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Koka, Vijay; Potti, Anil; Forseen, Scott E.; Pervez, Hassan; Fraiman, Genise; Koch, Michaël; Levitt, Ralph

doi:10.1097/00000421-200308000-00004

Cited by 15 publications

(11 citation statements)

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“…This array contains a variety of genes involved in glioma-associated pathways such as proliferation, survival, migration, invasion, and angiogenesis as well as tumor-immunological processes. As shown in Figure 1(a), treatment of glioma cells with ISCADOR Q reduced the expression of a variety of genes relevant for gliomagenesis: epidermal growth factor receptor 2 (EGFR2/HER2/ERBB2) stimulates proliferation and blocks apoptosis [44], whereas BIRC5/Survivin is a potent inhibitor of apoptosis [45]. PKB/AKT1 protein kinase plays a key role in multiple cellular processes such as glucose metabolism, cell proliferation, apoptosis, transcription, and cell migration [46, 47].…”

Section: Resultsmentioning

confidence: 99%

Fermented Mistletoe Extract as a Multimodal Antitumoral Agent in Gliomas

Podlech

Harter

Mittelbronn

et al. 2012

Evidence-Based Complementary and Alternative Medicine

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In Europe, commercially available extracts from the white-berry mistletoe (Viscum album L.) are widely used as a complementary cancer therapy. Mistletoe lectins have been identified as main active components and exhibit cytotoxic effects as well as immunomodulatory activity. Since it is still not elucidated in detail how mistle toe extracts such as ISCADOR communicate their effects, we analyzed the mechanisms that might be responsible for their antitumoral function on a molecular and functional level. ISCADOR-treated glioblastoma (GBM) cells down-regulate central genes involved in glioblastoma progression and malignancy such as the cytokine TGF-β and matrix-metalloproteinases. Using in vitro glioblastoma/immune cell co-cultivation assays as well as measurement of cell migration and invasion, we could demonstrate that in glioblastoma cells, lectin-rich ISCADOR M and ISCADOR Q significantly enforce NK-cell-mediated GBM cell lysis. Beside its immune stimulatory effect, ISCADOR reduces the migratory and invasive potential of glioblastoma cells. In a syngeneic as well as in a xenograft glioblastoma mouse model, both pretreatment of tumor cells and intratumoral therapy of subcutaneously growing glioblastoma cells with ISCADOR Q showed delayed tumor growth. In conclusion, ISCADOR Q, showing multiple positive effects in the treatment of glioblastoma, may be a candidate for concomitant treatment of this cancer.

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Section: Resultsmentioning

confidence: 99%

Fermented Mistletoe Extract as a Multimodal Antitumoral Agent in Gliomas

Podlech

Harter

Mittelbronn

et al. 2012

Evidence-Based Complementary and Alternative Medicine

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“…Several cell surface antigens have been identified as potential targets for GBM directed CAR T-cell therapies including HER2, IL-13Rα2, the EPH receptor A2 (EphA2) and EGFRvIII (14,30-32). We chose HER2 since this antigen is expressed by a high percentage of tumors (>70%) and signaling through HER2 deregulates cell proliferation, inhibits apoptosis, and increases the metastatic potential of cancer cells (33,34).…”

Section: Discussionmentioning

confidence: 99%

“…Despite the biological significance of HER2 signaling, the expression of HER2 on GBMs is low in comparison to breast cancer, rendering HER2 monoclonal antibodies ineffective (19,30). HER2-specific T cells allow targeting of the relatively low levels of HER2 expressed by GBMs because the overall avidity of receptors arrayed on a T-cell is greater than the avidity of a bivalent antibody, and engagement of even a limited number of T cell receptor molecules is sufficient to trigger a cytotoxic effector response (39,40).…”

Section: Discussionmentioning

confidence: 99%

HER2-Specific T Cells Target Primary Glioblastoma Stem Cells and Induce Regression of Autologous Experimental Tumors

