The Experts below are selected from a list of 7080 Experts worldwide ranked by ideXlab platform
Jeremy N Rich - One of the best experts on this subject based on the ideXlab platform.
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targeting Glioma Stem Cell derived pericytes disrupts the blood tumor barrier and improves chemotherapeutic efficacy
Cell Stem Cell, 2017Co-Authors: Wenchao Zhou, Cong Chen, Yu Shi, Ryan C Gimple, Xiaoguang Fang, Zhi Huang, Kui Zhai, Yi Fang Ping, Hua Feng, Jeremy N RichAbstract:Summary The blood-tumor barrier (BTB) is a major obstacle for drug delivery to malignant brain tumors such as glioblastoma (GBM). Disrupting the BTB is therefore highly desirable but complicated by the need to maintain the normal blood-brain barrier (BBB). Here we show that targeting Glioma Stem Cell (GSC)-derived pericytes specifically disrupts the BTB and enhances drug effusion into brain tumors. We found that pericyte coverage of tumor vasculature is inversely correlated with GBM patient survival after chemotherapy. Eliminating GSC-derived pericytes in xenograft models disrupted BTB tight junctions and increased vascular permeability. We identified BMX as an essential factor for maintaining GSC-derived pericytes. Inhibiting BMX with ibrutinib selectively targeted neoplastic pericytes and disrupted the BTB, but not the BBB, thereby increasing drug effusion into established tumors and enhancing the chemotherapeutic efficacy of drugs with poor BTB penetration. These findings highlight the clinical potential of targeting neoplastic pericytes to significantly improve treatment of brain tumors.
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hypoxia induced mixed lineage leukemia 1 regulates Glioma Stem Cell tumorigenic potential
Cell Death & Differentiation, 2012Co-Authors: John M Heddleston, Maricruz Rivera, S Minhas, Justin D Lathia, Andrew E Sloan, Othon Iliopoulos, Anita B Hjelmeland, Jeremy N RichAbstract:Normal Stem Cells reside in functional niches critical for self-renewal and maintenance. Neural and hematopoietic Stem Cell niches, in particular, are characterized by restricted availability of oxygen and the resulting regulation by hypoxia-inducible factors (HIFs). Glioblastoma multiforme (GBM) is the most common malignant brain tumor and also contains high degrees of hypoxia. Heterogeneity within the neoplastic compartment has been well characterized in GBM and may be derived from genetic and epigenetic sources that co-evolve during malignant progression. Recent experimental evidence has supported the importance of hypoxia in Glioma Stem Cell (GSC) niches. We hypothesized that HIFs require epigenetic-modifying proteins to promote tumor malignancy in GBM. Here we demonstrate that in GBM the histone methyltransferase mixed-lineage leukemia 1 (MLL1) is induced by hypoxia and enhances hypoxic responses. Loss of MLL1 reduces the expression of HIF transcripts and HIF2α protein. Targeting MLL1 by RNA interference inhibited the expression of HIF2α and target genes, including vascular endothelial growth factor (VEGF). GSCs expressed higher levels of MLL1 than matched non-Stem tumor Cells and depletion of MLL1 reduced GSC self-renewal, growth, and tumorigenicity. These studies have uncovered a novel mechanism mediating tumor hypoxic responses linking microenvironmental regulation of epigenetic-modifying proteins to Cellular heterogeneity and provide rationale for the design of more sophisticated clinical approaches targeting epigenetic regulation.
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Glioma Stem Cell maintenance the role of the microenvironment
Current Pharmaceutical Design, 2011Co-Authors: John M Heddleston, Jeremy N Rich, Masahiro Hitomi, Monica Venere, William A Flavahan, Kenneth Yang, Youngmi Kim, Sana Minhas, Anita B HjelmelandAbstract:Glioblastomas are highly lethal cancers for which conventional therapies provide only palliation. The Cellular heterogeneity of glioblastomas is manifest in genetic and epigenetic variation with both stochastic and hierarchical models informing Cellular phenotypes. At the apex of the hierarchy is a self-renewing, tumorigenic, cancer Stem Cell (CSC). The significance of CSCs is underscored by their resistance to cytotoxic therapies, invasive potential, and promotion of angiogenesis. Thus, targeting CSCs may offer therapeutic benefit and sensitize tumors to conventional treatment, demanding elucidation of CSC regulation. Attention has been paid to intrinsic Cellular syStems in CSCs, but recognition of extrinsic factors is evolving. Glioma Stem Cells (GSCs) are enriched in functional niches—prominently the perivascular space and hypoxic regions. These niches provide instructive cues to maintain GSCs and induce Cellular plasticity towards a Stem-like phenotype. GSC-maintaining niches may therefore offer novel therapeutic targets but also signal additional complexity with perhaps different pools of GSCs governed by different molecular mechanisms that must be targeted for tumor control.
