Antiangiogenic gene therapy targeting the endothelium-specific receptor tyrosine kinase Tie2

Angiogenesis is required for tumor growth and metastasis, and inhibition of angiogenesis is a promising approach for anticancer therapy. Tie2 (a.k.a Tek) is an endothelium-specific receptor tyrosine kinase known to play a role in tumor angiogenesis. To explore the therapeutic potential of blocking the Tie2 pathway, an adenoviral vector was constructed to deliver a recombinant, soluble Tie2 receptor (AdExTek) capable of blocking Tie2 activation. Two days after i.v. injection of AdExTek, the plasma concentration of ExTek exceeded 1 mg/ml and was maintained for about 8 days. Administration of AdExTek to mice with two different well established primary tumors, a murine mammary carcinoma (4T1) or a murine melanoma (B16F10.9), significantly inhibited the growth rate of both tumors (64% and 47%, respectively). To study the effect of ExTek on tumor metastasis, both tumor cell lines were coinjected i.v. with either AdExTek or a control virus. Mice coinjected with control virus developed numerous large, well vascularized lung metastases. In contrast, mice coinjected with AdExTek virus developed few, if any, grossly apparent metastases, and histologic examination revealed only small avascular clusters of tumor cells. Administration of AdExTek also inhibited tumor metastasis when delivered at the time of surgical excision of primary tumors in a clinically relevant model of tumor metastasis. This study demonstrates the potential utility of gene therapy for systemic delivery of an antiangiogenic agent targeting an endothelium-specific receptor, Tie2.

血管生成（angiogenesis）是肿瘤生长与转移的必要条件，而抑制血管生成是抗肿瘤治疗极具前景的策略。Tie2（又名Tek）是一种内皮特异性受体酪氨酸激酶（endothelium-specific receptor tyrosine kinase），已被证实参与肿瘤血管生成过程。为探究阻断Tie2通路的治疗潜力，研究人员构建了腺病毒载体（adenoviral vector）以递送重组可溶性Tie2受体（AdExTek），该受体可有效阻断Tie2的激活。在i.v.注射AdExTek后的第2天，ExTek的血浆浓度即超过1 mg/ml，并维持约8天。向携带两种已成功建立的原发肿瘤的小鼠——小鼠乳腺腺癌（4T1）与小鼠黑色素瘤（B16F10.9）——给予AdExTek治疗后，两种肿瘤的生长速率均受到显著抑制，抑制率分别为64%与47%。为研究ExTek对肿瘤转移的影响，研究人员将两种肿瘤细胞系分别与AdExTek或对照病毒进行i.v.共注射。注射对照病毒的小鼠肺部出现大量体积较大且血管丰富的肺转移灶；与之相反，注射AdExTek的小鼠仅出现极少（若有的话）肉眼可见的转移灶，组织学检查仅发现少量无血管的肿瘤细胞簇。在一个具有临床相关性的肿瘤转移模型中，在手术切除原发肿瘤时给予AdExTek治疗，同样可抑制肿瘤转移。本研究证实了基因治疗用于系统性递送靶向内皮特异性受体Tie2的抗血管生成药物的潜在应用价值。