Stem Cells Derived Suicide Gene Exosomes; a Promising Platform for Innovative Cancer Therapy

Dajana Vanova, Michal Andrezal, Ursula Altanerova, Miroslava Matuskova,  Cestmir Altaner

Abstract:

ABSTRACT: Innovative cancer treatments are needed for metastatic tumors that currently do not have adequate therapies. This review highlights recent progress in suicide gene small extracellular vesicles, particularly exosomes as a new form of intracellular anti-cancer drug. Suicide gene exosomes are produced by tumor-targeting human mesenchymal stem cells that have been genetically modified to express the yeast cytosine deaminase::uracil phosphoribosyl transferase fused gene (yCD::UPRT) along with the prodrug 5-fluorocytosine (5-FC). The yCD::UPRT-MSC-secretome containing tumor targeted exosomes, convert 5-FC into the cytotoxic compound 5-fluorouracil (5-FU) and its metabolites within the tumor environment. The second popular system we are investigating involves the suicide gene exosomes derived from thymidine kinase of Herpes Simplex Virus in conjunction with a prodrug ganciclovir. Extracellular vesicles secreted by tumor associated cells contribute to tumor growth and metastasis. When these cells are transduced with yCD::UPRT suicide gene, they can act as a source of therapeutic exosomes capable of intracellularly converting nontoxic prodrug 5-FC to a cytotoxic 5-FU. Combined action of suicide gene exosomes from MSCs and cancer associated fibroblasts (CAFs) is a promising platform for aggressive tumors treatment. Furthermore, suicide gene exosomes can be enhanced with additional anti-cancer drugs and customized for targeted delivery. In this review, we trace the history of these findings, present therapeutic outcomes from in vitro and in vivo studies, and explore the future potential of therapeutically beneficial exosomes for cancer treatment.