CXCR2-Expressing Tumor Cells Drive Vascular Mimicry in Antiangiogenic Therapy–Resistant Glioblastoma

Kartik Angara, Thaiz Ferraz Borin, Mohammad H. Rashid, Iryna Oleksandrivna Lebedyeva, Roxan Ara, Ping-Chang Lin, A. S.M. Iskander, Roni Jacob Bollag, Bhagelu Ram Achyut, Ali Syed Arbab

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

BACKGROUND: Glioblastoma (GBM) was shown to relapse faster and displayed therapeutic resistance to antiangiogenic therapies (AATs) through an alternative tumor cell-driven mechanism of neovascularization called vascular mimicry (VM). We identified highly upregulated interleukin 8 (IL-8)-CXCR2 axis in tumor cells in high-grade human glioma and AAT-treated orthotopic GBM tumors. METHODS: Human GBM tissue sections and tissue array were used to ascertain the clinical relevance of CXCR2-positive tumor cells in the formation of VM. We utilized U251 and U87 human tumor cells to understand VM in an orthotopic GBM model and AAT-mediated enhancement in VM was modeled using vatalanib (anti-VEGFR2) and avastin (anti-VEGF). Later, VM was inhibited by SB225002 (CXCR2 inhibitor) in a preclinical study. RESULTS: Overexpression of IL8 and CXCR2 in human datasets and histological analysis was identified as a bonafide candidate to validate VM through in vitro and animal model studies. AAT-treated tumors displayed a higher number of CXCR2-positive GBM-stem cells with endothelial-like phenotypes. Stable knockdown of CXCR2 expression in tumor cells led to decreased tumor growth as well as incomplete VM structures in the animal models. Similar data were obtained following SB225002 treatment. CONCLUSIONS: The present study suggests that tumor cell autonomous IL-8-CXCR2 pathway is instrumental in AAT-mediated resistance and VM formation in GBM. Therefore, CXCR2 can be targeted through SB225002 and can be combined with standard therapies to improve the therapeutic outcomes in clinical trials.

Original languageEnglish (US)
Pages (from-to)1070-1082
Number of pages13
JournalNeoplasia (United States)
Volume20
Issue number10
DOIs
StatePublished - Oct 1 2018

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Glioblastoma
Blood Vessels
Neoplasms
Interleukin-8
Therapeutics
Animal Models
Complementary Therapies
Glioma
Vascular Resistance
Vascular Endothelial Growth Factor A
Stem Cells
Clinical Trials
Phenotype
Recurrence
Growth

ASJC Scopus subject areas

  • Cancer Research

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CXCR2-Expressing Tumor Cells Drive Vascular Mimicry in Antiangiogenic Therapy–Resistant Glioblastoma. / Angara, Kartik; Borin, Thaiz Ferraz; Rashid, Mohammad H.; Lebedyeva, Iryna Oleksandrivna; Ara, Roxan; Lin, Ping-Chang; Iskander, A. S.M.; Bollag, Roni Jacob; Achyut, Bhagelu Ram; Arbab, Ali Syed.

In: Neoplasia (United States), Vol. 20, No. 10, 01.10.2018, p. 1070-1082.

Research output: Contribution to journalArticle

Angara, Kartik ; Borin, Thaiz Ferraz ; Rashid, Mohammad H. ; Lebedyeva, Iryna Oleksandrivna ; Ara, Roxan ; Lin, Ping-Chang ; Iskander, A. S.M. ; Bollag, Roni Jacob ; Achyut, Bhagelu Ram ; Arbab, Ali Syed. / CXCR2-Expressing Tumor Cells Drive Vascular Mimicry in Antiangiogenic Therapy–Resistant Glioblastoma. In: Neoplasia (United States). 2018 ; Vol. 20, No. 10. pp. 1070-1082.
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abstract = "BACKGROUND: Glioblastoma (GBM) was shown to relapse faster and displayed therapeutic resistance to antiangiogenic therapies (AATs) through an alternative tumor cell-driven mechanism of neovascularization called vascular mimicry (VM). We identified highly upregulated interleukin 8 (IL-8)-CXCR2 axis in tumor cells in high-grade human glioma and AAT-treated orthotopic GBM tumors. METHODS: Human GBM tissue sections and tissue array were used to ascertain the clinical relevance of CXCR2-positive tumor cells in the formation of VM. We utilized U251 and U87 human tumor cells to understand VM in an orthotopic GBM model and AAT-mediated enhancement in VM was modeled using vatalanib (anti-VEGFR2) and avastin (anti-VEGF). Later, VM was inhibited by SB225002 (CXCR2 inhibitor) in a preclinical study. RESULTS: Overexpression of IL8 and CXCR2 in human datasets and histological analysis was identified as a bonafide candidate to validate VM through in vitro and animal model studies. AAT-treated tumors displayed a higher number of CXCR2-positive GBM-stem cells with endothelial-like phenotypes. Stable knockdown of CXCR2 expression in tumor cells led to decreased tumor growth as well as incomplete VM structures in the animal models. Similar data were obtained following SB225002 treatment. CONCLUSIONS: The present study suggests that tumor cell autonomous IL-8-CXCR2 pathway is instrumental in AAT-mediated resistance and VM formation in GBM. Therefore, CXCR2 can be targeted through SB225002 and can be combined with standard therapies to improve the therapeutic outcomes in clinical trials.",
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T1 - CXCR2-Expressing Tumor Cells Drive Vascular Mimicry in Antiangiogenic Therapy–Resistant Glioblastoma

