlap et al, 2007;Ferletta et al, 2007;Liu et al, 2007;Tchougounova et al, 2007;Binning et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

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Oligodendrocyte progenitor cells can act as cell of origin for experimental glioma

et al. 2009

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Gliomas are primary brain tumors mainly affecting adults. The cellular origin is unknown. The recent identification of tumor-initiating cells in glioma, which share many similarities with normal neural stem cells, has suggested the cell of origin to be a transformed neural stem cell. In previous studies, using the RCAS/tv-a mouse model, platelet-derived growth factor B (PDGF-B)-induced gliomas have been generated from nestin or glial fibrillary acidic protein-expressing cells, markers of neural stem cells. To investigate if committed glial progenitor cells could be the cell of origin for glioma, we generated the Ctv-a mouse where tumor induction would be restricted to myelinating oligodendrocyte progenitor cells (OPCs) expressing 2 0 ,3 0 -cyclic nucleotide 3 0 -phosphodiesterase. We showed that PDGF-B transfer to OPCs could induce gliomas with an incidence of 33%. The majority of tumors resembled human WHO grade II oligodendroglioma based on close similarities in histopathology and expression of cellular markers. Thus, with the Ctv-a mouse we have showed that the cell of origin for glioma may be a committed glial progenitor cell.

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Section: Pdgf-b But Not Akt and K-ras Could Induce Tumors In Opcssupporting

confidence: 86%

Section: Discussionmentioning

confidence: 93%

Section: Discussionmentioning

confidence: 99%

Section: Pdgf-b But Not Akt and K-ras Could Induce Tumors In Opcsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Oligodendrocyte progenitor cells can act as cell of origin for experimental glioma

et al. 2009

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Genetic modeling of gliomas in mice: New tools to tackle old problems

Hambardzumyan

Parada

Holland

et al. 2011

Glia

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The recently published comprehensive profiles of genomic alterations in glioma have led to a refinement in our understanding of the molecular events that underlie this cancer. Using state-of-the-art genomic tools, several laboratories have created and characterized accurate genetically engineered mouse models of glioma based on specific genetic alterations observed in human tumors. These in vivo brain tumor models faithfully recapitulate the histopathology, etiology, and biology of gliomas and provide an exceptional experimental system to discover novel therapeutic targets and test therapeutic agents. This review focuses on mouse models of glioma with a special emphasis on genetically engineered models developed around key genetic glioma signature mutations in the PDGFR, EGFR and NF1 genes and pathways. The resulting animal models have provided insight into many fundamental and mechanistic facets of tumor initiation, maintenance and resistance to therapeutic intervention and will continue to do so in the future.

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Lineage tracing demonstrates no evidence of cholangiocyte epithelial-to-mesenchymal transition in murine models of hepatic fibrosis

et al. 2011

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Whether or not cholangiocytes or their hepatic progenitors undergo an epithelial-to-mesenchymal transition (EMT) to become matrix-producing myofibroblasts during biliary fibrosis is a significant ongoing controversy. To assess whether EMT is active during biliary fibrosis, we used Alfp-Cre × Rosa26-YFP mice, in which the epithelial cells of the liver (hepatocytes, cholangiocytes, and their bipotential progenitors) are heritably labeled at high efficiency with yellow fluorescent protein (YFP). Primary cholangiocytes isolated from our reporter strain were able to undergo EMT in vitro when treated with transforming growth factor-β1 alone or in combination with tumor necrosis factor-α, as indicated by adoption of fibroblastoid morphology, intracellular relocalization of E-cadherin, and expression of α-smooth muscle actin (α-SMA). To determine whether EMT occurs in vivo , we induced liver fibrosis in Alfp-Cre × Rosa26-YFP mice using the bile duct ligation (BDL) (2, 4, and 8 weeks), carbon tetrachloride (CCl4) (3 weeks), and 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC; 2 and 3 weeks) models. In no case did we find evidence of colocalization of YFP with the mesenchymal markers S100A4, vimentin, α-SMA, or procollagen 1α2, although these proteins were abundant in the peribiliary regions. Conclusion: Hepatocytes and cholangiocytes do not undergo EMT in murine models of hepatic fibrosis. (Hepatology 2011;)

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Loss of Arf causes tumor progression of PDGFB-induced oligodendroglioma

Cited by 82 publications

References 17 publications

Oligodendrocyte progenitor cells can act as cell of origin for experimental glioma

Oligodendrocyte progenitor cells can act as cell of origin for experimental glioma

Genetic modeling of gliomas in mice: New tools to tackle old problems

Lineage tracing demonstrates no evidence of cholangiocyte epithelial-to-mesenchymal transition in murine models of hepatic fibrosis

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