Selective blockade of matrix metalloprotease-14 with a monoclonal antibody abrogates invasion, angiogenesis, and tumor growth in ovarian cancer.
Selective blockade of matrix metalloprotease-14 with a monoclonal antibody abrogates invasion, angiogenesis, and tumor growth in ovarian cancer.
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DOI：
10.1158/0008-5472.can-12-1426
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发表时间：
2013-04-15
期刊：
影响因子：
11.2
通讯作者：
Agarwal A
中科院分区：
文献类型：
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作者：
Kaimal R;Aljumaily R;Tressel SL;Pradhan RV;Covic L;Kuliopulos A;Zarwan C;Kim YB;Sharifi S;Agarwal A
大多数卵巢癌患者被诊断为晚期进展，并且由于耐药性而经常经历肿瘤复发和复发。基质金属蛋白酶MMP-14在卵巢癌细胞表面的表达刺激肿瘤间质信号通路，促进血管生成和肿瘤生长。在92例患者的队列中，我们发现MMP-14在恶性卵巢肿瘤妇女的血清中升高。因此，我们研究了MMP-14单克隆抗体的临床前疗效，该抗体可以抑制体外侵袭性卵巢癌细胞的迁移和侵袭特性。MMP-14抗体破坏卵巢肿瘤间质通讯，在抑制小鼠血管生长方面与Avastin相当。这些对血管生成的影响与几个重要的血管生成因子的下调有关。此外，与IgG处理的对照相比，用抗MMP-14单一疗法处理的患有卵巢癌肿瘤的小鼠显示出肿瘤生长的显著和持续的消退，血管生成减少。在晚期腹膜卵巢癌模型中，MMP-14单克隆抗体腹腔内给药可有效抑制MMP-14依赖的侵袭和转移。总之，这些研究为MMP-14靶向作为晚期卵巢癌的辅助治疗策略提供了临床前概念验证。
Most ovarian cancer patients are diagnosed late in progression and often experience tumor recurrence and relapses due to drug resistance. Surface expression of matrix metalloprotease MMP-14 on ovarian cancer cells stimulates a tumor-stromal signaling pathway that promotes angiogenesis and tumor growth. In a cohort of 92 patients, we found that MMP-14 was increased in the serum of women with malignant ovarian tumors. Therefore, we investigated the preclinical efficacy of a MMP-14 monoclonal antibody that could inhibit the migratory and invasive properties of aggressive ovarian cancer cells in vitro. MMP-14 antibody disrupted ovarian tumor-stromal communication and was equivalent to Avastin in suppressing blood vessel growth in mice harboring matrigel plugs. These effects on angiogenesis correlated with down regulation of several important angiogenic factors. Further, mice with ovarian cancer tumors treated with anti-MMP-14 monotherapy showed a marked and sustained regression in tumor growth with decreased angiogenesis compared to IgG treated controls. In a model of advanced peritoneal ovarian cancer, MMP-14-dependent invasion and metastasis was effectively inhibited by intraperitoneal administration of monoclonal MMP-14 antibody. Together, these studies provide a preclinical proof-of-concept for MMP-14 targeting as an adjuvant treatment strategy for advanced ovarian cancer.