Estrogen Promotes Resistance to Bevacizumab in Murine Models of NSCLC

医学 富维斯特朗 贝伐单抗 雌激素 血管生成 血管内皮生长因子 癌症研究 内科学 雌激素受体 肿瘤科 内分泌学
作者
S. Patel,Matthew H. Herynk,Tina Cascone,Babita Saigal,Monique B. Nilsson,Hai T. Tran,Sumankalai Ramachandran,Lixia Diao,Jing Wang,Xiuning Le,John D. Minna,Ignacio I. Wistuba,John V. Heymach
出处
期刊:Journal of Thoracic Oncology [Elsevier BV]
卷期号:16 (12): 2051-2064 被引量:2
标识
DOI:10.1016/j.jtho.2021.07.007
摘要

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.To address this, we investigated the effects of estrogen on tumor growth, angiogenesis, and the response to BV in human xenograft models of NSCLC.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.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.
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