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首页> 外文期刊>Journal of cellular biochemistry. >Endostatin suppresses colorectal tumor-induced lymphangiogenesis by inhibiting expression of fibronectin extra domain A and integrin alpha9.
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Endostatin suppresses colorectal tumor-induced lymphangiogenesis by inhibiting expression of fibronectin extra domain A and integrin alpha9.

机译：内皮抑素通过抑制纤连蛋白额外域A和整联蛋白alpha9的表达来抑制大肠肿瘤诱导的淋巴管生成。

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摘要

Endostatin is a natural occurring anti-angiogenic peptide and has been shown to inhibit tumor lymphangiogenesis by suppressing the expression of tumor-stimulating growth factors. We have previously shown that fibronectin alternative extra domain A (EDA) facilitates lymphangiogenesis of colorectal tumors. Since it is known that EDA interacts with integrin alpha9 in the lymphatic endothelial cells (LECs), we hypothesized that endostatin may target EDA-integrin alpha9 pathway to inhibit colorectal tumor-induced lymphangiogenesis. To test this hypothesis, we examined the effect of endostatin on EDA secreted by SW480 colorectal cancer cells and treated human LECs with different doses of endostatin in the presence of conditional medium from SW480 cells. We found that endostatin significantly reduced EDA secretion by SW480 cells and the expression of integrin alpha9 in LECs. Immunofluorescence studies showed that EDA and integrin alpha9 colocalized on the cell membrane of LECs and these colocalizations were dramatically reduced by endostatin. Co-immunoprecipitation studies demonstrated that EDA interacted with integrin alpha9 in LECs, and showed that endostatin treatment inhibited the formation of EDA-integrin alpha9 complex in LECs. Furthermore, we found that the arrangement and polarity of LEC cytoskeletons were destroyed by endostatin substantially, leading to a reduced formation of tube-like structures of LECs and a suppressed chemotaxis of LECs toward SW480 cells. Consistently, EDA and integrin alpha9 expressions as well as lymphangiogenesis were significantly suppressed by endostatin in colorectal cancer xenografts. In conclusion, our results suggest that endostatin reduces colorectal tumor-induced lymphangiogenesis, at least in part, by inhibiting EDA-integrin alpha9 pathway.
机译：内皮抑素是一种天然的抗血管生成肽，已被证明可通过抑制刺激肿瘤的生长因子的表达来抑制肿瘤淋巴管生成。以前我们已经表明纤连蛋白替代额外域A（EDA）促进大肠肿瘤的淋巴管生成。由于已知EDA与淋巴管内皮细胞（LECs）中的整联蛋白alpha9相互作用，我们假设内皮抑素可能靶向EDA整联蛋白alpha9途径来抑制大肠肿瘤诱导的淋巴管生成。为了检验该假设，我们检查了内皮抑素对SW480大肠癌细胞分泌的EDA的影响，并在存在来自SW480细胞的条件培养基的情况下，用不同剂量的内皮抑素处理了人LEC。我们发现内皮抑素可显着降低SW480细胞的EDA分泌和LEC中整联蛋白alpha9的表达。免疫荧光研究表明，EDA和整联蛋白alpha9在LEC的细胞膜上共定位，而内皮抑素可显着降低这些共定位。免疫共沉淀研究表明，EDA与LECs中的整合素α9相互作用，并表明内皮抑素治疗抑制了LECs中EDA-整合素α9复合物的形成。此外，我们发现内皮抑素实质上破坏了LEC细胞骨架的排列和极性，从而导致LEC的管状结构形成减少，抑制了LEC对SW480细胞的趋化性。一致地，内皮抑素在结直肠癌异种移植物中显着抑制了EDA和整联蛋白alpha9的表达以及淋巴管生成。总之，我们的结果表明内皮抑素至少部分地通过抑制EDA整合素α9途径减少了大肠肿瘤诱导的淋巴管生成。

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