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acidic stress promotes a Glioma Stem Cell phenotype
Cell Death & Differentiation, 2011Co-Authors: Anita B Hjelmeland, Roger E. Mclendon, John M Heddleston, Justin D Lathia, Andrew E Sloan, Jennifer Macswords, Q Wu, Gaurav Choudhary, Daniel J Lindner, Jeremy N RichAbstract:Malignant Gliomas are lethal cancers that display Cellular hierarchies with cancer Stem Cells at the apex. Glioma Stem Cells (GSCs) are not uniformly distributed, but rather located in specialized niches, suggesting that the cancer Stem Cell phenotype is regulated by the tumor microenvironment. Indeed, recent studies show that hypoxia and its molecular responses regulate cancer Stem Cell maintenance. We now demonstrate that acidic conditions, independent of restricted oxygen, promote the expression of GSC markers, self-renewal and tumor growth. GSCs exert paracrine effects on tumor growth through elaboration of angiogenic factors, and low pH conditions augment this expression associated with induction of hypoxia inducible factor 2α (HIF2α), a GSC-specific regulator. Induction of HIF2α and other GSC markers by acidic stress can be reverted by elevating pH in vitro, suggesting that raising intratumoral pH may be beneficial for targeting the GSC phenotype. Together, our results suggest that exposure to low pH promotes malignancy through the induction of a cancer Stem Cell phenotype, and that culturing cancer Cells at lower pH reflective of endogenous tumor conditions may better retain the Cellular heterogeneity found in tumors.
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glioblastoma Stem Cells a neuropathologist s view
Journal of Oncology, 2011Co-Authors: Roger E. Mclendon, Jeremy N RichAbstract:Glioblastoma (WHO Grade IV) is both the most common primary brain tumor and the most malignant. Advances in the understanding of the biology of the tumor are needed in order to obtain a clearer picture of the mechanisms driving these tumors. To neuropathologists, glioblastoma is a tumor that represents a complex syStem of migrating pleomorphic tumor Cells, proliferating blood vessels, infiltrating inflammatory Cells, and necrosis. This review will highlight how the Glioma Stem Cell concept brings these elements together into a collective whole, interacting with microenvironmental influences in complex ways. Borrowing from chaos theory a vocabulary of “self organizing syStems” and “complex adaptive syStems” that seem useful in describing these pathologic features, a new paradigm of glioblastoma biology will be proposed that genetic changes should be understood in a three dimensional framework as they relate not only to the tumor Cells themselves but also to the multiCellular hierarchical unit, not isolated from, but responsive to, its local milieu. In this way we will come to better appreciate the impact our therapeutic interventions have on the regional phenotypic heterogeneity that exists within the tumor and the interCellular communications directing adaptation and progression.
Christine E Eyler - One of the best experts on this subject based on the ideXlab platform.
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Glioma Stem Cell proliferation and tumor growth are promoted by nitric oxide synthase 2
Cell, 2011Co-Authors: Christine E Eyler, Justin D Lathia, Jennifer Macswords, Jeongwu Lee, Kenneth Yan, Devin Chandlermilitello, Katherine L Misuraca, Michael T Forrester, Jonathan S Stamler, Steven A GoldmanAbstract:Malignant Gliomas are aggressive brain tumors with limited therapeutic options, and improvements in treatment require a deeper molecular understanding of this disease. As in other cancers, recent studies have identified highly tumorigenic subpopulations within malignant Gliomas, known generally as cancer Stem Cells. Here, we demonstrate that Glioma Stem Cells (GSCs) produce nitric oxide via elevated nitric oxide synthase-2 (NOS2) expression. GSCs depend on NOS2 activity for growth and tumorigenicity, distinguishing them from non-GSCs and normal neural progenitors. Gene expression profiling identified many NOS2-regulated genes, including the Cell-cycle inhibitor Cell division autoantigen-1 (CDA1). Further, high NOS2 expression correlates with decreased survival in human Glioma patients, and NOS2 inhibition slows Glioma growth in a murine intracranial model. These data provide insight into how GSCs are mechanistically distinct from their less tumorigenic counterparts and suggest that NOS2 inhibition may be an efficacious approach to treating this devastating disease.
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targeting a20 decreases Glioma Stem Cell survival and tumor growth
PLOS Biology, 2010Co-Authors: Anita B Hjelmeland, John M Heddleston, Justin D Lathia, Sarah Wickman, Christine E Eyler, Qing Shi, Jennifer Macswords, Jeongwu Lee, Roger E. MclendonAbstract:Glioblastomas are deadly cancers that display a functional Cellular hierarchy maintained by self-renewing glioblastoma Stem Cells (GSCs). GSCs are regulated by molecular pathways distinct from the bulk tumor that may be useful therapeutic targets. We determined that A20 (TNFAIP3), a regulator of Cell survival and the NF-κB pathway, is overexpressed in GSCs relative to non-Stem glioblastoma Cells at both the mRNA and protein levels. To determine the functional significance of A20 in GSCs, we targeted A20 expression with lentiviral-mediated delivery of short hairpin RNA (shRNA). Inhibiting A20 expression decreased GSC growth and survival through mechanisms associated with decreased Cell-cycle progression and decreased phosphorylation of p65/RelA. Elevated levels of A20 in GSCs contributed to apoptotic resistance: GSCs were less susceptible to TNFα-induced Cell death than matched non-Stem Glioma Cells, but A20 knockdown sensitized GSCs to TNFα-mediated apoptosis. The decreased survival of GSCs upon A20 knockdown contributed to the reduced ability of these Cells to self-renew in primary and secondary neurosphere formation assays. The tumorigenic potential of GSCs was decreased with A20 targeting, resulting in increased survival of mice bearing human Glioma xenografts. In silico analysis of a Glioma patient genomic database indicates that A20 overexpression and amplification is inversely correlated with survival. Together these data indicate that A20 contributes to Glioma maintenance through effects on the Glioma Stem Cell subpopulation. Although inactivating mutations in A20 in lymphoma suggest A20 can act as a tumor suppressor, similar point mutations have not been identified through Glioma genomic sequencing: in fact, our data suggest A20 may function as a tumor enhancer in Glioma through promotion of GSC survival. A20 anticancer therapies should therefore be viewed with caution as effects will likely differ depending on the tumor type.
