Acosta Montaño Paloma, Olvera Félix Eréndira, Castro Flores Veronica, Hernández García Arturo, Cadena-Nava Ruben D, Galindo Hernández Octavio, Juárez Patricia, Fournier Pierrick G J
Posgrado en Ciencias de la Vida, Centro de Investigación Científica y de Educación Superior de Ensenada (CICESE), Ensenada 22860, BC, Mexico.
Departamento de Innovación Biomédica, Centro de Investigación Científica y de Educación Superior de Ensenada (CICESE), Ensenada 22860, BC, Mexico.
Biology (Basel). 2024 Dec 19;13(12):1066. doi: 10.3390/biology13121066.
Liver metastases frequently occur in pancreatic and colorectal cancer. Their development is promoted by tumor-derived exosomes with the integrin αβ on their membrane. This integrin directs exosomes to the liver, where they promote a TGF-β-dependent pre-metastatic niche. We proposed the development of αβ exosomes to deliver anti-TGF-β therapy to the liver. This study demonstrates that the overexpression of αβ in 293T cells allows its transfer to the secreted exosomes. αβ overexpression increases exosome delivery to the liver, and αβ exosomes accumulate more in the liver compared to the lungs, kidneys, and brain in mice. We then sought 293T cells to directly produce and load an anti-TGF-β agent in their exosomes. First, we transduced 293T cells to express shRNAs against ; however, the exosomes isolated from these cells did not knock down in treated macrophages in vitro. However, when 293T expressed an mRNA coding a soluble form of betaglycan (sBG), a TGF-β inhibitor, this mRNA was detected in the isolated exosomes and the protein in the conditioned media of macrophages treated in vitro. In turn, this conditioned media decreased the TGF-β-induced phosphorylation of SMAD2/3 in hepatic cells in vitro. Our findings suggest that αβ exosomes could serve as nanocarriers for liver-targeted anti-TGF-β therapies.
肝转移在胰腺癌和结直肠癌中经常发生。肿瘤来源的外泌体膜上带有整合素αβ，可促进肝转移的发生。这种整合素将外泌体导向肝脏，在那里它们促进依赖转化生长因子-β（TGF-β）的前转移微环境的形成。我们提出开发αβ外泌体，以便将抗TGF-β疗法递送至肝脏。本研究表明，293T细胞中αβ的过表达使其能够转移至分泌的外泌体中。αβ过表达增加了外泌体向肝脏的递送，并且与小鼠的肺、肾和脑相比，αβ外泌体在肝脏中积累更多。然后，我们寻找能直接在其外泌体中产生并负载抗TGF-β药物的293T细胞。首先，我们转导293T细胞以表达针对……的短发夹RNA（shRNAs）；然而，从这些细胞中分离出的外泌体在体外处理的巨噬细胞中并未敲低……。但是，当293T表达编码可溶性β-聚糖（sBG，一种TGF-β抑制剂）的信使核糖核酸（mRNA）时，在分离出的外泌体中检测到了这种mRNA，并且在体外处理的巨噬细胞的条件培养基中也检测到了该蛋白。相应地，这种条件培养基在体外降低了TGF-β诱导的肝细胞中SMAD2/3的磷酸化。我们的研究结果表明，αβ外泌体可作为肝脏靶向抗TGF-β疗法的纳米载体。
