Clement V, Sanchez P, de Tribolet N, Radovanovic I, Ruiz i Altaba A.. HEDGEHOG-GLI1 signaling regulates human glioma growth, cancer stem cell self-renewal, and tumorigenicity. Curr Biol 17: 165-172

Department of Genetic Medicine and Development, University of Geneva Medical School, 8242 CMU, 1 rue Michel Servet, CH-1211 Geneva 4, Switzerland.
Current Biology (Impact Factor: 9.57). 02/2007; 17(2):165-72. DOI: 10.1016/j.cub.2006.11.033
Source: PubMed


Cancer stem cells are rare tumor cells characterized by their ability to self-renew and to induce tumorigenesis. They are present in gliomas and may be responsible for the lethality of these incurable brain tumors. In the most aggressive and invasive type, glioblastoma multiforme (GBM), an average of about one year spans the period between detection and death [1]. The resistence of gliomas to current therapies may be related to the existence of cancer stem cells [2-6]. We find that human gliomas display a stemness signature and demonstrate that HEDGEHOG (HH)-GLI signaling regulates the expression of stemness genes in and the self-renewal of CD133(+) glioma cancer stem cells. HH-GLI signaling is also required for sustained glioma growth and survival. It displays additive and synergistic effects with temozolomide (TMZ), the current chemotherapeutic agent of choice. TMZ, however, does not block glioma stem cell self-renewal. Finally, interference of HH-GLI signaling with cyclopamine or through lentiviral-mediated silencing demonstrates that the tumorigenicity of human gliomas in mice requires an active pathway. Our results reveal the essential role of HH-GLI signaling in controlling the behavior of human glioma cancer stem cells and offer new therapeutic possibilities.

