Paauwe M, Heijkants R C, Oudt C H, van Pelt G W, Cui C, Theuer C P, Hardwick J C H, Sier C F M, Hawinkels L J A C
Department of Molecular Cell Biology, Leiden University Medical Center, Leiden, The Netherlands.
Department of Gastroenterology-Hepatology, Leiden University Medical Center, Leiden, The Netherlands.
Oncogene. 2016 Aug 4;35(31):4069-79. doi: 10.1038/onc.2015.509. Epub 2016 Jan 25.
Endoglin, a transforming growth factor-β co-receptor, is highly expressed on angiogenic endothelial cells in solid tumors. Therefore, targeting endoglin is currently being explored in clinical trials for anti-angiogenic therapy. In this project, the redundancy between endoglin and vascular endothelial growth factor (VEGF) signaling in angiogenesis and the effects of targeting both pathways on breast cancer metastasis were explored. In patient samples, increased endoglin signaling after VEGF inhibition was observed. In vitro TRC105, an endoglin-neutralizing antibody, increased VEGF signaling in endothelial cells. Moreover, combined targeting of the endoglin and VEGF pathway, with the VEGF receptor kinase inhibitor SU5416, increased antiangiogenic effects in vitro and in a zebrafish angiogenesis model. Next, in a mouse model for invasive lobular breast cancer, the effects of TRC105 and SU5416 on tumor growth and metastasis were explored. Although TRC105 and SU5416 decreased tumor vascular density, tumor volume was unaffected. Strikingly, in mice treated with TRC105, or TRC105 and SU5416 combined, a strong inhibition in the number of metastases was seen. Moreover, upon resection of the primary tumor, strong inhibition of metastatic spread by TRC105 was observed in an adjuvant setting. To confirm these data, we assessed the effects of endoglin-Fc (an endoglin ligand trap) on metastasis formation. Similar to treatment with TRC105 in the resection model, endoglin-Fc-expressing tumors showed strong inhibition of distant metastases. These results show, for the first time, that targeting endoglin, either with neutralizing antibodies or a ligand trap, strongly inhibits metastatic spread of breast cancer in vivo.
内皮糖蛋白是一种转化生长因子-β共受体，在实体瘤的血管生成内皮细胞上高度表达。因此，目前正在临床试验中探索以内皮糖蛋白为靶点进行抗血管生成治疗。在本项目中，研究了内皮糖蛋白与血管内皮生长因子（VEGF）信号通路在血管生成中的冗余性以及同时靶向这两条通路对乳腺癌转移的影响。在患者样本中，观察到VEGF抑制后内皮糖蛋白信号增强。在体外，内皮糖蛋白中和抗体TRC105增加了内皮细胞中的VEGF信号。此外，将内皮糖蛋白和VEGF通路与VEGF受体激酶抑制剂SU5416联合靶向，在体外和斑马鱼血管生成模型中增强了抗血管生成作用。接下来，在侵袭性小叶乳腺癌小鼠模型中，研究了TRC105和SU5416对肿瘤生长和转移的影响。尽管TRC105和SU5416降低了肿瘤血管密度，但肿瘤体积未受影响。令人惊讶的是，在用TRC105或TRC105与SU5416联合治疗的小鼠中，转移灶数量受到强烈抑制。此外，在切除原发肿瘤后，在辅助治疗环境中观察到TRC105对转移扩散有强烈抑制作用。为了证实这些数据，我们评估了内皮糖蛋白-Fc（一种内皮糖蛋白配体陷阱）对转移形成的影响。与在切除模型中用TRC105治疗相似，表达内皮糖蛋白-Fc的肿瘤显示出对远处转移的强烈抑制。这些结果首次表明，用中和抗体或配体陷阱靶向内皮糖蛋白可在体内强烈抑制乳腺癌的转移扩散。
