Tumor-derived extracellular vesicles: reliable tools for Cancer diagnosis and clinical applications

Abstract

Background: Studies have recently revealed that almost every type of cells including tumor cells abundantly release small vesicles known as extracellular vesicles (EVs) into the extracellular milieu. EVs carry a repertoire of biological molecules including nucleic acids, proteins, lipids, and carbohydrates and transport their cargo between cells in the vicinity as well as distantly located cells and hence act as messengers of intercellular communication. In this review, we aimed to discuss the tumor-derived exosome biology and the pivotal roles of exosomes in cancer diagnosis and treatment.

Methods: In the present review study, the authors studied several articles over the past two decades published on the kinetics of EVs in tumor environment as well as on the application of these vesicles in cancer diagnosis and therapy.

Results: A growing body of evidence indicates that nucleic acids such as microRNAs (miRNAs) transferring by EVs participate to create a conducive tumor environment. As EV-associated miRNAs are tissue-specific and present in most biological fluids, they hold great potential for clinical application in cancer early diagnosis, prognosis, and treatment response. Furthermore, exosomes can serve as drug delivery vehicles transferring miRNAs as well as therapeutic agents to target cells. These nano-vesicles exhibit ideal properties in comparison with the synthetic carriers that attracted scientist's attention in the field of nanotechnology medicine. Scientists have employed different strategies to build exosomes-based drug delivery system. In general, two methods (direct engineering and indirect engineering) are being utilized to produce artificial exosomes. Para-clinical data have confirmed the beneficial effects of engineering exosomes in cancer therapy.

Conclusion: Exosomal miRNAs hold great promise for clinical application in early diagnosis and treatment of cancers. In addition, in spite of enthusiastic results obtained by engineered exosomes, however, there is an increasing concern over the use of optimal methods for engineering exosomes and the safety of engineered exosomes in clinical trials is still unclear.

Keywords: Biomarker; Cancer; Drug delivery; Extracellular vesicles; miRNA.

Fig. 1

The mechanism of exosomal miRNAs loading. In the nucleus, Pol-II enzyme transcribes primary miRNAs (pri-miRNA) from miRNA-related genes. DGCR8 and Drosha structure catalyzes pri-RNAs into pre-miRNAs form, which is transferred toward cytoplasm employing exportin-5 protein. At the cytoplasmic level, the pre-miRNAs are trimmed into double-stranded miRNAs through the Dicer complex action. Then Helices, a splicing enzyme, generates mature miRNAs which harbors single-stranded. In the final step, MVBs (exosomes) capture mature miRNAs via four possible mechanisms including: 3′ miRNA sequence-dependent pathway, nSMase2-dependent pathway, the miRNAISC-based pathway, and sumoylated hnRNPs-related pathway. Other biological materials are sorted into exosomes through endocytosis, Golgi apparatus, different protein complexes, and ESCRT machinery randomly or/and preferentially. Of note, after exosome maturation, MVB could back fuse with the PM in which decorate the mother cell PM with specific receptors (I). Another fate is that MVB combine to the PM and exports its cargoes to the ECM (pathway II). Scientists believe that MVB may select degradation pathway where it combine with lysosomes (pathway III) and its content is degraded. Different proteins such as Rab-GTPase and SNAREs contribute in intracellular MVB trafficking and fusion. Three possible mechanisms were proposed by which exosomes can alter target cell function, I: endocytotic pathway; II: ligand-receptor interaction; III: direct fusion

Fig. 2

A diagram of the miRNAs application in clinical trials depended on the available data up to May 2019. Data show the majority of miRNA-related clinical trial belongs to breast cancer. Diseases are presented based on the percentage of the clinical trials deal with miRNAs

Fig. 3

Categories of different methods used to design exosome-based delivery system. In the direct method different compounds such as hydrophilic or hydrophobic drugs and also siRNAs are added to purified exosomes suspension, subsequently, exosomes encompass those compounds. In addition, liposome carrying drugs can be used to construct optional exosome-liposome hybrid vesicles (a). In the indirect method parental cells are modified to produce artificial exosomes. In this way, cells co-cultured with different therapeutic agents (b) or by using a vector, manipulated to express optional cargoes in exosomes (c)