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Available from: Pilar Sánchez-Gómez, Apr 10, 2014
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    • "For example, a population of Gli1-expressing cells is present in the juvenile pons, correlating with the time in human development when pontine gliomas occur [86]. In both pontine gliomas and glioblastoma multiforme, the most common adult brain tumor, inhibition of Shh signaling via the small molecule cyclopamine inhibits the propagation of glioma cells in sphere culture and/or intracranial xenograft models [10] [85] [86]. Shh, therefore, is likely an important mitogen or selfrenewal factor not only under normal conditions, but also during oncogenesis in the juvenile or postnatal brain. "
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    ABSTRACT: Sonic hedgehog (Shh) is a pleiotropic factor in the developing central nervous system (CNS), driving proliferation, specification, and axonal targeting in multiple sites within the forebrain, hindbrain, and spinal cord. Studies in embryonic CNS have shown how gradients of this morphogen are translated by neuroepithelial precursors to determine the types of neurons and glial cells they produce 0005 and 0010. Shh also has a well-characterized role as a mitogen for specific progenitor cell types in neural development 0015 and 0020. As we begin to appreciate that Shh continues to act in the adult brain, a central question is what functional role this ligand plays when major morphogenetic and proliferative processes are no longer in operation. A second fundamental question is whether similar signaling mechanisms operate in embryonic and adult CNS. In the two major germinal zones of the adult brain, Shh signaling modulates the self-renewal and specification of astrocyte-like primary progenitors, frequently referred to as neural stem cells (NSCs). It also may regulate the response of the mature brain to injury, as Shh signaling has been variously proposed to enhance or inhibit the development of a reactive astrocyte phenotype. The identity of cells producing the Shh ligand, and the conditions that trigger its release, are also areas of growing interest; both germinal zones in the adult brain contain Shh-responsive cells but do not autonomously produce this ligand. Here, we review recent findings revealing the function of this fascinating pathway in the postnatal and adult brain, and highlight ongoing areas of investigation into its actions long past the time when it shapes the developing brain.
    Seminars in Cell and Developmental Biology 09/2014; 33. DOI:10.1016/j.semcdb.2014.05.008 · 6.27 Impact Factor
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    • "On the other hand, genetic and/or epigenetic changes leading to irreversible activation of GLIA, and GLI1 [52], can drive a variety of malignant states ranging from cancers of the brain, skin, breast, prostate and digestive tract to malignancies of the hematopoietic system (e.g. [16,52–60]). "
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    ABSTRACT: Canonical Hedgehog (HH) signaling leads to the regulation of the GLI code: the sum of all positive and negative functions of all GLI proteins. In humans, the three GLI factors encode context-dependent activities with GLI1 being mostly an activator and GLI3 often a repressor. Modulation of GLI activity occurs at multiple levels, including by co-factors and by direct modification of GLI structure. Surprisingly, the GLI proteins, and thus the GLI code, is also regulated by multiple inputs beyond HH signaling. In normal development and homeostasis these include a multitude of signaling pathways that regulate proto-oncogenes, which boost positive GLI function, as well as tumor suppressors, which restrict positive GLI activity. In cancer, the acquisition of oncogenic mutations and the loss of tumor suppressors - the oncogenic load - regulates the GLI code towards progressively more activating states. The fine and reversible balance of GLI activating GLIA and GLI repressing GLIR states is lost in cancer. Here, the acquisition of GLIA levels above a given threshold is predicted to lead to advanced malignant stages. In this review we highlight the concepts of the GLI code, the oncogenic load, the context-dependency of GLI action, and different modes of signaling integration such as that of HH and EGF. Targeting the GLI code directly or indirectly promises therapeutic benefits beyond the direct blockade of individual pathways.
    Seminars in Cell and Developmental Biology 09/2014; 33(100). DOI:10.1016/j.semcdb.2014.05.003 · 6.27 Impact Factor
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    • "CD133 was shown to promote the tumorigenic capacity of GCS by activation of the PI3K/Akt pathway via the interaction with the regulatory subunit of PI3K p85. The elevated expression of the activating co-receptor Smoothened (Smo) and the transcription factor Glioma-Associated Oncogene homolog 1 (Gli 1) on the one hand, and the strongly reduced expression of the repressor receptors Patched 1 (Ptch1) and hedgehog-interacting protein (Hip) on the other hand, confer the GSC the unique self-renewal and tumorgenicity potential [7, 11, 12]. The deregulation of the HH pathway represses the retinoblastoma tumor suppressor-gene (Rb) and induces expression of the proto-onco gene N-myc, a key transcription factor which is overexpressed in malignant glioma cells [13]. "
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    ABSTRACT: The existence of therapy resistant glioma stem cells is responsible for the high recurrence rate and incurability of glioblastomas. The Hedgehog pathway activity plays an essential role for self-renewal capacity and survival of glioma stem cells. We examined the potential of the Sonic hedgehog ligand for sensitizing of glioma stem cells to endogenous nano-irradiation. We demonstrate that the Sonic hedgehog ligand preferentially and efficiently activated glioma stem cells to enter the radiation sensitive G2/M phase. Concomitant inhibition of de novo thymidine synthesis with fluorodeoxyuridine and treatment with the Auger electron emitting thymidine analogue 5-[I-125]-Iodo-4’-thio-2’-deoxyuridine ([I-125]ITdU) leads to a fatal nanoirradiation in sensitized glioma stem cells. Targeting of proliferating glioma stem cells with DNA-incorporated [I-125]ITdU efficiently invokes the intrinsic apoptotic pathway despite active DNA repair mechanisms. Further, [I-125]ITdU completely inhibits survival of glioma stem cells in vitro. Analysis of non-stem glioblastoma cells and normal human astrocytes reveals that glioma stem cells differentially respond to Sonic hedgehog ligand. These data demonstrate a highly efficient and controllable single-cell kill therapeutic model for targeting glioma stem cells.
    Oncotarget 06/2014; 5(14):5483-5493. DOI:10.18632/oncotarget.2123 · 6.36 Impact Factor
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