Researchers have identified a mechanism by which tumor-derived extracellular vesicles (EVs) can move from the bloodstream into urine, offering biological support for urine-based cancer testing. The findings, published in Science Advances, suggest that the kidney glomerulus plays an active role in transferring circulating EVs into the urinary space, a process the authors describe as supporting the concept of a “urinary biopsy.”
EVs are small membrane-bound particles released by cells that carry proteins, nucleic acids, and other molecular cargo. Because these vesicles can reflect the molecular characteristics of their cells of origin, tumor-derived EVs are being studied as biomarkers in liquid biopsy approaches. Urine is an attractive sample type because it can be collected noninvasively, but it has been unclear how EVs released by tumors outside the urinary tract appear in urine.
In this study, Kawaguchi and colleagues investigated the pathway by which circulating tumor-derived EVs enter the urinary compartment. The team engineered several cancer cell types – including glioma, lung cancer, and pancreatic cancer cells – to produce labeled EVs that could be tracked in vivo. The vesicles carried molecular tags such as CRISPR guide RNAs or a bioluminescent reporter known as green-enhanced nano-lantern (GeNL), allowing the researchers to monitor their distribution.
Using mouse models, the investigators tracked the movement of tumor-derived EVs from the bloodstream to the kidney and into urine. Imaging and molecular analyses indicated that the glomerulus – the kidney’s primary filtration structure – does not simply allow passive filtration of these vesicles. Instead, glomerular cells appear to internalize circulating EVs and transport them across the filtration barrier through a process consistent with transcytosis.
Further experiments examined the behavior of glomerular endothelial cells and podocytes in culture. These cells were shown to take up tumor-derived EVs through endocytosis and subsequently release vesicles containing tumor-derived components. During this process, vesicles appeared to undergo changes in size and surface characteristics.
In animal models, the researchers detected GeNL-labeled tumor-derived EVs in urine at levels higher than those observed in plasma, suggesting selective routing of these vesicles into the urinary space. The findings indicate that glomerular processing may concentrate or enrich certain circulating EV populations in urine.
The authors report that this mechanism provides a biological explanation for earlier observations that urinary EVs can contain tumor-associated biomarkers from cancers outside the urinary tract. For diagnostic laboratories, the results may help clarify how systemic tumor signals can be detected through urine-based liquid biopsy approaches.
The study also highlights that EV populations detected in urine may reflect processing by kidney cells, which could influence the composition of vesicles and their biomarker content. Understanding this pathway may help guide the development of diagnostic assays that analyze tumor-derived EVs in urine.
The researchers note that additional work will be needed to determine how widely this mechanism applies across tumor types and to evaluate its relevance in human clinical samples. Further studies will also be required to assess how glomerular processing affects the stability and diagnostic value of tumor-derived biomarkers carried by EVs.
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