{"title":"细胞外小泡中的乳粘素免疫阻断剂可抑制 sEV 介导的促转移能力的增强","authors":"Eduardo Durán-Jara, Matías del Campo, Valentina Gutiérrez, Ignacio Wichmann, César Trigo, Marcelo Ezquer, Lorena Lobos-González","doi":"10.1186/s40659-023-00477-8","DOIUrl":null,"url":null,"abstract":"Tumor-derived small extracellular vesicles (sEVs) can promote tumorigenic and metastatic capacities in less aggressive recipient cells mainly through the biomolecules in their cargo. However, despite recent advances, the specific molecules orchestrating these changes are not completely defined. Lactadherin is a secreted glycoprotein typically found in the milk fat globule membrane. Its overexpression has been associated with increased tumorigenesis and metastasis in breast cancer (BC) and other tumors. However, neither its presence in sEVs secreted by BC cells, nor its role in sEV-mediated intercellular communication have been described. The present study focused on the role of lactadherin-containing sEVs from metastatic MDA-MB-231 triple-negative BC (TNBC) cells (sEV-MDA231) in the promotion of pro-metastatic capacities in non-tumorigenic and non-metastatic recipient cells in vitro, as well as their pro-metastatic role in a murine model of peritoneal carcinomatosis. We show that lactadherin is present in sEVs secreted by BC cells and it is higher in sEV-MDA231 compared with the other BC cell-secreted sEVs measured through ELISA. Incubation of non-metastatic recipient cells with sEV-MDA231 increases their migration and, to some extent, their tumoroid formation capacity but not their anchorage-independent growth. Remarkably, lactadherin blockade in sEV-MDA231 results in a significant decrease of those sEV-mediated changes in vitro. Similarly, intraperitoneally treatment of mice with MDA-MB-231 BC cells and sEV-MDA231 greatly increase the formation of malignant ascites and tumor micronodules, effects that were significantly inhibited when lactadherin was previously blocked in those sEV-MDA231. As to our knowledge, our study provides the first evidence on the role of lactadherin in metastatic BC cell-secreted sEVs as promoter of: (i) metastatic capacities in less aggressive recipient cells, and ii) the formation of malignant ascites and metastatic tumor nodules. These results increase our understanding on the role of lactadherin in sEVs as promoter of metastatic capacities which can be used as a therapeutic option for BC and other malignancies.","PeriodicalId":9084,"journal":{"name":"Biological Research","volume":null,"pages":null},"PeriodicalIF":4.3000,"publicationDate":"2024-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Lactadherin immunoblockade in small extracellular vesicles inhibits sEV-mediated increase of pro-metastatic capacities\",\"authors\":\"Eduardo Durán-Jara, Matías del Campo, Valentina Gutiérrez, Ignacio Wichmann, César Trigo, Marcelo Ezquer, Lorena Lobos-González\",\"doi\":\"10.1186/s40659-023-00477-8\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"Tumor-derived small extracellular vesicles (sEVs) can promote tumorigenic and metastatic capacities in less aggressive recipient cells mainly through the biomolecules in their cargo. However, despite recent advances, the specific molecules orchestrating these changes are not completely defined. Lactadherin is a secreted glycoprotein typically found in the milk fat globule membrane. Its overexpression has been associated with increased tumorigenesis and metastasis in breast cancer (BC) and other tumors. However, neither its presence in sEVs secreted by BC cells, nor its role in sEV-mediated intercellular communication have been described. The present study focused on the role of lactadherin-containing sEVs from metastatic MDA-MB-231 triple-negative BC (TNBC) cells (sEV-MDA231) in the promotion of pro-metastatic capacities in non-tumorigenic and non-metastatic recipient cells in vitro, as well as their pro-metastatic role in a murine model of peritoneal carcinomatosis. We show that lactadherin is present in sEVs secreted by BC cells and it is higher in sEV-MDA231 compared with the other BC cell-secreted sEVs measured through ELISA. Incubation of non-metastatic recipient cells with sEV-MDA231 increases their migration and, to some extent, their tumoroid formation capacity