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erythropoietin receptor signaling through stat3 is required for Glioma Stem Cell maintenance
Genes & Cancer, 2010Co-Authors: Yiting Cao, Roger E. Mclendon, Justin D Lathia, Anita B Hjelmeland, Christine E Eyler, Hui Wang, Jeremy N RichAbstract:Recombinant erythropoietin (EPO) is a growth factor used in the treatment of chemotherapy-induced anemia, but recent studies suggest that EPO may accelerate cancer growth. Although several cancers express EPO receptors (EPORs), the mechanism by which EPOR promotes tumor growth remains poorly understood. Glioblastomas display a Cellular hierarchy of self-renewal and tumor propagation restricted to Glioma Stem Cells (GSCs). The authors find that GSCs express higher levels of EPOR than matched nonStem Glioma Cells. Prospective enrichment for EPOR on GSCs increased neurosphere formation, suggesting that EPOR can select for a subset of GSCs with increased self-renewal capacity. Targeting EPOR expression with lentiviral-mediated short-hairpin RNA (shRNA) reduced GSC growth, survival, and neurosphere formation capacity, defining a crucial role for EPOR in GSC maintenance. The authors further find that STAT3 is an important mediator of EPOR signals in GSCs. EPOR knockdown attenuated the basal activation of STAT3 present in GSCs, and a small-molecule inhibitor of STAT3 reduced GSC growth and survival. EPOR signaling was critical for survival in vivo, as targeting EPOR expression decreased GSC tumorigenic potential. Elevated EPOR expression is also associated with poor patient outcome. Thus, EPOR on GSCs promotes tumor growth and may explain the poor survival of cancer patients treated with EPO.
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targeting interleukin 6 signaling suppresses Glioma Stem Cell survival and tumor growth
Stem Cells, 2009Co-Authors: Hui Wang, John M Heddleston, Justin D Lathia, Christine E Eyler, Jialiang Wang, Jennifer L Elderbroom, Joseph J Gallagher, Jesse Schuschu, Jennifer MacswordsAbstract:Glioblastomas are the most common and most lethal primary brain tumor. Recent studies implicate an important role for a restricted population of neoplastic Cells (Glioma Stem Cells (GSCs)) in Glioma maintenance and recurrence. We now demonstrate that GSCs preferentially express two interleukin 6 (IL6) receptors: IL6 receptor alpha (IL6R alpha) and glycoprotein 130 (gp130). Targeting IL6R alpha or IL6 ligand expression in GSCs with the use of short hairpin RNAs (shRNAs) significantly reduces growth and neurosphere formation capacity while increasing apoptosis. Perturbation of IL6 signaling in GSCs attenuates signal transducers and activators of transcription three (STAT3) activation, and small molecule inhibitors of STAT3 potently induce GSC apoptosis. These data indicate that STAT3 is a downstream mediator of prosurvival IL6 signals in GSCs. Targeting of IL6R alpha or IL6 expression in GSCs increases the survival of mice bearing intracranial human Glioma xenografts. IL6 is clinically significant because elevated IL6 ligand and receptor expression are associated with poor Glioma patient survival. The potential utility of anti-IL6 therapies is demonstrated by decreased growth of subcutaneous human GSC-derived xenografts treated with IL6 antibody. Together, our data indicate that IL6 signaling contributes to Glioma malignancy through the promotion of GSC growth and survival, and that targeting IL6 may offer benefit for Glioma patients.
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turning cancer Stem Cells inside out an exploration of Glioma Stem Cell signaling pathways
Journal of Biological Chemistry, 2009Co-Authors: Hui Wang, Christine E Eyler, Anita B Hjelmeland, Jeremy N RichAbstract:Tumors are complex collections of heterogeneous Cells with recruited vasculature, inflammatory Cells, and stromal elements. Neoplastic Cells frequently display a hierarchy in differentiation status. Recent studies suggest that brain tumors have a limited population of neoplastic Cells called cancer Stem Cells with the capacity for sustained self-renewal and tumor propagation. Brain tumor Stem Cells contribute to therapeutic resistance and tumor angiogenesis. In this minireview, we summarize recent data regarding critical signaling pathways involved in brain tumor Stem Cell biology and discuss how targeting these molecules may contribute to the development of novel anti-Glioma therapies.
Anita B Hjelmeland - One of the best experts on this subject based on the ideXlab platform.
