NATURE REVIEWS | UROLOGY ADVANCE ONLINE PUBLICATION | 1 University of Sao Paulo, Brazil (M.N., F.F., L.N.). University of Turin, Italy (G.C.). BIOMATCELL VINN Excellence Center of Biomaterials and Cell Therapy, University of Gothenburg, Sweden (H.V., K.E., X.W.). University Medical Center Freiburg, Germany (I.N.). Princess Margaret Cancer Center, 101 College Street, TMDT 9‑807, Toronto, ON M5G 1L7, Canada (S.P., T.K.). Monash University, Australia (N.S.). University of Gujrat, Pakistan (N.M.A.). Correspondence to: T.K. thomas.kislinger@ utoronto.ca The emerging role of extracellular vesicles as biomarkers for urogenital cancers Muhammad Nawaz, Giovanni Camussi, Hadi Valadi, Irina Nazarenko, Karin Ekström, Xiaoqin Wang, Simona Principe, Neelam Shah, Naeem M. Ashraf, Farah Fatima, Luciano Neder and Thomas Kislinger Abstract | The knowledge gained from comprehensive profiling projects that aim to define the complex genomic alterations present within cancers will undoubtedly improve our ability to detect and treat those diseases, but the influence of these resources on our understanding of basic cancer biology is still to be demonstrated. Extracellular vesicles have gained considerable attention in past years, both as mediators of intercellular signalling and as potential sources for the discovery of novel cancer biomarkers. In general, research on extracellular vesicles investigates either the basic mechanism of vesicle formation and cargo incorporation, or the isolation of vesicles from available body fluids for biomarker discovery. A deeper understanding of the cargo molecules present in extracellular vesicles obtained from patients with urogenital cancers, through high‑ throughput proteomics or genomics approaches, will aid in the identification of novel diagnostic and prognostic biomarkers, and can potentially lead to the discovery of new therapeutic targets. Nawaz, M. et al. Nat. Rev. Urol. advance online publication 18 November 2014; doi:10.1038/nrurol.2014.301 Introduction Urogenital cancers—cancers of the reproductive and renal organs—are major causes of morbidity and mor- tality worldwide. 1,2 The multistage, stochastic and heterogeneous nature of these malignancies, resulting from genetic and epigenetic modifications, poses a fundamental challenge to monitoring. Although surgi- cal treatment and chemotherapy for urogenital cancers have improved in the last decade, the prognoses for these diseases remain poor, as existing tests are not sufficiently sensitive or specific to diagnose urogenital cancers at early stages, and none has been shown to significantly decrease overall mortality. Current diag- nostic procedures include general examinations and biopsies, such as image-guided prostate biopsy, 3 cysto- scopy and transurethral resection of the bladder, 4 nephrectomy and percutaneous renal tumour biopsies, 5 all of which lack sensitivity and can be associated with significant health complications (for example, biopsies are invasive procedures associated with bleeding and risk of infections). Moreover, the location of urogenital cancers deep within the pelvic region makes them hard to access. Thus, in the absence of early symptoms, cancers are diagnosed at an advanced stage, by which time patients have poor outcomes and tumours have often metastasized. Extracellular vesicles have gained considerable atten- tion in the past 10 years as potential sources for bio- marker discovery. These small (40–5000 nm diameter) membrane-bound vesicles are categorized into exosomes, microvesicles or ectosomes, apoptotic bodies 6–10 or Golgi vesicles 11 on the basis of their size, origin, morphology and mode of release. Well-known for biological effects, such as signalling and transfer of cargo, extracellular vesicles are secreted under various pathophysiologic con- ditions into the extracellular environment by a variety of cell types, promoting tumour progression, survival, invasion and angiogenesis, 12–17 as well as influencing the immune response, cell-to-cell communication, extracellular matrix degradation, coagulation, stem- cell renewal, cardiovascular functions and resistance to drugs (Figure 1). 18–30 Surprisingly, the biomolecular cargo of extracellular vesicles is stable in biological fluids and protected against exogenous RNases and proteases, owing to its encapsula- tion within membrane vesicles, 23,31,32 or association with RNA-binding or DNA-binding proteins 33–35 or lipo- protein complexes. 36,37 Thus, extracellular vesicles might be stable under adverse physical conditions, such as extremes in pH, long-term storage and multiple freeze– thaw cycles, 33,38 making them an appealing source for biomarker development. Several reports indicate that cancer cells release more extracellular vesicles than normal cells, 17,39,40 and that the biomolecular cargo (that is, proteins, nucleic acids and lipids) is reflective of the cell of origin. 41,42 Consequently, knowledge about the content of extracellular vesicles derived from tumour cells with differing stages of aggression could be used to establish new diagnostic approaches using patient-derived vesicles from body fluids. The detection of biomarkers in body fluids has major advantages over the use of tissue markers, which most often require invasive biopsies that can be diffi- cult to perform and potentially dangerous. Urine-based Competing interests The authors declare no competing interests. REVIEWS © 2014 Macmillan Publishers Limited. All rights reserved