Ligand-dependent activation of the hedgehog pathway in glioma progenitor cells

Ehtesham, Moneeb; Sarangi, Anuraag; Valadez, J. Gerardo; Chanthaphaychith, Siprachanh; Bêcher, Mark W.; Abel, Ty W.; Thompson, Reid C.; Cooper, Michael K.

doi:10.1038/sj.onc.1210359

Cited by 125 publications

(142 citation statements)

References 31 publications

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“…Because of the established role for Hh signaling both in normal neural precursor cells (9,15,17,18) and in other brain tumors, such as medulloblastoma (19)(20)(21)(22), we postulated that the Hh pathway might play a role in transformation of this ventral PPC population. To test the functional and possibly oncogenic role of the Hh pathway in ventral pontine Olig2 + precursor cells, we used a genetic mouse model in which the Hh pathway is specifically up-regulated in Olig2 + cells.…”

Section: Resultsmentioning

confidence: 99%

Hedgehog-responsive candidate cell of origin for diffuse intrinsic pontine glioma

Monje

Mitra

Freret

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

283

300

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Diffuse intrinsic pontine gliomas (DIPGs) are highly aggressive tumors of childhood that are almost universally fatal. Our understanding of this devastating cancer is limited by a dearth of available tissue for study and by the lack of a faithful animal model. Intriguingly, DIPGs are restricted to the ventral pons and occur during a narrow window of middle childhood, suggesting dysregulation of a postnatal neurodevelopmental process. Here, we report the identification of a previously undescribed population of immunophenotypic neural precursor cells in the human and murine brainstem whose temporal and spatial distributions correlate closely with the incidence of DIPG and highlight a candidate cell of origin. Using early postmortem DIPG tumor tissue, we have established in vitro and xenograft models and find that the Hedgehog (Hh) signaling pathway implicated in many developmental and oncogenic processes is active in DIPG tumor cells. Modulation of Hh pathway activity has functional consequences for DIPG selfrenewal capacity in neurosphere culture. The Hh pathway also appears to be active in normal ventral pontine precursor-like cells of the mouse, and unregulated pathway activity results in hypertrophy of the ventral pons. Together, these findings provide a foundation for understanding the cellular and molecular origins of DIPG, and suggest that the Hh pathway represents a potential therapeutic target in this devastating pediatric tumor.Hedgehog pathway | cancer stem cells | brainstem glioma

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Section: Resultsmentioning

confidence: 99%

Hedgehog-responsive candidate cell of origin for diffuse intrinsic pontine glioma

Monje

Mitra

Freret

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

283

300

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“…Moreover, Gli activity correlates with tumor grade in a genetically engineered mouse model (Becher et al, 2008). Several groups have investigated the role of Hedgehog-Gli signaling in GSCs and found that this signaling pathway regulates self-renewal and tumorigenic potential of GSCs (Clement et al, 2007;Ehtesham et al, 2007;Bar et al, 2007;Xu et al, 2008). Treatment of GSCs with the Hedgehog inhibitor cyclopamine or Gli RNA interference suppresses self-renewal and proliferation while increases apoptotic cell death.…”

Section: Hedgehog-gli Signalingmentioning

confidence: 99%

Cancer stem cells in glioblastoma—molecular signaling and therapeutic targeting

et al. 2010

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Glioblastomas (GBMs) are highly lethal primary brain tumors. Despite current therapeutic advances in other solid cancers, the treatment of these malignant gliomas remains essentially palliative. GBMs are extremely resistant to conventional radiation and chemotherapies. We and others have demonstrated that a highly tumorigenic subpopulation of cancer cells called GBM stem cells (GSCs) promotes therapeutic resistance. We also found that GSCs stimulate tumor angiogenesis by expressing elevated levels of VEGF and contribute to tumor growth, which has been translated into a useful therapeutic strategy in the treatment of recurrent or progressive GBMs. Furthermore, stem cell-like cancer cells (cancer stem cells) have been shown to promote metastasis. Although GBMs rarely metastasize beyond the central nervous system, these highly infiltrative cancers often invade into normal brain tissues preventing surgical resection, and GSCs display an aggressive invasive phenotype. These studies suggest that targeting GSCs may effectively reduce tumor recurrence and significantly improve GBM treatment. Recent studies indicate that cancer stem cells share core signaling pathways with normal somatic or embryonic stem cells, but also display critical distinctions that provide important clues into useful therapeutic targets. In this review, we summarize the current understanding and advances in glioma stem cell research, and discuss potential targeting strategies for future development of anti-GSC therapies.

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“…Relevant benefits of primary orthotopic glioma xenografts include infiltrative growth that typifies diffuse gliomas and the retention of genetic alterations and important signaling mechanisms that can be exceedingly difficult to maintain in cultured glioma cells. For example, isocitrate dehydrogenase mutations and Sonic hedgehog ligand production can be maintained in primary orthotopic xenografts 15,16 but only rarely in cultured glioma cells 14,[17][18][19] . It is important to consider significant disadvantages of primary orthotopic xenografts, however, depending upon experimental needs.…”

Section: Discussionmentioning

confidence: 99%

Primary Orthotopic Glioma Xenografts Recapitulate Infiltrative Growth and Isocitrate Dehydrogenase I Mutation

Valadez

Sarangi

Lundberg

et al. 2014

JoVE

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Malignant gliomas constitute a heterogeneous group of highly infiltrative glial neoplasms with distinct clinical and molecular features. Primary orthotopic xenografts recapitulate the histopathological and molecular features of malignant glioma subtypes in preclinical animal models. To model WHO grades III and IV malignant gliomas in transplantation assays, human tumor cells are xenografted into an orthotopic site, the brain, of immunocompromised mice. In contrast to secondary xenografts that utilize cultured tumor cells, human glioma cells are dissociated from resected specimens and transplanted without prior passage in tissue culture to generate primary xenografts. The procedure in this report details tumor sample preparation, intracranial transplantation into immunocompromised mice, monitoring for tumor engraftment and tumor harvesting for subsequent passage into recipient animals or analysis. Tumor cell preparation requires 2 hr and surgical procedure requires 20 min/animal. Video LinkThe video component of this article can be found at

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Ligand-dependent activation of the hedgehog pathway in glioma progenitor cells

Cited by 125 publications

References 31 publications

Hedgehog-responsive candidate cell of origin for diffuse intrinsic pontine glioma

Hedgehog-responsive candidate cell of origin for diffuse intrinsic pontine glioma

Cancer stem cells in glioblastoma—molecular signaling and therapeutic targeting

Primary Orthotopic Glioma Xenografts Recapitulate Infiltrative Growth and Isocitrate Dehydrogenase I Mutation

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