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hypoxia induced mixed lineage leukemia 1 regulates Glioma Stem Cell tumorigenic potential
Cell Death & Differentiation, 2012Co-Authors: John M Heddleston, Maricruz Rivera, S Minhas, Justin D Lathia, Andrew E Sloan, Othon Iliopoulos, Anita B Hjelmeland, Jeremy N RichAbstract:Normal Stem Cells reside in functional niches critical for self-renewal and maintenance. Neural and hematopoietic Stem Cell niches, in particular, are characterized by restricted availability of oxygen and the resulting regulation by hypoxia-inducible factors (HIFs). Glioblastoma multiforme (GBM) is the most common malignant brain tumor and also contains high degrees of hypoxia. Heterogeneity within the neoplastic compartment has been well characterized in GBM and may be derived from genetic and epigenetic sources that co-evolve during malignant progression. Recent experimental evidence has supported the importance of hypoxia in Glioma Stem Cell (GSC) niches. We hypothesized that HIFs require epigenetic-modifying proteins to promote tumor malignancy in GBM. Here we demonstrate that in GBM the histone methyltransferase mixed-lineage leukemia 1 (MLL1) is induced by hypoxia and enhances hypoxic responses. Loss of MLL1 reduces the expression of HIF transcripts and HIF2α protein. Targeting MLL1 by RNA interference inhibited the expression of HIF2α and target genes, including vascular endothelial growth factor (VEGF). GSCs expressed higher levels of MLL1 than matched non-Stem tumor Cells and depletion of MLL1 reduced GSC self-renewal, growth, and tumorigenicity. These studies have uncovered a novel mechanism mediating tumor hypoxic responses linking microenvironmental regulation of epigenetic-modifying proteins to Cellular heterogeneity and provide rationale for the design of more sophisticated clinical approaches targeting epigenetic regulation.
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Glioma Stem Cell maintenance the role of the microenvironment
Current Pharmaceutical Design, 2011Co-Authors: John M Heddleston, Jeremy N Rich, Masahiro Hitomi, Monica Venere, William A Flavahan, Kenneth Yang, Youngmi Kim, Sana Minhas, Anita B HjelmelandAbstract:Glioblastomas are highly lethal cancers for which conventional therapies provide only palliation. The Cellular heterogeneity of glioblastomas is manifest in genetic and epigenetic variation with both stochastic and hierarchical models informing Cellular phenotypes. At the apex of the hierarchy is a self-renewing, tumorigenic, cancer Stem Cell (CSC). The significance of CSCs is underscored by their resistance to cytotoxic therapies, invasive potential, and promotion of angiogenesis. Thus, targeting CSCs may offer therapeutic benefit and sensitize tumors to conventional treatment, demanding elucidation of CSC regulation. Attention has been paid to intrinsic Cellular syStems in CSCs, but recognition of extrinsic factors is evolving. Glioma Stem Cells (GSCs) are enriched in functional niches—prominently the perivascular space and hypoxic regions. These niches provide instructive cues to maintain GSCs and induce Cellular plasticity towards a Stem-like phenotype. GSC-maintaining niches may therefore offer novel therapeutic targets but also signal additional complexity with perhaps different pools of GSCs governed by different molecular mechanisms that must be targeted for tumor control.
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acidic stress promotes a Glioma Stem Cell phenotype
Cell Death & Differentiation, 2011Co-Authors: Anita B Hjelmeland, Roger E. Mclendon, John M Heddleston, Justin D Lathia, Andrew E Sloan, Jennifer Macswords, Q Wu, Gaurav Choudhary, Daniel J Lindner, Jeremy N RichAbstract:Malignant Gliomas are lethal cancers that display Cellular hierarchies with cancer Stem Cells at the apex. Glioma Stem Cells (GSCs) are not uniformly distributed, but rather located in specialized niches, suggesting that the cancer Stem Cell phenotype is regulated by the tumor microenvironment. Indeed, recent studies show that hypoxia and its molecular responses regulate cancer Stem Cell maintenance. We now demonstrate that acidic conditions, independent of restricted oxygen, promote the expression of GSC markers, self-renewal and tumor growth. GSCs exert paracrine effects on tumor growth through elaboration of angiogenic factors, and low pH conditions augment this expression associated with induction of hypoxia inducible factor 2α (HIF2α), a GSC-specific regulator. Induction of HIF2α and other GSC markers by acidic stress can be reverted by elevating pH in vitro, suggesting that raising intratumoral pH may be beneficial for targeting the GSC phenotype. Together, our results suggest that exposure to low pH promotes malignancy through the induction of a cancer Stem Cell phenotype, and that culturing cancer Cells at lower pH reflective of endogenous tumor conditions may better retain the Cellular heterogeneity found in tumors.
