A peptide derived from the nonreceptor binding region of urokinase plasminogen activator (uPA) inhibits tumor progression and angiogenesis and induces tumor cell death in vivo
A peptide derived from the nonreceptor binding region of urokinase plasminogen activator (uPA) inhibits tumor progression and angiogenesis and induces tumor cell death in vivo
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DOI：
10.1096/fj.14.10.1400
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发表时间：
2000-07-01
期刊：
影响因子：
4.8
通讯作者：
Rabbani, SA
中科院分区：
文献类型：
--
作者：
Guo, YJ;Higazi, AA;Rabbani, SA
尿激酶型纤溶酶原激活物（uPA）在包括乳腺癌在内的多种恶性肿瘤的发生发展中起重要作用。我们已经确定了一个非竞争性拮抗剂的uPA-uPAR相互作用的uPA的非受体结合区（氨基酸136-143）。这种8-mer加帽肽（Angstrom 6）在体外以剂量依赖性方式抑制乳腺癌细胞侵袭和内皮细胞迁移，而不改变细胞倍增时间。腹腔注射Angstrom 6可显著抑制乳腺癌细胞生长和转移模型中的肿瘤生长，并抑制淋巴结转移的发展。Angstrom 6处理动物的实验肿瘤切片在组织学和免疫组化分析中观察到大面积的肿瘤坏死和广泛的TUNEL阳性染色。这种治疗也导致因子VIII阳性肿瘤微血管热点的减少。这些结果鉴定了uPA中参与uPA-uPAR相互作用的新表位，并表明基于该表位的拮抗剂能够在体内不存在直接细胞毒性作用的情况下通过调节肿瘤微环境来抑制肿瘤进展。
Urokinase plasminogen activator (uPA) plays an important role in the progression of several malignancies including breast cancer. We have identified a noncompetitive antagonist of the uPA-uPAR interaction derived from a nonreceptor binding region of uPA (amino acids 136-143). This 8-mer capped peptide (Angstrom 6) inhibited breast cancer cell invasion and endothelial cell migration in a dose-dependent manner in vitro without altering cell doubling time. Intraperitoneal administration of Angstrom 6 resulted in a significant inhibition of tumor growth and suppressed the development of lymph node metastases in several models of breast cancer cell growth and metastasis, Large areas of tumor necrosis and extensive positive staining by TUNEL were observed on histological and inmunohistochemical analysis of experimental tumor sections from Angstrom 6-treated animals.;is treatment also resulted in a decrease in factor VIII-positive tumor microvessel hot-spots. These results identify a new epitope in uPA that is involved in the uPA-uPAR interaction and indicate that an antagonist based on this epitope is able to inhibit tumor progression by modulating the tumor microenvironment in the absence of direct cytotoxic effects in vivo.