The emergence of extracellular vesicles in urology: fertility, cancer, biomarkers and targeted pharmacotherapy

Abstract

Extracellular vesicles (EV) are small membrane-bound vesicles enriched in a selective repertoire of mRNA, miRNA, proteins and cell surface receptors from parental cells and are actively involved in the transmission of inter and intracellular signals. Cancer cells produce EV that contain cargo including DNA, mRNA, miRNA and proteins that allow EV to create epigenetic changes in target cells both locally and systemically. Cancer-derived EV play critical roles in tumorigenesis, cancer cell migration, metastasis, evasion of host immune defense, chemoresistance, and they promote a premetastatic niche favourable to micrometastatic seeding. Their unique molecular profiles acquired from originator cells and their presence in numerous body fluids, including blood and urine, make them promising candidates as biomarkers for prostate, renal and bladder cancers. EV may ultimately serve as targets for therapy and as platforms for personalized medicine in urology. As urologic malignancy comprises 28% of new solid tumour diagnoses and 15% of cancer-related deaths, EV-related research is rapidly emerging and providing unique insights into disease progression. In this report, we review the current literature on EV in the setting of genitourinary fertility and malignancy.

Keywords: biomarkers; extracellular vesicles; genitourinary fertility and malignancy; prostasomes; prostate, renal and bladder cancer.

Fig. 1

Extracellular vesicle (EV) origin: EV may originate from the endosomal compartment by exocytosis of vesicles formed within the multivesicular bodies or (a) from the cell surface by budding of plasma membrane. These shedding vesicles, sorted from the cell surface by budding of cell plasma membrane, are also named microvesicles. (b) Exocytic multivesicular bodies fuse with membrane after cell stimulation and release by exocytosis vesicles named exosomes. (b) These multivesicular bodies are created within the Golgi apparatus as a result of endosome compartmentalization. The insets are representative transmission electron microscopy of exosome generation from a multivesicular body and of vesicle generation by budding of plasma membrane (modified, in part, from Refs. (3) and 7).

Fig. 2

Tumour-derived EV and local invasion and metastasis: EV derived from primary tumour act to enhance matrix remodelling via a) matrix metalloproteinase (MMP) and urokinase-type plasminogen activator (uPA), enhance b) endothelial angiogenesis via vascular endothelial growth factor (VEGF) and c) EV released from PC3 cells activate fibroblasts sending antiapoptotic signals and growth signals (23,25). Ultimately, EV tumour release leads to downstream enhanced tumour cell migration, adhesion and invasion.

Fig. 3

Tumour cells release extracellular vesicles that can influence the malignant phenotype. Various examples include and are not limited to: (a) drug resistance; EV can influence the efflux of chemotherapeutic drugs via various mechanisms including ATPase and drug transporters. (b) apoptosis; through FasL and TRAIL, EV can induce apoptosis in activated antitumor T cells, abrogating T-cell-mediated apoptosis of tumour cells. (c) Local invasion and metastasis; EV can promote local invasion by activating fibroblasts and reducing fibroblast apoptosis, enhancing extracellular matrix degradation (mRNAs for MMP2 and MMP9), promoting angiogenesis (mRNA VEGF, FGF2, angiopoietin1) and increasing tumour cell adhesion. EV may enhance metastasis by promoting a pre-metastatic niche in lung tissue via upregulation of VEGFR1 expression, MMP2 in lung blood vessels and MMP9 in alveolar epithelial cells and blood vessels. (d) Immunosuppression; EV can alter monocyte differentiation into myeloid suppressive cells. This inhibits T-cell proliferation. Inhibiting T-cell responses upstream would abrogate antitumor immune potential. This figure is modified from (66).

Fig. 4

Tumour extracellular vesicles and chemoresistance (67). Tumour EV act in 2 ways to reduce the efficacy of chemotherapy. (1) intracytoplasmic chemotherapy exportation via shedding vesicles. (2) Antibody sequestration.