Placenta growth factor-1 antagonizes VEGF-induced angiogenesis and tumor growth by the formation of functionally inactive PlGF-1/VEGF heterodimers
Placenta growth factor-1 antagonizes VEGF-induced angiogenesis and tumor growth by the formation of functionally inactive PlGF-1/VEGF heterodimers
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DOI：
10.1016/s1535-6108(02)00028-4
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发表时间：
2002-02-01
期刊：
影响因子：
50.3
通讯作者：
Cao, YH
中科院分区：
文献类型：
--
作者：
Eriksson, A;Cao, RH;Cao, YH
肿瘤生长和转移需要新血管同时生长，新血管受到血管生成因子的刺激，包括大多数肿瘤分泌的血管内皮生长因子（VEGF）。尽管 VEGF 的血管生成特性和分子机制已得到充分研究，但其相关同源物胎盘生长因子 (PIGF) 的生物学功能却知之甚少。在这里，我们证明，当两种因子在鼠纤维肉瘤细胞中共表达时，PIGF-1（PIGF基因的一种选择性剪接亚型）会拮抗VEGF诱导的血管生成。产生 VEGF 的肿瘤细胞中 PIGF-1 的过度表达导致 PIGF-1/VEGF 异二聚体的形成和大多数小鼠 VEGF 同二聚体的耗尽。 PIGF-1/VEGF 的异二聚体形式缺乏在体外和体内诱导血管生成的能力。同样，PIGF-1/VEGF 无法激活 VEGFR-2 介导的信号通路。此外，当将表达PIGF-1的肿瘤细胞植入同基因小鼠体内时，PIGF-1抑制鼠纤维肉瘤的生长约90%。相比之下，鼠肿瘤细胞中人 VEGF 的过度表达会导致原发性纤维肉瘤和早期肝转移加速呈指数增长。我们的数据表明，当两种因子在同一细胞群中合成时，VEGF 家族的成员 PIGF-1 可充当 VEGF 的天然拮抗剂。潜在的机制是由于功能上无活性的异二聚体的形成。
Tumor growth and metastasis require concomitant growth of new blood vessels, which are stimulated by angiogenic factors, including vascular endothelial growth factor (VEGF), secreted by most tumors. Whereas the angiogenic property and molecular mechanisms of VEGF have been well studied, the biological function of its related homolog, placenta growth factor (PIGF), is poorly understood. Here we demonstrate that PIGF-1, an alternatively spliced isoform of the PIGF gene, antagonizes VEGF-induced angiogenesis when both factors are coexpressed in murine fibrosarcoma cells. Overexpression of PIGF-1 in VEGF-producing tumor cells results in the formation of PIGF-1/VEGF heterodimers and depletion of the majority of mouse VEGF homodimers. The heterodimeric form of PIGF-1/VEGF lacks the ability to induce angiogenesis in vitro and in vivo. Similarly, PIGF-1/VEGF fails to activate the VEGFR-2-mediated signaling pathways. Further, PIGF-1 inhibits the growth of a murine fibrosarcoma by approximately 90% when PIGF-1-expressing tumor cells are implanted in syngeneic mice. In contrast, overexpression of human VEGF in murine tumor cells causes accelerated and exponential growth of primary fibrosarcomas and early hepatic metastases. Our data demonstrate that PIGF-1, a member of the VEGF family, acts as a natural antagonist of VEGF when both factors are synthesized in the same population of cells. The underlying mechanism is due to the formation of functionally inactive heterodimers.