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Urothelial cells undergo epithelial-to-mesenchymal transition after exposure to
muscle invasive bladder cancer exosomes
#MMPMID26280654
Franzen CA
; Blackwell RH
; Todorovic V
; Greco KA
; Foreman KE
; Flanigan RC
; Kuo PC
; Gupta GN
Oncogenesis
2015[Aug]; 4
(8
): e163
PMID26280654
show ga
Bladder cancer, the fourth most common noncutaneous malignancy in the United
States, is characterized by high recurrence rate, with a subset of these cancers
progressing to a deadly muscle invasive form of disease. Exosomes are small
secreted vesicles that contain proteins, mRNA and miRNA, thus potentially
modulating signaling pathways in recipient cells. Epithelial-to-mesenchymal
transition (EMT) is a process by which epithelial cells lose their cell polarity
and cell-cell adhesion and gain migratory and invasive properties to become
mesenchymal stem cells. EMT has been implicated in the initiation of metastasis
for cancer progression. We investigated the ability of bladder cancer-shed
exosomes to induce EMT in urothelial cells. Exosomes were isolated by
ultracentrifugation from T24 or UMUC3 invasive bladder cancer cell conditioned
media or from patient urine or bladder barbotage samples. Exosomes were then
added to the urothelial cells and EMT was assessed. Urothelial cells treated with
bladder cancer exosomes showed an increased expression in several mesenchymal
markers, including ?-smooth muscle actin, S100A4 and snail, as compared with
phosphate-buffered saline (PBS)-treated cells. Moreover, treatment of urothelial
cells with bladder cancer exosomes resulted in decreased expression of epithelial
markers E-cadherin and ?-catenin, as compared with the control, PBS-treated
cells. Bladder cancer exosomes also increased the migration and invasion of
urothelial cells, and this was blocked by heparin pretreatment. We further showed
that exosomes isolated from patient urine and bladder barbotage samples were able
to induce the expression of several mesenchymal markers in recipient urothelial
cells. In conclusion, the research presented here represents both a new insight
into the role of exosomes in transition of bladder cancer into invasive disease,
as well as an introduction to a new platform for exosome research in urothelial
cells.
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