TY  - JOUR
A1  - Ciardiello, Chiara
A1  - Leone, Alessandra
A1  - Lanuti, Paola
A1  - Roca, Maria S.
A1  - Moccia, Tania
A1  - Minciacchi, Valentina R.
A1  - Minopoli, Michele
A1  - Gigantino, Vincenzo
A1  - De Cecio, Rossella
A1  - Rippa, Massimo
A1  - Petti, Lucia
A1  - Capone, Francesca
A1  - Vitagliano, Carlo
A1  - Milone, Maria Rita
A1  - Pucci, Biagio
A1  - Lombardi, Rita
A1  - Iannelli, Federica
A1  - Di Gennaro, Elena
A1  - Bruzzese, Francesca
A1  - Marchisio, Marco
A1  - Carriero, Maria Vincenza
A1  - Di Vizio, Dolores
A1  - Budillon, Alfredo
T1  - Large oncosomes overexpressing integrin alpha-V promote prostate cancer adhesion and invasion via AKT activation
T2  - Journal of experimental & clinical cancer research
N2  - Background: Molecular markers for prostate cancer (PCa) are required to improve the early definition of patient outcomes. Atypically large extracellular vesicles (EVs), referred as "Large Oncosomes" (LO), have been identified in highly migratory and invasive PCa cells. We recently developed and characterized the DU145R80 subline, selected from parental DU145 cells as resistant to inhibitors of mevalonate pathway. DU145R80 showed different proteomic profile compared to parental DU145 cells, along with altered cytoskeleton dynamics and a more aggressive phenotype.
Methods: Immunofluorescence staining and western blotting were used to identify blebbing and EVs protein cargo. EVs, purified by gradient ultra-centrifugations, were analyzed by tunable resistive pulse sensing and multi-parametric flow cytometry approach coupled with high-resolution imaging technologies. LO functional effects were tested in vitro by adhesion and invasion assays and in vivo xenograft model in nude mice. Xenograft and patient tumor tissues were analyzed by immunohistochemistry.
Results: We found spontaneous blebbing and increased shedding of LO from DU145R80 compared to DU145 cells. LO from DU145R80, compared to those from DU145, carried increased amounts of key-molecules involved in PCa progression including integrin alpha V (αV-integrin). By incubating DU145 cells with DU145R80-derived LO we demonstrated that αV-integrin on LO surface was functionally involved in the increased adhesion and invasion of recipient cells, via AKT. Indeed either the pre-incubation of LO with an αV-integrin blocking antibody, or a specific AKT inhibition in recipient cells are able to revert the LO-induced functional effects. Moreover, DU145R80-derived LO also increased DU145 tumor engraftment in a mice model. Finally, we identified αV-integrin positive LO-like structures in tumor xenografts as well as in PCa patient tissues. Increased αV-integrin tumor expression correlated with high Gleason score and lymph node status.
Conclusions: Overall, this study is the first to demonstrate the critical role of αV-integrin positive LO in PCa aggressive features, adding new insights in biological function of these large EVs and suggesting their potential use as PCa prognostic markers.
KW  - Extracellular vesicles
KW  - Oncosomes
KW  - Prostate cancer
KW  - Alpha-V integrin
KW  - AKT
Y1  - 2019
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/52970
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-529706
SN  - 1756-9966
SN  - 0392-9078
N1  - Open Access: This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
VL  - 38
IS  - 1, Art. 317
SP  - 1
EP  - 16
PB  - Springer ; BioMed Central
CY  - Berlin ; Heidelberg ; London
ER  -