Targeting liver sinusoidal endothelial cells with miR‐20a‐loaded nanoparticles reduces murine colon cancer metastasis to the liver

• Published in: International journal of cancer Vol. 143; no. 3; pp. 709 - 719
• Main Authors: Marquez, Joana, Fernandez‐Piñeiro, Ines, Araúzo‐Bravo, Marcos J., Poschmann, Gereon, Stühler, Kai, Khatib, Abdel‐Majid, Sanchez, Alejandro, Unda, Fernando, Ibarretxe, Gaskon, Bernales, Irantzu, Badiola, Iker
• Format: Journal Article
• Language: English
• Published: United States Wiley Subscription Services, Inc 01-08-2018
• Subjects: Cancer; Chondroitin sulfate; Colon cancer; Colorectal cancer; Endothelial cells; Genetic transformation; Genomes; Hepatocytes; Liver; Liver cancer; liver metastasis; liver sinusoidal endothelial cells; Medical research; Metastases; Metastasis; miRNA; nanomedicine; Nanoparticles; Phenotypes; Sorbitan; therapy; miRNA; nanomedicine; liver metastasis; liver sinusoidal endothelial cells; therapy
• ISSN: 0020-7136; 1097-0215
• DOI: 10.1002/ijc.31343

Phenotypic transformation of liver sinusoidal endothelial cells is one of the most important stages of liver metastasis progression. The miRNA effects on liver sinusoidal endothelial cells during liver metastasis have not yet been studied. Herein, whole genome analysis of miRNA expression in these cells during colorectal liver metastasis revealed repressed expression of microRNA‐20a. Importantly, downregulation of miR‐20a occurs in parallel with upregulation of its known protein targets. To restore normal miR‐20a levels in liver sinusoidal endothelial cells, we developed chondroitin sulfate‐sorbitan ester nanoparticles conjugated with miR‐20a in a delivery system that specifically targets liver sinusoidal endothelial cells. The restoration of normal mir‐20a levels in these cells induced downregulation of the expression of its protein targets, and this also resulted in a reduction of in vitro LSEC migration and a reduction of in vivo activation and tumor‐infiltrating capacity and ability of the tumor decreased by ∼80% in a murine liver metastasis model.
What's new?
In liver metastasis, liver sinusoidal endothelial cells (LSECs) are among the first cell types to interact with incoming tumor cells, resulting in LSEC activation and transformation. Little is known, however, about the mechanisms driving this process. This study shows that the microRNA miR‐20a is downregulated in tumor‐colonized LSECs and that its restoration via exogenous delivery can reverse tumor‐associated increases in LSEC migratory capacity. In mice, delivery of miR‐20a via chondroitin sulfate‐functionalized nanoparticles further resulted in decreased liver metastasis progression and reduced activation of tumor‐infiltrated LSECs. The findings provide insight into a novel and potentially valuable therapeutic strategy for liver metastasis.