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targeting a20 decreases Glioma Stem Cell survival and tumor growth
PLOS Biology, 2010Co-Authors: Anita B Hjelmeland, John M Heddleston, Justin D Lathia, Sarah Wickman, Christine E Eyler, Qing Shi, Jennifer Macswords, Jeongwu Lee, Roger E. MclendonAbstract:Glioblastomas are deadly cancers that display a functional Cellular hierarchy maintained by self-renewing glioblastoma Stem Cells (GSCs). GSCs are regulated by molecular pathways distinct from the bulk tumor that may be useful therapeutic targets. We determined that A20 (TNFAIP3), a regulator of Cell survival and the NF-κB pathway, is overexpressed in GSCs relative to non-Stem glioblastoma Cells at both the mRNA and protein levels. To determine the functional significance of A20 in GSCs, we targeted A20 expression with lentiviral-mediated delivery of short hairpin RNA (shRNA). Inhibiting A20 expression decreased GSC growth and survival through mechanisms associated with decreased Cell-cycle progression and decreased phosphorylation of p65/RelA. Elevated levels of A20 in GSCs contributed to apoptotic resistance: GSCs were less susceptible to TNFα-induced Cell death than matched non-Stem Glioma Cells, but A20 knockdown sensitized GSCs to TNFα-mediated apoptosis. The decreased survival of GSCs upon A20 knockdown contributed to the reduced ability of these Cells to self-renew in primary and secondary neurosphere formation assays. The tumorigenic potential of GSCs was decreased with A20 targeting, resulting in increased survival of mice bearing human Glioma xenografts. In silico analysis of a Glioma patient genomic database indicates that A20 overexpression and amplification is inversely correlated with survival. Together these data indicate that A20 contributes to Glioma maintenance through effects on the Glioma Stem Cell subpopulation. Although inactivating mutations in A20 in lymphoma suggest A20 can act as a tumor suppressor, similar point mutations have not been identified through Glioma genomic sequencing: in fact, our data suggest A20 may function as a tumor enhancer in Glioma through promotion of GSC survival. A20 anticancer therapies should therefore be viewed with caution as effects will likely differ depending on the tumor type.
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erythropoietin receptor signaling through stat3 is required for Glioma Stem Cell maintenance
Genes & Cancer, 2010Co-Authors: Yiting Cao, Roger E. Mclendon, Justin D Lathia, Anita B Hjelmeland, Christine E Eyler, Hui Wang, Jeremy N RichAbstract:Recombinant erythropoietin (EPO) is a growth factor used in the treatment of chemotherapy-induced anemia, but recent studies suggest that EPO may accelerate cancer growth. Although several cancers express EPO receptors (EPORs), the mechanism by which EPOR promotes tumor growth remains poorly understood. Glioblastomas display a Cellular hierarchy of self-renewal and tumor propagation restricted to Glioma Stem Cells (GSCs). The authors find that GSCs express higher levels of EPOR than matched nonStem Glioma Cells. Prospective enrichment for EPOR on GSCs increased neurosphere formation, suggesting that EPOR can select for a subset of GSCs with increased self-renewal capacity. Targeting EPOR expression with lentiviral-mediated short-hairpin RNA (shRNA) reduced GSC growth, survival, and neurosphere formation capacity, defining a crucial role for EPOR in GSC maintenance. The authors further find that STAT3 is an important mediator of EPOR signals in GSCs. EPOR knockdown attenuated the basal activation of STAT3 present in GSCs, and a small-molecule inhibitor of STAT3 reduced GSC growth and survival. EPOR signaling was critical for survival in vivo, as targeting EPOR expression decreased GSC tumorigenic potential. Elevated EPOR expression is also associated with poor patient outcome. Thus, EPOR on GSCs promotes tumor growth and may explain the poor survival of cancer patients treated with EPO.
Justin D Lathia - One of the best experts on this subject based on the ideXlab platform.
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hypoxia induced mixed lineage leukemia 1 regulates Glioma Stem Cell tumorigenic potential
Cell Death & Differentiation, 2012Co-Authors: John M Heddleston, Maricruz Rivera, S Minhas, Justin D Lathia, Andrew E Sloan, Othon Iliopoulos, Anita B Hjelmeland, Jeremy N RichAbstract:Normal Stem Cells reside in functional niches critical for self-renewal and maintenance. Neural and hematopoietic Stem Cell niches, in particular, are characterized by restricted availability of oxygen and the resulting regulation by hypoxia-inducible factors (HIFs). Glioblastoma multiforme (GBM) is the most common malignant brain tumor and also contains high degrees of hypoxia. Heterogeneity within the neoplastic compartment has been well characterized in GBM and may be derived from genetic and epigenetic sources that co-evolve during malignant progression. Recent experimental evidence has supported the importance of hypoxia in Glioma Stem Cell (GSC) niches. We hypothesized that HIFs require epigenetic-modifying proteins to promote tumor malignancy in GBM. Here we demonstrate that in GBM the histone methyltransferase mixed-lineage leukemia 1 (MLL1) is induced by hypoxia and enhances hypoxic responses. Loss of MLL1 reduces the expression of HIF transcripts and HIF2α protein. Targeting MLL1 by RNA interference inhibited the expression of HIF2α and target genes, including vascular endothelial growth factor (VEGF). GSCs expressed higher levels of MLL1 than matched non-Stem tumor Cells and depletion of MLL1 reduced GSC self-renewal, growth, and tumorigenicity. These studies have uncovered a novel mechanism mediating tumor hypoxic responses linking microenvironmental regulation of epigenetic-modifying proteins to Cellular heterogeneity and provide rationale for the design of more sophisticated clinical approaches targeting epigenetic regulation.