AU - Angara, Kartik

AU - Borin, Thaiz Ferraz

AU - Rashid, Mohammad H.

AU - Lebedyeva, Iryna Oleksandrivna

AU - Ara, Roxan

AU - Lin, Ping-Chang

AU - Iskander, A. S.M.

AU - Bollag, Roni Jacob

AU - Achyut, Bhagelu Ram

AU - Arbab, Ali Syed

PY - 2018/10/1

Y1 - 2018/10/1

N2 - BACKGROUND: Glioblastoma (GBM) was shown to relapse faster and displayed therapeutic resistance to antiangiogenic therapies (AATs) through an alternative tumor cell-driven mechanism of neovascularization called vascular mimicry (VM). We identified highly upregulated interleukin 8 (IL-8)-CXCR2 axis in tumor cells in high-grade human glioma and AAT-treated orthotopic GBM tumors. METHODS: Human GBM tissue sections and tissue array were used to ascertain the clinical relevance of CXCR2-positive tumor cells in the formation of VM. We utilized U251 and U87 human tumor cells to understand VM in an orthotopic GBM model and AAT-mediated enhancement in VM was modeled using vatalanib (anti-VEGFR2) and avastin (anti-VEGF). Later, VM was inhibited by SB225002 (CXCR2 inhibitor) in a preclinical study. RESULTS: Overexpression of IL8 and CXCR2 in human datasets and histological analysis was identified as a bonafide candidate to validate VM through in vitro and animal model studies. AAT-treated tumors displayed a higher number of CXCR2-positive GBM-stem cells with endothelial-like phenotypes. Stable knockdown of CXCR2 expression in tumor cells led to decreased tumor growth as well as incomplete VM structures in the animal models. Similar data were obtained following SB225002 treatment. CONCLUSIONS: The present study suggests that tumor cell autonomous IL-8-CXCR2 pathway is instrumental in AAT-mediated resistance and VM formation in GBM. Therefore, CXCR2 can be targeted through SB225002 and can be combined with standard therapies to improve the therapeutic outcomes in clinical trials.

AB - BACKGROUND: Glioblastoma (GBM) was shown to relapse faster and displayed therapeutic resistance to antiangiogenic therapies (AATs) through an alternative tumor cell-driven mechanism of neovascularization called vascular mimicry (VM). We identified highly upregulated interleukin 8 (IL-8)-CXCR2 axis in tumor cells in high-grade human glioma and AAT-treated orthotopic GBM tumors. METHODS: Human GBM tissue sections and tissue array were used to ascertain the clinical relevance of CXCR2-positive tumor cells in the formation of VM. We utilized U251 and U87 human tumor cells to understand VM in an orthotopic GBM model and AAT-mediated enhancement in VM was modeled using vatalanib (anti-VEGFR2) and avastin (anti-VEGF). Later, VM was inhibited by SB225002 (CXCR2 inhibitor) in a preclinical study. RESULTS: Overexpression of IL8 and CXCR2 in human datasets and histological analysis was identified as a bonafide candidate to validate VM through in vitro and animal model studies. AAT-treated tumors displayed a higher number of CXCR2-positive GBM-stem cells with endothelial-like phenotypes. Stable knockdown of CXCR2 expression in tumor cells led to decreased tumor growth as well as incomplete VM structures in the animal models. Similar data were obtained following SB225002 treatment. CONCLUSIONS: The present study suggests that tumor cell autonomous IL-8-CXCR2 pathway is instrumental in AAT-mediated resistance and VM formation in GBM. Therefore, CXCR2 can be targeted through SB225002 and can be combined with standard therapies to improve the therapeutic outcomes in clinical trials.

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