Targeting EGFR activity in blood vessels is sufficient to inhibit tumor growth and is accompanied by an increase in VEGFR-2 dependence in tumor endothelial cells
Targeting EGFR activity in blood vessels is sufficient to inhibit tumor growth and is accompanied by an increase in VEGFR-2 dependence in tumor endothelial cells
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DOI：
10.1016/j.mvr.2008.01.002
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发表时间：
2008-05-01
影响因子：
3.1
通讯作者：
Klagsbrun, Michael
中科院分区：
文献类型：
--
作者：
Amin, Dhara N.;Bielenberg, Diane R.;Klagsbrun, Michael
表皮生长因子受体（EGFR）靶向剂如激酶抑制剂减少肿瘤生长和进展。我们先前已经报道，EGFR不仅由肿瘤细胞表达，而且也由肿瘤内皮细胞（EC）表达（Amin，D. N.，希达，K.，Bielenberg，D. R.，Klagsbrun，M.，2006.肿瘤内皮细胞表达表皮生长因子受体（EGFR），但不表达ErbB 3，并对EGF和EGFR激酶抑制剂有反应。Cancer Res.66，2173-80）。因此，靶向肿瘤血管EGFR可能是抑制肿瘤生长的可行策略。我们在此描述了一种黑色素瘤异种移植模型，其中肿瘤细胞表达很少或不表达EGFR，但肿瘤血管表达活化的EGFR。EGFR激酶抑制剂吉非替尼（易瑞沙）与对照小鼠相比，肿瘤生长延迟，大小减少了38%，表面上是由于靶向血管。从吉非替尼处理的小鼠的肿瘤中分离EC。这些EC不能增殖响应于EGF，并显示相对较弱的MAPK和AKT信号的激活响应于EGF相比，从媒介物处理的小鼠分离的肿瘤EC。相比之下，吉非替尼治疗小鼠的肿瘤EC在mRNA和蛋白水平上表达更高水平的VEGFR-2。此外，这些细胞在体外对EGFR激酶抑制剂不太敏感，但对VEGFR-2激酶抑制剂更敏感。这些结果表明，在吉非替尼治疗小鼠的肿瘤EC中，存在从依赖EGFR活性到通过VEGFR-2信号传导的转换。我们的数据为靶向肿瘤血管系统中EGF和VEGF信号传导的联合治疗提供了分子基础。(c)2008年爱思唯尔公司All rights reserved.
Epidermal growth factor receptor (EGFR) targeting agents such as kinase inhibitors reduce tumor growth and progression. We have previously reported that EGFR is not only expressed by the tumor cells but by the tumor endothelial cells (EC) as well (Amin, D. N., Hida, K., Bielenberg, D. R., Klagsbrun, M., 2006. Tumor endothelial cells express epidermal growth factor receptor (EGFR) but not ErbB3 and are responsive to EGF and to EGFR kinase inhibitors. Cancer Res. 66, 2173-80). Thus, targeting tumor blood vessel EGFR may be a viable strategy for tumor growth inhibition. We describe here a melanoma xenograft model where the tumor cells express very little or no EGFR but the tumor blood vessels express activated EGFR. The EGFR kinase inhibitor, gefitinib (Iressa), retarded tumor growth with a size decrease of 38% compared to control mice, ostensibly due to targeting of the blood vessels. EC were isolated from tumors of gefitinib-treated mice. These EC were unable to proliferate in response to EGF and displayed relatively weaker activation of MAPK and AKT signaling in response to EGF compared to tumor EC isolated from vehicle-treated mice. In contrast, the tumor EC from gefitinib-treated mice expressed higher levels of VEGFR-2 both at the mRNA and protein level. In addition, these cells were less sensitive to EGFR kinase inhibitors in vitro but more sensitive to a VEGFR-2 kinase inhibitor. These results suggest that in tumor EC from gefitinib-treated mice there is a switch from dependence on EGFR activity to signaling via VEGFR-2. Our data provide a molecular rationale for combination therapies targeting both EGF and VEGF signaling on the tumor vasculature. (c) 2008 Elsevier Inc. All rights reserved.