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Glioma Stem Cell proliferation and tumor growth are promoted by nitric oxide synthase 2
Cell, 2011Co-Authors: Christine E Eyler, Justin D Lathia, Jennifer Macswords, Jeongwu Lee, Kenneth Yan, Devin Chandlermilitello, Katherine L Misuraca, Michael T Forrester, Jonathan S Stamler, Steven A GoldmanAbstract:Malignant Gliomas are aggressive brain tumors with limited therapeutic options, and improvements in treatment require a deeper molecular understanding of this disease. As in other cancers, recent studies have identified highly tumorigenic subpopulations within malignant Gliomas, known generally as cancer Stem Cells. Here, we demonstrate that Glioma Stem Cells (GSCs) produce nitric oxide via elevated nitric oxide synthase-2 (NOS2) expression. GSCs depend on NOS2 activity for growth and tumorigenicity, distinguishing them from non-GSCs and normal neural progenitors. Gene expression profiling identified many NOS2-regulated genes, including the Cell-cycle inhibitor Cell division autoantigen-1 (CDA1). Further, high NOS2 expression correlates with decreased survival in human Glioma patients, and NOS2 inhibition slows Glioma growth in a murine intracranial model. These data provide insight into how GSCs are mechanistically distinct from their less tumorigenic counterparts and suggest that NOS2 inhibition may be an efficacious approach to treating this devastating disease.
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acidic stress promotes a Glioma Stem Cell phenotype
Cell Death & Differentiation, 2011Co-Authors: Anita B Hjelmeland, Roger E. Mclendon, John M Heddleston, Justin D Lathia, Andrew E Sloan, Jennifer Macswords, Q Wu, Gaurav Choudhary, Daniel J Lindner, Jeremy N RichAbstract:Malignant Gliomas are lethal cancers that display Cellular hierarchies with cancer Stem Cells at the apex. Glioma Stem Cells (GSCs) are not uniformly distributed, but rather located in specialized niches, suggesting that the cancer Stem Cell phenotype is regulated by the tumor microenvironment. Indeed, recent studies show that hypoxia and its molecular responses regulate cancer Stem Cell maintenance. We now demonstrate that acidic conditions, independent of restricted oxygen, promote the expression of GSC markers, self-renewal and tumor growth. GSCs exert paracrine effects on tumor growth through elaboration of angiogenic factors, and low pH conditions augment this expression associated with induction of hypoxia inducible factor 2α (HIF2α), a GSC-specific regulator. Induction of HIF2α and other GSC markers by acidic stress can be reverted by elevating pH in vitro, suggesting that raising intratumoral pH may be beneficial for targeting the GSC phenotype. Together, our results suggest that exposure to low pH promotes malignancy through the induction of a cancer Stem Cell phenotype, and that culturing cancer Cells at lower pH reflective of endogenous tumor conditions may better retain the Cellular heterogeneity found in tumors.
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targeting a20 decreases Glioma Stem Cell survival and tumor growth
PLOS Biology, 2010Co-Authors: Anita B Hjelmeland, John M Heddleston, Justin D Lathia, Sarah Wickman, Christine E Eyler, Qing Shi, Jennifer Macswords, Jeongwu Lee, Roger E. MclendonAbstract:Glioblastomas are deadly cancers that display a functional Cellular hierarchy maintained by self-renewing glioblastoma Stem Cells (GSCs). GSCs are regulated by molecular pathways distinct from the bulk tumor that may be useful therapeutic targets. We determined that A20 (TNFAIP3), a regulator of Cell survival and the NF-κB pathway, is overexpressed in GSCs relative to non-Stem glioblastoma Cells at both the mRNA and protein levels. To determine the functional significance of A20 in GSCs, we targeted A20 expression with lentiviral-mediated delivery of short hairpin RNA (shRNA). Inhibiting A20 expression decreased GSC growth and survival through mechanisms associated with decreased Cell-cycle progression and decreased phosphorylation of p65/RelA. Elevated levels of A20 in GSCs contributed to apoptotic resistance: GSCs were less susceptible to TNFα-induced Cell death than matched non-Stem Glioma Cells, but A20 knockdown sensitized GSCs to TNFα-mediated apoptosis. The decreased survival of GSCs upon A20 knockdown contributed to the reduced ability of these Cells to self-renew in primary and secondary neurosphere formation assays. The tumorigenic potential of GSCs was decreased with A20 targeting, resulting in increased survival of mice bearing human Glioma xenografts. In silico analysis of a Glioma patient genomic database indicates that A20 overexpression and amplification is inversely correlated with survival. Together these data indicate that A20 contributes to Glioma maintenance through effects on the Glioma Stem Cell subpopulation. Although inactivating mutations in A20 in lymphoma suggest A20 can act as a tumor suppressor, similar point mutations have not been identified through Glioma genomic sequencing: in fact, our data suggest A20 may function as a tumor enhancer in Glioma through promotion of GSC survival. A20 anticancer therapies should therefore be viewed with caution as effects will likely differ depending on the tumor type.
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erythropoietin receptor signaling through stat3 is required for Glioma Stem Cell maintenance
Genes & Cancer, 2010Co-Authors: Yiting Cao, Roger E. Mclendon, Justin D Lathia, Anita B Hjelmeland, Christine E Eyler, Hui Wang, Jeremy N RichAbstract:Recombinant erythropoietin (EPO) is a growth factor used in the treatment of chemotherapy-induced anemia, but recent studies suggest that EPO may accelerate cancer growth. Although several cancers express EPO receptors (EPORs), the mechanism by which EPOR promotes tumor growth remains poorly understood. Glioblastomas display a Cellular hierarchy of self-renewal and tumor propagation restricted to Glioma Stem Cells (GSCs). The authors find that GSCs express higher levels of EPOR than matched nonStem Glioma Cells. Prospective enrichment for EPOR on GSCs increased neurosphere formation, suggesting that EPOR can select for a subset of GSCs with increased self-renewal capacity. Targeting EPOR expression with lentiviral-mediated short-hairpin RNA (shRNA) reduced GSC growth, survival, and neurosphere formation capacity, defining a crucial role for EPOR in GSC maintenance. The authors further find that STAT3 is an important mediator of EPOR signals in GSCs. EPOR knockdown attenuated the basal activation of STAT3 present in GSCs, and a small-molecule inhibitor of STAT3 reduced GSC growth and survival. EPOR signaling was critical for survival in vivo, as targeting EPOR expression decreased GSC tumorigenic potential. Elevated EPOR expression is also associated with poor patient outcome. Thus, EPOR on GSCs promotes tumor growth and may explain the poor survival of cancer patients treated with EPO.
