Exosomes Prove Superior for Transporting Anticancer MicroRNAs

Cancer researchers used modified exosomes to transport inhibitory siRNA molecules to block the activity of the KRAS oncogene and thereby suppress cancer development in multiple mouse models of pancreatic cancer and significantly increase overall survival.

Exosomes are cell-derived vesicles that are present in many and perhaps all biological fluids, including blood, urine, and cultured medium of cell cultures. The reported diameter of exosomes is between 30 and 100 nanometers, which is larger than low-density lipoproteins but much smaller than red blood cells. Exosomes, which contain RNA, proteins, lipids, and metabolites that are reflective of the cell type of origin, are either released from the cell when multivesicular bodies fuse with the plasma membrane, or they are released directly from the plasma membrane. Exosomes have specialized functions and play a key role in coagulation, intercellular signaling, and waste management. Consequently, there is a growing interest in the clinical applications of exosomes for prognosis, therapy, and as biomarkers for health and disease.

Investigators at the University of Texas MD Anderson Cancer Center (Houston, USA) derived exosomes from normal fibroblast-like mesenchymal cells and genetically engineered them to carry short interfering RNA (siRNA) or short hairpin RNA (shRNA) specific for the oncogene KrasG12D, a common mutation in pancreatic cancer.

The investigators reported in the June 7, 2017, online edition of the journal Nature that compared to liposomes, the engineered exosomes (known as iExosomes) targeted oncogenic KRAS with an enhanced efficacy that was dependent on CD47, and was facilitated by the process of macropinocytosis.

CD47 (integrin associated protein) is involved in a range of cellular processes, including apoptosis, proliferation, adhesion, and migration. Furthermore, it plays a key role in immune and angiogenic responses. CD47 is ubiquitously expressed in human cells and has been found to be overexpressed in many different tumor cells.

Treatment with iExosomes loaded with inhibitory microRNAs was found to suppress cancer development in multiple mouse models of pancreatic cancer and significantly increased overall survival.

"Our studies suggest that exosomes exhibit a superior ability to deliver siRNA molecules and suppress aggressive pancreatic tumor growth when compared to liposomes," said contributing author Dr. Valerie LeBleu, assistant professor of cancer biology at the University of Texas MD Anderson Cancer Center. "We also demonstrated that the presence of CD47 on exosomes' allows for evasion from phagocytosis by the circulating monocytes."

Related Links:
University of Texas MD Anderson Cancer Center