Estrogen Promotes Resistance to Bevacizumab in Murine Models of NSCLC
Copyright © 2021. Published by Elsevier Inc..
INTRODUCTION: Subgroup analyses from clinical studies have suggested that among patients with metastatic NSCLC receiving chemotherapy, females may derive less benefit from the addition of the vascular endothelial growth factor (VEGF) monoclonal antibody bevacizumab (BV) than males. This has raised the question of whether estrogen may affect the response to antiangiogenic therapy.
METHODS: To address this, we investigated the effects of estrogen on tumor growth, angiogenesis, and the response to BV in human xenograft models of NSCLC.
RESULTS: We observed that estrogen induced marked resistance to BV, which was accompanied by a 2.3-fold increase in tumor vascular pericyte coverage (p = 0.01) and an up-regulation of proangiogenic factors, VEGF and platelet-derived growth factor-BB. We also investigated the role of infiltrating myeloid cells, a population that has been associated with resistance to anti-VEGF therapies. We observed that estrogen induced a greater than twofold increase (p = 0.001) in the recruitment of tumor-infiltrating myeloid cells and concomitant increases in the myeloid recruitment factors, G-CSF and CXCL1. Blockade of the estrogen receptor pathway using fulvestrant resensitized tumors to VEGF targeting as evidenced by reduced tumor vasculature and an increase in overall survival in our NSCLC xenograft models.
CONCLUSIONS: Collectively, these data provide evidence that estrogen may promote resistance to VEGF-targeted therapies, potentially by enhancing pericyte coverage and myeloid recruitment, and suggest that estrogen receptor blockade merits further investigation as an approach to enhance the effects of antiangiogenic therapy.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2021 |
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| Erschienen: |
2021 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:16 |
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| Enthalten in: |
Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer - 16(2021), 12 vom: 15. Dez., Seite 2051-2064 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Patel, Sonia A [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 03.12.2021 Date Revised 08.07.2023 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1016/j.jtho.2021.07.007 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM328558923 |
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| 100 | 1 | |a Patel, Sonia A |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Estrogen Promotes Resistance to Bevacizumab in Murine Models of NSCLC |
| 264 | 1 | |c 2021 | |
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| 500 | |a Date Completed 03.12.2021 | ||
| 500 | |a Date Revised 08.07.2023 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2021. Published by Elsevier Inc. | ||
| 520 | |a INTRODUCTION: Subgroup analyses from clinical studies have suggested that among patients with metastatic NSCLC receiving chemotherapy, females may derive less benefit from the addition of the vascular endothelial growth factor (VEGF) monoclonal antibody bevacizumab (BV) than males. This has raised the question of whether estrogen may affect the response to antiangiogenic therapy | ||
| 520 | |a METHODS: To address this, we investigated the effects of estrogen on tumor growth, angiogenesis, and the response to BV in human xenograft models of NSCLC | ||
| 520 | |a RESULTS: We observed that estrogen induced marked resistance to BV, which was accompanied by a 2.3-fold increase in tumor vascular pericyte coverage (p = 0.01) and an up-regulation of proangiogenic factors, VEGF and platelet-derived growth factor-BB. We also investigated the role of infiltrating myeloid cells, a population that has been associated with resistance to anti-VEGF therapies. We observed that estrogen induced a greater than twofold increase (p = 0.001) in the recruitment of tumor-infiltrating myeloid cells and concomitant increases in the myeloid recruitment factors, G-CSF and CXCL1. Blockade of the estrogen receptor pathway using fulvestrant resensitized tumors to VEGF targeting as evidenced by reduced tumor vasculature and an increase in overall survival in our NSCLC xenograft models | ||
| 520 | |a CONCLUSIONS: Collectively, these data provide evidence that estrogen may promote resistance to VEGF-targeted therapies, potentially by enhancing pericyte coverage and myeloid recruitment, and suggest that estrogen receptor blockade merits further investigation as an approach to enhance the effects of antiangiogenic therapy | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a Bevacizumab | |
| 650 | 4 | |a Estrogen | |
| 650 | 4 | |a Fulvestrant | |
| 650 | 4 | |a Non–small cell lung cancer | |
| 650 | 4 | |a Pericytes | |
| 650 | 4 | |a Tumor endothelium | |
| 650 | 7 | |a Angiogenesis Inhibitors |2 NLM | |
| 650 | 7 | |a Estrogens |2 NLM | |
| 650 | 7 | |a Vascular Endothelial Growth Factor A |2 NLM | |
| 650 | 7 | |a Bevacizumab |2 NLM | |
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| 700 | 1 | |a Herynk, Matthew H |e verfasserin |4 aut | |
| 700 | 1 | |a Cascone, Tina |e verfasserin |4 aut | |
| 700 | 1 | |a Saigal, Babita |e verfasserin |4 aut | |
| 700 | 1 | |a Nilsson, Monique B |e verfasserin |4 aut | |
| 700 | 1 | |a Tran, Hai |e verfasserin |4 aut | |
| 700 | 1 | |a Ramachandran, Sumankalai |e verfasserin |4 aut | |
| 700 | 1 | |a Diao, Lixia |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Jing |e verfasserin |4 aut | |
| 700 | 1 | |a Le, Xiuning |e verfasserin |4 aut | |
| 700 | 1 | |a Minna, John |e verfasserin |4 aut | |
| 700 | 1 | |a Wistuba, Ignacio I |e verfasserin |4 aut | |
| 700 | 1 | |a Heymach, John V |e verfasserin |4 aut | |
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