Kaushal Joshi - One of the best experts on this subject based on the ideXlab platform.
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Abstract 1941: GSK3 signaling is critical to Glioma Stem Cell growth and survival
Tumor Biology, 2014Co-Authors: Angel Alvarez, Ichiro Nakano, Kaushal Joshi, Sung Hak Kim, Andrey Ugolkov, Irina N. Gaisina, Alan P. Kozikowski, Jeffrey J. Raizer, Andrew P. MazarAbstract:Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA GSK3 is an attractive therapeutic target in cancer, known for its role in regulating proliferation, differentiation, metabolism, and apoptosis. Previous studies demonstrate the effectiveness of GSK3 inhibition on established Glioma Cell lines and patient-derived Glioma Stem Cell lines in vitro and in vivo. In Glioma Cell lines, GSK3 inhibition induces apoptosis through c-MYC activation, mitochondrial destabilization, and reduction of NF-κB activity. We have characterized a novel set of GSK3 inhibitors for their ability to inhibit glycogen synthase phosphorylation, reduce levels of XIAP, and induce Cell death in cancer Cells. However, it is uncertain if this mechanism is functional with respect to cancer Stem Cells and Glioma tumor subtype. The need to investigate the mechanistic effects of GSK3 in cancer Stem Cells is important given their malignancy, innate resistance to therapy, and tumorigenicity. Moreover, the intraCellular signaling and transcription networks may differ in Glioma Stem Cells, particularly among Cells with different subtypes. We have recently demonstrated that cancer Stem Cells isolated from Glioma patients can be segregated into either a proneural or mesenchymal subtype based on their gene expression pattern. The oncogenic activity of genes like c-MYC in Glioma Stem Cells and differences between Glioma Stem Cell subtypes, such as NF-κB activation, raises questions as to whether GSK3 inhibition will be effective against both subtypes and if their effects utilize distinct mechanisms of inhibition. In this study, we examine the effects of two established and two novel GSK3 inhibitors on Glioma Stem Cells with respect to tumor subtype and investigate their mechanisms of action. Our in vitro data shows that GSK3 inhibition significantly reduces growth and causes Cell death in both proneural and mesenchymal Glioma Stem Cells. Using a Glioma Stem Cell xenograft model, we test the effectiveness of GSK3 inhibition as a single agent and in conjunction with clinically-approved chemotherapeutic agents. The characterization of cancer Stem Cell inhibitors and their effectiveness in different tumor subtypes has significant clinical implications. Our work supports the therapeutic potential of novel GSK3 inhibitors for the treatment of malignant Gliomas. Note: This abstract was not presented at the meeting. Citation Format: Angel Alvarez, Andrey Ugolkov, Irina Gaisina, Alan P. Kozikowski, Kaushal Joshi, Sunghak Kim, Ichiro Nakano, Jeffrey J. Raizer, Andrew P. Mazar, Bo Hu, Shi-Yuan Cheng. GSK3 signaling is critical to Glioma Stem Cell growth and survival. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1941. doi:10.1158/1538-7445.AM2014-1941
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tumor specific activation of the c jun melk pathway regulates Glioma Stem Cell growth in a p53 dependent manner
Stem Cells, 2013Co-Authors: Yeshavanth Banasavadisiddegowda, Kaushal Joshi, Habibe Kurt, Yuko Nakamura, Snehalata Gupta, Ichiro NakanoAbstract:Accumulated evidence suggests that Glioma Stem Cells (GSCs) may contribute to therapy resistance in high-grade Glioma (HGG). Although recent studies have shown that the serine/threonine kinase maternal embryonic leucine-zipper kinase (MELK) is abundantly expressed in various cancers, the function and mechanism of MELK remain elusive. Here, we demonstrate that MELK depletion by shRNA diminishes the growth of GSC-derived mouse intracranial tumors in vivo, induces glial fibrillary acidic protein (+) glial differentiation of GSCs leading to decreased malignancy of the resulting tumors, and prolongs survival periods of tumor-bearing mice. Tissue microarray analysis with 91 HGG tumors demonstrates that the proportion of MELK (+) Cells is a statistically significant indicator of postsurgical survival periods. Mechanistically, MELK is regulated by the c-Jun NH(2)-terminal kinase (JNK) signaling and forms a complex with the oncoprotein c-JUN in GSCs but not in normal progenitors. MELK silencing induces p53 expression, whereas p53 inhibition induces MELK expression, indicating that MELK and p53 expression are mutually exclusive. Additionally, MELK silencing-mediated GSC apoptosis is partially rescued by both pharmacological p53 inhibition and p53 gene silencing, indicating that MELK action in GSCs is p53 dependent. Furthermore, irradiation of GSCs markedly elevates MELK mRNA and protein expression both in vitro and in vivo. Clinically, recurrent HGG tumors following the failure of radiation and chemotherapy exhibit a statistically significant elevation of MELK protein compared with untreated newly diagnosed HGG tumors. Together, our data indicate that GSCs, but not normal Cells, depend on JNK-driven MELK/c-JUN signaling to regulate their survival, maintain GSCs in an immature state, and facilitate tumor radioresistance in a p53-dependent manner.
