Gene Expression Analysis Reveals Distinct Pathways of Resistance to Bevacizumab in Xenograft Models of Human ER-Positive Breast Cancer.
Gene Expression Analysis Reveals Distinct Pathways of Resistance to Bevacizumab in Xenograft Models of Human ER-Positive Breast Cancer.
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DOI：
10.7150/jca.8466
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发表时间：
2014
影响因子：
3.9
通讯作者：
Sledge GW Jr
中科院分区：
文献类型：
--
作者：
Gökmen-Polar Y;Goswami CP;Toroni RA;Sanders KL;Mehta R;Sirimalle U;Tanasa B;Shen C;Li L;Ivan M;Badve S;Sledge GW Jr
贝伐单抗是一种靶向血管内皮生长因子（VEGF）的重组抗体，可改善转移性乳腺癌的无进展生存期，但不能改善总生存期。为了在分子水平上进一步了解对贝伐单抗的耐药机制，我们开发了VEGF和非VEGF驱动的er阳性mcf7衍生异种移植物模型，以比较不同时间点的肿瘤反应。过表达VEGF基因（MV165）的异种移植物最初对贝伐单抗敏感，但最终获得耐药性。相比之下，亲代MCF7细胞衍生的肿瘤对贝伐单抗从头不敏感。qRT-PCR验证的微阵列分析显示，在vegf驱动的肿瘤中，Follistatin （FST）和NOTCH是与耐药相关的主要信号通路（P<0.05）。基于VEGF的存在，贝伐单抗治疗导致宏细胞和PAM50基因表达模式的改变。在短期和长期贝伐单抗治疗后的vegf驱动模型中，观察到内在亚型（管状到肌上皮/基底样）的变化与与癌症干细胞表型相关的基因表达增加相关（P<0.05）。我们的研究结果表明，VEGF表达的存在或缺失会影响对贝伐单抗治疗和基因途径的反应。特别是，在vegf表达模型中，长期贝伐单抗治疗将癌细胞转移到更具侵袭性的肌上皮/基底亚型，而在非vegf模型中则不然。这些发现可以阐明患者抗VEGF治疗的不同结果，并强调基于VEGF表达的患者分层的重要性。我们的数据强烈建议在临床环境中考虑患者亚组的治疗和设计新的联合疗法。
Bevacizumab, the recombinant antibody targeting vascular endothelial growth factor (VEGF), improves progression-free but not overall survival in metastatic breast cancer. To seek further insights in resistance mechanisms to bevacizumab at the molecular level, we developed VEGF and non-VEGF-driven ER-positive MCF7-derived xenograft models allowing comparison of tumor response at different timepoints. VEGF gene (MV165) overexpressing xenografts were initially sensitive to bevacizumab, but eventually acquired resistance. In contrast, parental MCF7 cells derived tumors were de novo insensitive to bevacizumab. Microarray analysis with qRT-PCR validation revealed that Follistatin (FST) and NOTCH were the top signaling pathways associated with resistance in VEGF-driven tumors (P<0.05). Based on the presence of VEGF, treatment with bevacizumab resulted in altered patterns of metagenes and PAM50 gene expression. In VEGF-driven model after short and long-term bevacizumab treatments, a change in the intrinsic subtype (luminal to myoepithelial/basal-like) was observed in association with increased expression of genes implicated with cancer stem cell phenotype (P<0.05). Our results show that the presence or absence of VEGF expression affects the response to bevacizumab therapy and gene pathways. In particular, long-term bevacizumab treatment shifts the cancer cells to a more aggressive myoepithelial/basal subtype in VEGF-expressing model, but not in non-VEGF model. These findings could shed light on variable results to anti-VEGF therapy in patients and emphasize the importance of patient stratification based on the VEGF expression. Our data strongly suggest consideration of patient subgroups for treatment and designing novel combinatory therapies in the clinical setting.
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影响因子：
11.5
作者：
Konecny, GE;Meng, YG;Pegram, MD
通讯作者：
Pegram, MD
影响因子：
11.2
作者：
Bertucci, F;Finetti, P;Viens, P
通讯作者：
Viens, P
影响因子：
15.9
作者：
Cascone, Tina;Herynk, Matthew H.;Heymach, John V.
通讯作者：
Heymach, John V.
DOI：
10.1073/pnas.0708148104
发表时间：
2007-10-23
影响因子：
11.1
作者：
Ebos, John M. L.;Lee, Christina R.;Kerbel, Robert S.
通讯作者：
Kerbel, Robert S.
DOI：
10.1093/jnci/89.2.139
发表时间：
1997-01-15
期刊：
JOURNAL OF THE NATIONAL CANCER INSTITUTE
影响因子：
--
作者：
Gasparini, G;Toi, M;Tominaga, T
通讯作者：
Tominaga, T