A novel monoclonal antibody to secreted frizzled-related protein 2 inhibits tumor growth.
A novel monoclonal antibody to secreted frizzled-related protein 2 inhibits tumor growth.
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DOI：
10.1158/1535-7163.mct-12-1066
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发表时间：
2013-05
影响因子：
5.7
通讯作者：
Klauber-DeMore N
中科院分区：
文献类型：
--
作者：
Fontenot E;Rossi E;Mumper R;Snyder S;Siamakpour-Reihani S;Ma P;Hilliard E;Bone B;Ketelsen D;Santos C;Patterson C;Klauber-DeMore N
分泌型卷曲相关蛋白2（SFRP 2）在人血管肉瘤和乳腺癌中过表达，并通过激活钙调磷酸酶/NFATc 3途径刺激血管生成。关于SFRP 2是β-连环蛋白的拮抗剂还是激动剂，文献中存在相互矛盾的报道。这些研究的目的是评估SFRP 2拮抗作用对肿瘤生长和Wnt信号传导的影响，并评估SFRP 2是否是可行的治疗靶点。使用体外增殖、迁移和管形成试验评估了SFRP 2单克隆抗体（mAb）的抗血管生成和抗肿瘤特性;以及体内血管肉瘤和三阴性乳腺癌模型。使用蛋白质印迹法在用SFRP 2 mAb处理的内皮细胞和肿瘤细胞中评估Wnt信号传导。在荷瘤和非荷瘤小鼠中生成药代动力学（PK）和生物分布数据。SFRP 2 mAb显示在体外诱导抗肿瘤和抗血管生成作用，并抑制内皮细胞和肿瘤细胞中β-连环蛋白和NFATc 3的活化。与对照组相比，用SFRP 2 mAb治疗裸鼠中的SVR血管肉瘤同种异体移植物使肿瘤体积减少了58%（p=0.004）。与对照组相比，SFRP 2 mAb治疗MDA-MB-231乳腺癌异种移植物使肿瘤体积减少了52%（p=0.03），而贝伐珠单抗并未显着减少肿瘤体积。药代动力学研究表明，抗体在血液中长时间循环，并优先在SFRP 2阳性肿瘤中积累。总之，拮抗SFRP 2抑制内皮细胞和肿瘤细胞中β-连环蛋白和NFATc 3的活化，并且是抑制血管肉瘤和三阴性乳腺癌的新的治疗方法。
Secreted frizzled related protein 2 (SFRP2) is overexpressed in human angiosarcoma and breast cancer, and stimulates angiogenesis via activation of the calcineurin/ NFATc3 pathway. There are conflicting reports in the literature as to whether SFRP2 is an antagonist or agonist of ß-catenin. The aims of these studies were to assess the effects of SFRP2 antagonism on tumor growth and Wnt-signaling, and to evaluate whether SFRP2 is a viable therapeutic target. The anti-angiogenic and anti-tumor properties of SFRP2 monoclonal antibody (mAb) were assessed using in vitro proliferation, migration, and tube formation assays; and in vivo angiosarcoma and triple negative breast cancer models. Wnt-signaling was assessed in endothelial and tumor cells treated with SFRP2 mAb using Western blotting. Pharmacokinetic (PK) and biodistribution data were generated in tumor-bearing and non-tumor bearing mice. SFRP2 mAb was shown to induce anti-tumor and anti-angiogenic effects in vitro, and inhibit activation of ß-catenin and NFATc3 in endothelial and tumor cells. Treatment of SVR angiosarcoma allografts in nude mice with the SFRP2 mAb decreased tumor volume by 58% compared to control (p=0.004). Treatment of MDA-MB-231 breast carcinoma xenografts with SFRP2 mAb decreased tumor volume by 52% (p=0.03) compared to control, while bevacizumab did not significantly reduce tumor volume. Pharmacokinetic studies show the antibody is long circulating in the blood and preferentially accumulates in SFRP2-positive tumors. In conclusion, antagonizing SFRP2 inhibits activation of ß-catenin and NFATc3 in endothelial and tumor cells, and is a novel therapeutic approach to inhibiting angiosarcoma and triple negative breast cancer.