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impairment of Glioma Stem Cell survival and growth by a novel inhibitor for survivin ran protein complex
Clinical Cancer Research, 2013Co-Authors: Hacer Guvenc, Marat S. Pavlyukov, Kaushal Joshi, Habibe Kurt, Ping Mao, Christopher S. Hong, Ryosuke Yamada, Chang-hyuk Kwon, Yeshavanth Banasavadisiddegowda, Deepak BhasinAbstract:Purpose: Glioblastoma multiforme (GBM) is a devastating disease. Recent studies suggest that the Stem Cell properties of GBM contribute to the development of therapy resistance. Experimental Design: The expression of Survivin and Ran was evaluated by immunohistochemistry with GBM tissues, and quantitative reverse transcriptase (qRT)-PCR and immunocytochemistry with patient-derived GBM sphere cultures. With a computational structure-based drug design, 11 small-molecule compounds were designed, synthesized, and evaluated as inhibitor candidates for the molecular interaction of Survivin protein. The molecular mechanism of the lead compound, LLP-3, was determined by Western blot, ELISA, in situ proximity ligation assay, and immunocytochemistry. The effects of LLP-3 treatment on GSCs were evaluated both in vitro and in vivo . Quantitative immunohistochemistry was carried out to compare Survivin expression in tissues from 44 newly diagnosed and 31 recurrent post-chemoradiation GBM patients. Lastly, the sensitivities of temozolomide-resistant GBM spheres to LLP-3 were evaluated in vitro . Results: Survivin and Ran were strongly expressed in GBM tissues, particularly in the perivasculature, and also in patient-derived GSC cultures. LLP-3 treatment disrupted the Survivin–Ran protein complex in cancer Cells and abolished the growth of patient-derived GBM spheres in vitro and in vivo . This inhibition was dependent on caspase activity and associated with p53 status of Cells. Immunohistochemistry showed that Survivin expression is significantly increased in recurrent GBM compared with newly diagnosed tumors, and temozolomide-resistant GBM spheres exhibited high sensitivities to LLP-3 treatment. Conclusions: Disruption of the Survivin–Ran complex by LLP-3 abolishes survival and growth of GSCs both in vitro and in vivo , indicating an attractive novel therapeutic approach for GBM. Clin Cancer Res; 19(3); 631–42. ©2012 AACR .
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Impairment of Glioma Stem Cell Survival and Growth by a Novel Inhibitor for Survivin–Ran Protein Complex
Clinical cancer research : an official journal of the American Association for Cancer Research, 2012Co-Authors: Hacer Guvenc, Marat S. Pavlyukov, Kaushal Joshi, Habibe Kurt, Yeshavanth Banasavadi-siddegowda, Ping Mao, Christopher S. Hong, Ryosuke Yamada, Chang-hyuk Kwon, Deepak BhasinAbstract:Purpose: Glioblastoma multiforme (GBM) is a devastating disease. Recent studies suggest that the Stem Cell properties of GBM contribute to the development of therapy resistance. Experimental Design: The expression of Survivin and Ran was evaluated by immunohistochemistry with GBM tissues, and quantitative reverse transcriptase (qRT)-PCR and immunocytochemistry with patient-derived GBM sphere cultures. With a computational structure-based drug design, 11 small-molecule compounds were designed, synthesized, and evaluated as inhibitor candidates for the molecular interaction of Survivin protein. The molecular mechanism of the lead compound, LLP-3, was determined by Western blot, ELISA, in situ proximity ligation assay, and immunocytochemistry. The effects of LLP-3 treatment on GSCs were evaluated both in vitro and in vivo . Quantitative immunohistochemistry was carried out to compare Survivin expression in tissues from 44 newly diagnosed and 31 recurrent post-chemoradiation GBM patients. Lastly, the sensitivities of temozolomide-resistant GBM spheres to LLP-3 were evaluated in vitro . Results: Survivin and Ran were strongly expressed in GBM tissues, particularly in the perivasculature, and also in patient-derived GSC cultures. LLP-3 treatment disrupted the Survivin–Ran protein complex in cancer Cells and abolished the growth of patient-derived GBM spheres in vitro and in vivo . This inhibition was dependent on caspase activity and associated with p53 status of Cells. Immunohistochemistry showed that Survivin expression is significantly increased in recurrent GBM compared with newly diagnosed tumors, and temozolomide-resistant GBM spheres exhibited high sensitivities to LLP-3 treatment. Conclusions: Disruption of the Survivin–Ran complex by LLP-3 abolishes survival and growth of GSCs both in vitro and in vivo , indicating an attractive novel therapeutic approach for GBM. Clin Cancer Res; 19(3); 631–42. ©2012 AACR .