Ahmed

Salsman

Kew

et al. 2010

Clinical Cancer Research

330

283

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Purpose Glioblastoma (GBM) is the most aggressive human primary brain tumor and is currently incurable. Immunotherapies have the potential to target GBM stem cells, which are resistant to conventional therapies. Human epidermal growth factor receptor 2 (HER2) is a validated immunotherapy target and we determined if HER2-specific T cells can be generated from patients with disease that will target autologous HER2-positive GBMs and their CD133-positive stem cell compartment. Experimental design HER2-specific T cells from 10 consecutive GBM patients were generated by transduction with a retroviral vector encoding a HER2-specific chimeric antigen receptor (CAR). The effector function of HER2-specific T cells against autologous GBM cells, including CD133-positive stem cells, was evaluated in vitro and in an orthotopic murine xenograft model. Results Stimulation of HER2-specific T cells with HER2-positive autologous GBM cells resulted in T-cell proliferation and secretion of IFN-γ and IL-2 in a HER2-dependent manner. Patients’ HER2-specific T cells killed CD133-positive and CD133-negative cells derived from primary HER2-positive GBMs, whereas HER2-negative tumor cells were not killed. Injection of HER2-specific T cells induced sustained regression of established autologous GBM xenografts established in the brain of SCID mice. Conclusions Gene transfer allows the reliable generation of HER2-specific T cells from GBM patients, which have potent antitumor activity against autologous HER2-positive tumors including their putative stem cells. Hence, the adoptive transfer of HER2-redirected T-cells may be a promising immunotherapeutic approach for GBM.

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“…Likewise, human epidermal growth factor-like receptor 2 (HER2) induces HIF-1α expression in normoxia; however, the mechanism depends on increased synthesis of HIF-1α, not VHL-dependent degradation 33,34 . HER2 expression correlates with the breast cancer progression and is an important diagnostic biomarker and therapeutic target for breast cancer, but is overexpressed in only 10–15% of GBM tumors 35–37 . Here we describe a distinct, phospho-Pfn-1-driven mechanism that prevents recognition of prolyl hydroxylated HIF-1α by VHL, thereby facilitating accumulation of the modified protein in tumor EC, even in a normoxic microenvironment.…”

Section: Discussionmentioning

confidence: 99%

Profilin-1 phosphorylation directs angiocrine expression and glioblastoma progression through HIF-1α accumulation

et al. 2014

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SUMMARY The tumor vascular microenvironment supports tumorigenesis by supplying not only oxygen and diffusible nutrients but also by secreting soluble factors that promote tumorigenesis. Here we identify a feed-forward mechanism in which endothelial cells (EC), in response to tumor-derived mediators, release angiocrines driving aberrant vascularization and glioblastoma multiforme (GBM) progression through a hypoxia-independent induction of hypoxia-inducible factor (HIF)-1α. Phosphorylation of profilin-1 (Pfn-1) at Tyr129 in EC induces binding to tumor suppressor protein von Hippel-Lindau (VHL), prevents VHL-mediated degradation of prolyl-hydroxylated HIF-1α, culminating in HIF-1α accumulation even in normoxia. Elevated HIF-1α induces expression of multiple angiogenic factors, leading to vascular abnormality and tumor progression. In a genetic model of GBM, mice with an EC-specific defect in Pfn-1 phosphorylation exhibit reduced tumor angiogenesis, normalized vasculature, and improved survival. Moreover, EC-specific Pfn-1 phosphorylation is associated with tumor aggressiveness in human glioma. These findings suggest that targeting Pfn-1 phosphorylation may offer a selective strategy for therapeutic intervention of malignant solid tumors.

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Cited by 15 publications

References 0 publications

Fermented Mistletoe Extract as a Multimodal Antitumoral Agent in Gliomas

Fermented Mistletoe Extract as a Multimodal Antitumoral Agent in Gliomas

HER2-Specific T Cells Target Primary Glioblastoma Stem Cells and Induce Regression of Autologous Experimental Tumors

Profilin-1 phosphorylation directs angiocrine expression and glioblastoma progression through HIF-1α accumulation

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