Regulation of Glioblastoma Tumor-Propagating Cells by the Integrin Partner Tetraspanin CD151

Tilghman, Jessica; Schiapparelli, Paula; Lal, Bachuchu; Ying, Mingyao; Quiñones‐Hinojosa, Alfredo; Xia, Shuli; Laterra, John

doi:10.1016/j.neo.2016.02.003

Cited by 24 publications

(17 citation statements)

References 67 publications

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“…We measured the efficacy of ispinesib in vitro against three GBM cell lines: GBM1A, TP53(−/−), and PTEN(−/−). GBM1A is a human GBM line that has glioma TIC features 30 . TP53(−/−), and PTEN(−/−) are PDGF-driven murine GBM cell lines 31 .…”

Section: Resultsmentioning

confidence: 99%

Enhancing Brain Retention of a KIF11 Inhibitor Significantly Improves its Efficacy in a Mouse Model of Glioblastoma

Gampa

Kenchappa

Mohammad

et al. 2020

Sci Rep

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Glioblastoma, the most lethal primary brain cancer, is extremely proliferative and invasive. Tumor cells at tumor/brain-interface often exist behind a functionally intact blood-brain barrier (BBB), and so are shielded from exposure to therapeutic drug concentrations. An ideal glioblastoma treatment needs to engage targets that drive proliferation as well as invasion, with brain penetrant therapies. One such target is the mitotic kinesin KIF11, which can be inhibited with ispinesib, a potent molecularly-targeted drug. Although, achieving durable brain exposures of ispinesib is critical for adequate tumor cell engagement during mitosis, when tumor cells are vulnerable, for efficacy. Our results demonstrate that the delivery of ispinesib is restricted by P-gp and Bcrp efflux at BBB. Thereby, ispinesib distribution is heterogeneous with concentrations substantially lower in invasive tumor rim (intact BBB) compared to glioblastoma core (disrupted BBB). We further find that elacridar-a P-gp and Bcrp inhibitor-improves brain accumulation of ispinesib, resulting in remarkably reduced tumor growth and extended survival in a rodent model of glioblastoma. Such observations show the benefits and feasibility of pairing a potentially ideal treatment with a compound that improves its brain accumulation, and supports use of this strategy in clinical exploration of cell cycle-targeting therapies in brain cancers. Glioblastoma (GBM), the most common and lethal of primary brain tumors, has two defining phenotypes: uncontrollable proliferation and diffuse infiltration within the brain 1-6. These features together allow tumor cells to invade regions of brain with an intact blood-brain barrier (BBB), enabling them to proliferate in an environment protected from potentially effective therapeutics. Thus, an ideal therapeutic needs to not only target both proliferation and invasion, but also penetrate the BBB and be retained within tumor-infiltrated brain long enough to kill tumor cells when they are vulnerable to the drug. The microtubule (MT)-based cytoskeleton is essential for both mitotic spindle function, which drives GBM proliferation, and cell motility, which drives GBM infiltration 7. Several MT-targeting agents inhibit spindle function, including the taxanes and vinca alkaloids, and these drugs have been successfully used for treating a variety of malignancies 8. However, MTs are essential for peripheral and central nervous system (PNS, CNS) function, and dose-limiting neurotoxicity has been observed with these MT-targeting drugs 8,9. This has served as an impetus for developing drugs that target other components of mitotic spindle. One such group are MT-associated molecular motors, referred to as mitotic kinesins, which play multiple roles in mitotic spindle function and cell motility 10,11. A member of the mitotic kinesins is KIF11 (kinesin family member 11) 12,13. Over the last twenty years, more than 50 highly specific and potent small-molecule inhibitors of KIF11 have been developed 10. While these drugs are not neurotoxic ...

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Section: Resultsmentioning

confidence: 99%

Enhancing Brain Retention of a KIF11 Inhibitor Significantly Improves its Efficacy in a Mouse Model of Glioblastoma

Gampa

Kenchappa

Mohammad

et al. 2020

Sci Rep

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“…α3 integrin was also shown to be overexpressed in GIC and to promote invasion [ 71 ]. Of note, the cell surface tetraspanin family member CD151 was recently found as a novel regulator of GIC by interacting with α6 and α3 [ 108 ]. Recently, a monoclonal antibody screening identified α7 integrin as a functional GIC marker.…”

