Calreticulin and calreticulin fragments are endothelial cell inhibitors that suppress tumor growth
Calreticulin and calreticulin fragments are endothelial cell inhibitors that suppress tumor growth
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DOI：
10.1182/blood.v94.7.2461.419a26_2461_2468
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发表时间：
1999-10-01
期刊：
影响因子：
20.3
通讯作者：
Tosato, G
中科院分区：
文献类型：
--
作者：
Pike, SE;Yao, L;Tosato, G
几种血管生成抑制剂是本身作为血管生成抑制剂没有活性的较大蛋白质的片段。Vasostatin是钙网蛋白的N-末端结构域，包括氨基酸1-180，是一种在体内发挥抗肿瘤作用的血管生成抑制剂。在本研究中，我们研究了全长钙网蛋白分子是否具有血管抑素的抗血管生成和抗肿瘤活性。与vasostatin类似，钙网蛋白在体外选择性抑制内皮细胞增殖，但不抑制其他谱系的细胞，并在体内抑制血管生成。当接种到无胸腺小鼠，钙网蛋白抑制Burkitt肿瘤的生长与vasostatin。钙网蛋白缺乏N-末端1-120个氨基酸抑制内皮细胞增殖在体外和Burkitt肿瘤生长在体内与vasostatin。包含氨基酸120-180的内部钙网蛋白片段也与钙网蛋白和vasostatin一起抑制体外内皮细胞增殖和体内血管生成。这些结果表明，vasostatin的抗血管生成活性存在于一个结构域，该结构域可从全长钙网蛋白分子进入，并定位于钙网蛋白N-末端氨基酸120-180。因此，钙网蛋白和钙网蛋白片段是直接靶向内皮细胞的血管生成抑制剂，抑制血管生成，并抑制肿瘤生长。这一信息可能是关键的病理性血管生成，癌症和其他疾病的基础设计有针对性的抑制剂。这是美国政府的工作。它的使用没有限制。
Several angiogenesis inhibitors are fragments of larger proteins that are themselves not active as angiogenesis inhibitors. Vasostatin, the N-terminal domain of calreticulin inclusive of amino acids 1-180, is an angiogenesis inhibitor that exerts antitumor effects in vivo. In the present study, we examined whether the full-length calreticulin molecule shares the antiangiogenic and antitumor activities of vasostatin. Similar to vasostatin, calreticulin selectively inhibited endothelial cell proliferation in vitro, but not cells of other lineages, and suppressed angiogenesis in vivo. When inoculated into athymic mice, calreticulin inhibited Burkitt tumor growth comparably with vasostatin. Calreticulin lacking the N-terminal 1-120 amino acids inhibited endothelial cell proliferation in vitro and Burkitt tumor growth in vivo comparably with vasostatin. An internal calreticulin fragment encompassing amino acids 120-180 also inhibited endothelial cell proliferation in vitro and angiogenesis in vivo comparably with calreticulin and vasostatin. These results suggest that the antiangiogenic activities of vasostatin reside in a domain that is accessible from the full-length calreticulin molecule and localize to calreticulin N-terminal amino acids 120-180, Thus, calreticulin and calreticulin fragments are inhibitors of angiogenesis that directly target endothelial cells, inhibit angiogenesis, and suppress tumor growth. This information may be critical in designing targeted inhibitors of pathological angiogenesis that underlies cancer and other diseases. This is a US government work. There are no restrictions on its use.