Effects of the Anti-Tumorigenic Agent AT101 on Human Glioblastoma Cells in the Microenvironmental Glioma Stem Cell Niche

Glioblastoma (GBM) is a barely treatable disease due to its profound chemoresistance. A distinct inter- and intratumoral heterogeneity reflected by specialized microenvironmental niches and different tumor cell subpopulations allows GBMs to evade therapy regimens. Thus, there is an urgent need to develop alternative treatment strategies. A promising candidate for the treatment of GBMs is AT101, the R(-) enantiomer of gossypol. The present study evaluates the effects of AT101, alone or in combination with temozolomide (TMZ), in a microenvironmental glioma stem cell niche model of two GBM cell lines (U251MG and U87MG). AT101 was found to induce strong cytotoxic effects on U251MG and U87MG stem-like cells in comparison to the respective native cells. Moreover, a higher sensitivity against treatment with AT101 was observed upon incubation of native cells with a stem-like cell-conditioned medium. This higher sensitivity was reflected by a specific inhibitory influence on the p-p42/44 signaling pathway. Further, the expression of CXCR7 and the interleukin-6 receptor was significantly regulated upon these stimulatory conditions. Since tumor stem-like cells are known to mediate the development of tumor recurrences and were observed to strongly respond to the AT101 treatment, this might represent a promising approach to prevent the development of GBM recurrences.

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The hypoxic peri-arteriolar glioma stem cell niche, an integrated concept of five types of niches in human glioblastoma

Biochimica et Biophysica Acta (BBA) - Reviews on Cancer ◽

10.1016/j.bbcan.2018.04.008 ◽

2018 ◽

Vol 1869 (2) ◽

pp. 346-354 ◽

Cited By ~ 12

Author(s):

Diana A. Aderetti ◽

Vashendriya V.V. Hira ◽

Remco J. Molenaar ◽

Cornelis J.F. van Noorden

Keyword(s):

Stem Cell ◽

Stem Cell Niche ◽

Glioma Stem Cell ◽

Human Glioblastoma ◽

Integrated Concept ◽

Cell Niche

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IMMU-37. SINGLE-CELL SYSTEMS NEUROIMMUNOLOGY REVEALS IMMUNOSUPPRESSIVE CORRELATES WITH VENTRICULAR STEM CELL NICHE CONTACT IN HUMAN GLIOBLASTOMA

Neuro-Oncology ◽

10.1093/neuonc/noz175.529 ◽

2019 ◽

Vol 21 (Supplement_6) ◽

pp. vi127-vi127

Author(s):

Todd Bartkowiak ◽

Sierra Barone ◽

Allison Greenplate ◽

Justine Sinnaeve ◽

Nalin Leelatian ◽

...

Keyword(s):

Stem Cell ◽

Single Cell ◽

Stem Cell Niche ◽

Immune Cell ◽

Cell Mass ◽

Treatment Strategies ◽

Myeloid Cell ◽

Standard Of Care ◽

Immune Parameters ◽

Cell Niche

Abstract Glioblastomas make up more than 60% of adult primary brain tumors and carry a median survival of less than 15 months despite aggressive standard therapy. Immunotherapy, which is now standard of care for many solid tumors, offers an appealing therapeutic approach that may improve outcomes for glioblastoma patients. Predictive features in glioblastomas that may inform responsiveness to different immunotherapeutic modalities, however, are still lacking. Recent studies have demonstrated that patients whose tumors show radiographic contact with the lateral ventricles, and thus the stem cell niche of the ventricular-subventricular zone (V-SVZ), have reduced survival outcomes compared to patients whose tumors do not contact the V-SVZ. We therefore hypothesized that tumor contact with the V-SVZ engenders a unique, immunosuppressive microenvironment that promotes tumor growth by suppressing anti-tumor immunity. Glioblastoma tumors, obtained in accordance with the Declaration of Helsinki and with institutional IRB approval (#131870, #030372, #181970), were disaggregated into single-cell suspensions and multi-dimensional single-cell mass cytometry was performed to interrogate >30 immune parameters in thirteen immune populations infiltrating human glioblastomas. Using advanced computational dimensionality-reduction tools (Citrus, t-SNE, FlowSOM, and MEM), we identified distinctions among the abundance and phenotypes of tumor-infiltrating immune cells. Firstly, on the basis of tumor contact with the V-SVZ, Citrus identified differential abundance of five T and myeloid cell subsets among glioblastomas. Secondly, differential expression of five functional immune markers was observed in seven distinct immune cell subsets infiltrating glioblastoma tumors. Further, both immune abundance and marker expression correlated with patient outcome. Manual gating analysis and parallel computational pipelines confirmed that comparable cell subsets could be identified with traditional approaches and unsupervised algorithmic analysis. These results provide key insights into the immune microenvironment of glioblastomas. In addition, several clinically actionable immunotherapeutic targets were uncovered that may be used to optimize treatment strategies for glioblastomas based on V-SVZ contact status.

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