but not their anchorage-independent growth. Remarkably, lactadherin blockade in sEV-MDA231 results in a significant decrease of those sEV-mediated changes in vitro. Similarly, intraperitoneally treatment of mice with MDA-MB-231 BC cells and sEV-MDA231 greatly increase the formation of malignant ascites and tumor micronodules, effects that were significantly inhibited when lactadherin was previously blocked in those sEV-MDA231. As to our knowledge, our study provides the first evidence on the role of lactadherin in metastatic BC cell-secreted sEVs as promoter of: (i) metastatic capacities in less aggressive recipient cells, and ii) the formation of malignant ascites and metastatic tumor nodules. 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引用次数: 0
摘要
源于肿瘤的小细胞外囊泡(sEVs)主要通过其载体中的生物大分子促进侵袭性较低的受体细胞的致瘤和转移能力。然而,尽管最近取得了一些进展,但协调这些变化的特定分子尚未完全确定。Lactadherin 是一种分泌型糖蛋白,通常存在于牛奶脂肪球膜中。它的过表达与乳腺癌(BC)和其他肿瘤的发生和转移有关。然而,它在 BC 细胞分泌的 sEV 中的存在及其在 sEV 介导的细胞间通讯中的作用均未得到描述。本研究的重点是转移性 MDA-MB-231 三阴性 BC(TNBC)细胞(sEV-MDA231)中含乳黏连蛋白的 sEV 在体外促进非致瘤性和非转移性受体细胞促转移能力中的作用,以及它们在小鼠腹膜癌转移模型中的促转移作用。我们的研究表明,乳粘素存在于 BC 细胞分泌的 sEV 中,而且与通过 ELISA 测定的其他 BC 细胞分泌的 sEV 相比,sEV-MDA231 中的乳粘素含量更高。用 sEV-MDA231 培养非转移性受体细胞可增加它们的迁移能力,并在一定程度上增加它们形成类肿瘤的能力,但不会增加它们的锚定依赖性生长。值得注意的是,在 sEV-MDA231 中阻断乳粘连蛋白可显著降低这些由 sEV 在体外介导的变化。同样,用MDA-MB-231 BC细胞和sEV-MDA231腹腔处理小鼠,会大大增加恶性腹水和肿瘤小结节的形成,而之前在这些sEV-MDA231中阻断乳粘连蛋白会显著抑制这些效应。据我们所知,我们的研究首次证明了乳黏附素在转移性 BC 细胞分泌的 sEV 中的作用:(i) 侵袭性较低的受体细胞的转移能力,以及 (ii) 恶性腹水和转移性肿瘤结节的形成。这些结果加深了我们对 sEVs 中乳粘连蛋白作为转移能力促进因子的作用的了解,这种作用可作为治疗 BC 和其他恶性肿瘤的一种选择。
Lactadherin immunoblockade in small extracellular vesicles inhibits sEV-mediated increase of pro-metastatic capacities
Tumor-derived small extracellular vesicles (sEVs) can promote tumorigenic and metastatic capacities in less aggressive recipient cells mainly through the biomolecules in their cargo. However, despite recent advances, the specific molecules orchestrating these changes are not completely defined. Lactadherin is a secreted glycoprotein typically found in the milk fat globule membrane. Its overexpression has been associated with increased tumorigenesis and metastasis in breast cancer (BC) and other tumors. However, neither its presence in sEVs secreted by BC cells, nor its role in sEV-mediated intercellular communication have been described. The present study focused on the role of lactadherin-containing sEVs from metastatic MDA-MB-231 triple-negative BC (TNBC) cells (sEV-MDA231) in the promotion of pro-metastatic capacities in non-tumorigenic and non-metastatic recipient cells in vitro, as well as their pro-metastatic role in a murine model of peritoneal carcinomatosis. We show that lactadherin is present in sEVs secreted by BC cells and it is higher in sEV-MDA231 compared with the other BC cell-secreted sEVs measured through ELISA. Incubation of non-metastatic recipient cells with sEV-MDA231 increases their migration and, to some extent, their tumoroid formation capacity but not their anchorage-independent growth. Remarkably, lactadherin blockade in sEV-MDA231 results in a significant decrease of those sEV-mediated changes in vitro. Similarly, intraperitoneally treatment of mice with MDA-MB-231 BC cells and sEV-MDA231 greatly increase the formation of malignant ascites and tumor micronodules, effects that were significantly inhibited when lactadherin was previously blocked in those sEV-MDA231. As to our knowledge, our study provides the first evidence on the role of lactadherin in metastatic BC cell-secreted sEVs as promoter of: (i) metastatic capacities in less aggressive recipient cells, and ii) the formation of malignant ascites and metastatic tumor nodules. These results increase our understanding on the role of lactadherin in sEVs as promoter of metastatic capacities which can be used as a therapeutic option for BC and other malignancies.
期刊介绍:
Biological Research is an open access, peer-reviewed journal that encompasses diverse fields of experimental biology, such as biochemistry, bioinformatics, biotechnology, cell biology, cancer, chemical biology, developmental biology, evolutionary biology, genetics, genomics, immunology, marine biology, microbiology, molecular biology, neuroscience, plant biology, physiology, stem cell research, structural biology and systems biology.