Section: Roles Of Integrins In Glioblastomamentioning

confidence: 99%

Interest of integrins targeting in glioblastoma according to tumor heterogeneity and cancer stem cell paradigm: an update

et al. 2017

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Glioblastomas are malignant brain tumors with dismal prognosis despite standard treatment with surgery and radio/chemotherapy. These tumors are defined by an important cellular heterogeneity and notably contain a particular subpopulation of Glioblastoma-initiating cells, which recapitulate the heterogeneity of the original Glioblastoma. In order to classify these heterogeneous tumors, genomic profiling has also been undertaken to classify these heterogeneous tumors into several subtypes. Current research focuses on developing therapies, which could take into account this cellular and genomic heterogeneity. Among these targets, integrins are the subject of numerous studies since these extracellular matrix transmembrane receptors notably controls tumor invasion and progression. Moreover, some of these integrins are considered as membrane markers for the Glioblastoma-initiating cells subpopulation. We reviewed here integrin expression according to glioblastoma molecular subtypes and cell heterogeneity. We discussed their roles in glioblastoma invasion, angiogenesis, therapeutic resistance, stemness and microenvironment modulations, and provide an overview of clinical trials investigating integrins in glioblastomas. This review highlights that specific integrins could be identified as selective glioblastoma cells markers and that their targeting represents new diagnostic and/or therapeutic strategies.

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“…Two human GBM neurosphere cell lines HSR-GBM1A (GBM1A) and HSR-GBM1B (GBM1B) were used in the current study. The neurosphere cultures were enriched for GSCs, and have been extensively characterized by us and others in terms of their stem cell marker expression, differentiation potential, and tumor initiation capacity [ 8 , 9 , 33 – 35 ]. We engineered tet-on stable neurosphere cell lines to express flag-tagged KLF9.…”

Section: Resultsmentioning

confidence: 99%

Krüppel-like factor 9 and histone deacetylase inhibitors synergistically induce cell death in glioblastoma stem-like cells

Tung

Wang

et al. 2018

BMC Cancer

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BackgroundThe dismal prognosis of patients with glioblastoma (GBM) is attributed to a rare subset of cancer stem cells that display characteristics of tumor initiation, growth, and resistance to aggressive treatment involving chemotherapy and concomitant radiation. Recent research on the substantial role of epigenetic mechanisms in the pathogenesis of cancers has prompted the investigation of the enzymatic modifications of histone proteins for therapeutic drug targeting. In this work, we have examined the function of Krüppel-like factor 9 (KLF9), a transcription factor, in chemotherapy sensitization to histone deacetylase inhibitors (HDAC inhibitors).MethodsSince GBM neurosphere cultures from patient-derived gliomas are enriched for GBM stem-like cells (GSCs) and form highly invasive and proliferative xenografts that recapitulate the features demonstrated in human patients diagnosed with GBM, we established inducible KLF9 expression systems in these GBM neurosphere cells and investigated cell death in the presence of epigenetic modulators such as histone deacetylase (HDAC) inhibitors.ResultsWe demonstrated that KLF9 expression combined with HDAC inhibitor panobinostat (LBH589) dramatically induced glioma stem cell death via both apoptosis and necroptosis in a synergistic manner. The combination of KLF9 expression and LBH589 treatment affected cell cycle by substantially decreasing the percentage of cells at S-phase. This phenomenon is further corroborated by the upregulation of cell cycle inhibitors p21 and p27. Further, we determined that KLF9 and LBH589 regulated the expression of pro- and anti- apoptotic proteins, suggesting a mechanism that involves the caspase-dependent apoptotic pathway. In addition, we demonstrated that apoptosis and necrosis inhibitors conferred minimal protective effects against cell death, while inhibitors of the necroptosis pathway significantly blocked cell death.ConclusionsOur findings suggest a detailed understanding of how KLF9 expression in cancer cells with epigenetic modulators like HDAC inhibitors may promote synergistic cell death through a mechanism involving both apoptosis and necroptosis that will benefit novel combinatory antitumor strategies to treat malignant brain tumors.

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Regulation of Glioblastoma Tumor-Propagating Cells by the Integrin Partner Tetraspanin CD151

Cited by 24 publications

References 67 publications

Enhancing Brain Retention of a KIF11 Inhibitor Significantly Improves its Efficacy in a Mouse Model of Glioblastoma

Enhancing Brain Retention of a KIF11 Inhibitor Significantly Improves its Efficacy in a Mouse Model of Glioblastoma

Interest of integrins targeting in glioblastoma according to tumor heterogeneity and cancer stem cell paradigm: an update

Krüppel-like factor 9 and histone deacetylase inhibitors synergistically induce cell death in glioblastoma stem-like cells

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