Caveolin-1 modulates the ability of Ewing's sarcoma to metastasize.
Caveolin-1 modulates the ability of Ewing's sarcoma to metastasize.
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DOI：
10.1158/1541-7786.mcr-10-0060
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发表时间：
2010-11
期刊：
影响因子：
--
通讯作者：
Tirado OM
中科院分区：
文献类型：
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作者：
Sáinz-Jaspeado M;Lagares-Tena L;Lasheras J;Navid F;Rodriguez-Galindo C;Mateo-Lozano S;Notario V;Sanjuan X;Garcia Del Muro X;Fabra A;Tirado OM
转移是肿瘤进展的最后阶段，被认为是导致高达90%的实体瘤相关死亡的原因。Caveolin-1 （CAV1）调节与恶性肿瘤进展相关的多种癌症相关过程。在本研究中，我们验证了CAV1调节ESFT细胞转移能力的假设。首先，我们通过免疫染色组织芯片分析了CAV1的表达，该芯片包含43个已知EWS易位的石蜡包埋ESFT肿瘤。虽然没有证据表明CAV1的表达与分期、大小或肿瘤部位有显著相关性，但所有转移样本（10/10）均有显著的高表达，提示高含量的CAV1可能促进ESFT的转移。为了确定CAV1对ESFT细胞迁移和侵袭能力的影响，我们通过稳定转染先前验证的shRNA构建物，降低了TC252和A673细胞中CAV1的表达。体外迁移和侵袭实验显示，两种细胞系CAV1敲除后的细胞迁移和侵袭量均显著低于对照细胞（p≤0.01）。另外，经尾静脉注射注入Balb/c裸鼠的对照A673细胞在肺中有较强的定植。相比之下，注射CAV1敲低细胞的动物没有发生转移或在显著延迟后发生肺转移（P<0.0001）。最后，我们发现CAV1在调节ESFT转移中发挥关键作用的分子机制涉及MMP的产生和激活以及SPARC的表达控制，SPARC是已知的肺定植决定因素。
Metastasis is the final stage of tumor progression and is thought to be responsible for up to 90% of deaths associated with solid tumors. Caveolin-1 (CAV1) regulates multiple cancer-associated processes related to malignant tumor progression. In the present study we tested the hypothesis that CAV1 modulates the metastatic ability of ESFT cells. First, we analyzed the expression of CAV1 by immunostaining a tissue microarray containing 43 paraffin-embedded ESFT tumors with known EWS translocations. Even though no evidence was found for a significant association between CAV1 expression and stage, size or tumor site, all metastatic samples (10/10) had significantly high CAV1 expression, suggesting that high CAV1 content could positively contribute to enhance ESFT metastasis. To determine the effect of CAV1 on the migratory and invasive capabilities of ESFT cells, we knocked down CAV1 expression in TC252 and A673 cells by stably transfecting a previously validated shRNA construct. In vitro, migration and invasion assays showed that, for both cell lines CAV1 knocked-down cells migrated and invaded significantly less (p≤0.01) than control cells. Moreover, control A673 cells introduced into Balb/c nude mice by tail vein injection strongly colonized the lungs. In contrast, animals injected with CAV1 knocked-down cells showed either no incidence of metastasis or developed lung metastases after a significant delay (P<0.0001). Finally, we show that the molecular mechanisms by which CAV1 carries out its key role in regulating ESFT metastasis involve MMP production and activation as well as the control of the expression of SPARC, a known determinant of lung colonization.