Exosomes: Emerging Modulators of Pancreatic Cancer Drug Resistance

Abstract

Pancreatic cancer (PaC) is one of the most lethal tumors worldwide, difficult to diagnose, and with inadequate therapeutical chances. The most used therapy is gemcitabine, alone or in combination with nanoparticle albumin-bound paclitaxel (nab-paclitaxel), and the multidrug FOLFIRINOX. Unfortunately, PaC develops resistance early, thus reducing the already poor life expectancy of patients. The mechanisms responsible for drug resistance are not fully elucidated, and exosomes seem to be actively involved in this phenomenon, thanks to their ability to transfer molecules regulating this process from drug-resistant to drug-sensitive PaC cells. These extracellular vesicles are released by both normal and cancer cells and seem to be essential mediators of intercellular communications, especially in cancer, where they are secreted at very high numbers. This review illustrates the role of exosomes in PaC drug resistance. This manuscript first provides an overview of the pharmacological approaches used in PaC and, in the last part, focuses on the mechanisms exploited by the exosomes released by cancer cells to induce drug resistance.

Keywords: exosomes in pancreatic cancer; gemcitabine resistance; pancreatic cancer drug resistance.

Figure 1

Exosome composition. A schematic illustration of exosome structure and composition.

Figure 2

Principal mechanisms of exosome formation in cells. The figure illustrates the ESCRT-dependent and -independent pathways involved in exosome formation and the three ways used by exosomes to enter the target cells. (1) Direct fusion with the plasma membrane; (2) endocytosis; (3) direct interaction with plasma membrane receptors.

Figure 3

Principal functions of exosomes in PaC. The figure briefly resumes functions and mechanisms controlled by exosomes in PaC.

Figure 4

Exosomal trafficking between cancer and TME cells and gemcitabine resistance in PaC cells. Exosomes from drug-resistant PaC cells and/or from tumor-associated macrophages, fibroblasts, and stem cells contain proteins or miRNAs able to confer chemoresistance to gemcitabine-sensitive PaC cells.