Bone marrow derived myeloid cells orchestrate antiangiogenic resistance in glioblastoma through coordinated molecular networks

B. R. Achyut, Adarsh Shankar, A. S M Iskander, Roxan Ara, Kartik Angara, Peng Zeng, Robert A. Knight, Alfonso G. Scicli, Ali S. Arbab

Research output: Contribution to journalArticle

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Abstract

Glioblastoma (GBM) is a hypervascular and malignant form of brain tumors. Anti-angiogenic therapies (AAT) were used as an adjuvant against VEGF-VEGFR pathway to normalize blood vessels in clinical and preclinical studies, which resulted into marked hypoxia and recruited bone marrow derived cells (BMDCs) to the tumor microenvironment (TME). In vivo animal models to track BMDCs and investigate molecular mechanisms in AAT resistance are rare. We exploited recently established chimeric mouse to develop orthotopic U251 tumor, which uses as low as 5 × 106 GFP+ BM cells in athymic nude mice and engrafted >70% GFP+ cells within 14 days. Our unpublished data and published studies have indicated the involvement of immunosuppressive myeloid cells in therapeutic resistance in glioma. Similarly, in the present study, vatalanib significantly increased CD68+ myeloid cells, and CD133+, CD34+ and Tie2+ endothelial cell signatures. Therefore, we tested inhibition of CSF1R+ myeloid cells using GW2580 that reduced tumor growth by decreasing myeloid (Gr1+ CD11b+ and F4/80+) and angiogenic (CD202b+ and VEGFR2+) cell signatures in TME. CSF1R blockade significantly decreased inflammatory, proangiogenic and immunosuppressive molecular signatures compared to vehicle, vatalanib or combination. TCK1 or CXCL7, a potent chemoattractant and activator of neutrophils, was observed as most significantly decreased cytokine in CSF1R blockade. ERK MAPK pathway was involved in cytokine network regulation. In conclusion, present study confirmed the contribution of myeloid cells in GBM development and therapeutic resistance using chimeric mouse model. We identified novel molecular networks including CXCL7 chemokine as a promising target for future studies. Nonetheless, survival studies are required to assess the beneficial effect of CSF1R blockade.

Original languageEnglish (US)
Pages (from-to)416-26
Number of pages11
JournalCancer Letters
Volume369
Issue number2
DOIs
StatePublished - Dec 28 2015

Fingerprint

Myeloid Cells
Glioblastoma
Bone Marrow
Tumor Microenvironment
Immunosuppressive Agents
Nude Mice
Bone Marrow Cells
Cytokines
MAP Kinase Signaling System
Chemotactic Factors
Therapeutics
Chemokines
Brain Neoplasms
Glioma
Vascular Endothelial Growth Factor A
Blood Vessels
Neoplasms
Neutrophils
Endothelial Cells
Animal Models

Keywords

  • Bone marrow
  • Glioblastoma
  • Resistance
  • Tumor angiogenesis
  • Tumor microenvironment
  • VEGF

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Bone marrow derived myeloid cells orchestrate antiangiogenic resistance in glioblastoma through coordinated molecular networks. / Achyut, B. R.; Shankar, Adarsh; Iskander, A. S M; Ara, Roxan; Angara, Kartik; Zeng, Peng; Knight, Robert A.; Scicli, Alfonso G.; Arbab, Ali S.

In: Cancer Letters, Vol. 369, No. 2, 28.12.2015, p. 416-26.

Research output: Contribution to journalArticle

Achyut, BR, Shankar, A, Iskander, ASM, Ara, R, Angara, K, Zeng, P, Knight, RA, Scicli, AG & Arbab, AS 2015, 'Bone marrow derived myeloid cells orchestrate antiangiogenic resistance in glioblastoma through coordinated molecular networks', Cancer Letters, vol. 369, no. 2, pp. 416-26. https://doi.org/10.1016/j.canlet.2015.09.004
Achyut, B. R. ; Shankar, Adarsh ; Iskander, A. S M ; Ara, Roxan ; Angara, Kartik ; Zeng, Peng ; Knight, Robert A. ; Scicli, Alfonso G. ; Arbab, Ali S. / Bone marrow derived myeloid cells orchestrate antiangiogenic resistance in glioblastoma through coordinated molecular networks. In: Cancer Letters. 2015 ; Vol. 369, No. 2. pp. 416-26.
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AU - Shankar, Adarsh

AU - Iskander, A. S M

AU - Ara, Roxan

AU - Angara, Kartik

AU - Zeng, Peng

AU - Knight, Robert A.

AU - Scicli, Alfonso G.

AU - Arbab, Ali S.

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PY - 2015/12/28

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AB - Glioblastoma (GBM) is a hypervascular and malignant form of brain tumors. Anti-angiogenic therapies (AAT) were used as an adjuvant against VEGF-VEGFR pathway to normalize blood vessels in clinical and preclinical studies, which resulted into marked hypoxia and recruited bone marrow derived cells (BMDCs) to the tumor microenvironment (TME). In vivo animal models to track BMDCs and investigate molecular mechanisms in AAT resistance are rare. We exploited recently established chimeric mouse to develop orthotopic U251 tumor, which uses as low as 5 × 106 GFP+ BM cells in athymic nude mice and engrafted >70% GFP+ cells within 14 days. Our unpublished data and published studies have indicated the involvement of immunosuppressive myeloid cells in therapeutic resistance in glioma. Similarly, in the present study, vatalanib significantly increased CD68+ myeloid cells, and CD133+, CD34+ and Tie2+ endothelial cell signatures. Therefore, we tested inhibition of CSF1R+ myeloid cells using GW2580 that reduced tumor growth by decreasing myeloid (Gr1+ CD11b+ and F4/80+) and angiogenic (CD202b+ and VEGFR2+) cell signatures in TME. CSF1R blockade significantly decreased inflammatory, proangiogenic and immunosuppressive molecular signatures compared to vehicle, vatalanib or combination. TCK1 or CXCL7, a potent chemoattractant and activator of neutrophils, was observed as most significantly decreased cytokine in CSF1R blockade. ERK MAPK pathway was involved in cytokine network regulation. In conclusion, present study confirmed the contribution of myeloid cells in GBM development and therapeutic resistance using chimeric mouse model. We identified novel molecular networks including CXCL7 chemokine as a promising target for future studies. Nonetheless, survival studies are required to assess the beneficial effect of CSF1R blockade.

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