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2016 ; 7
(15
): 19709-22
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Oncogenic epithelial cell-derived exosomes containing Rac1 and PAK2 induce
angiogenesis in recipient endothelial cells
#MMPMID26919098
Gopal SK
; Greening DW
; Hanssen EG
; Zhu HJ
; Simpson RJ
; Mathias RA
Oncotarget
2016[Apr]; 7
(15
): 19709-22
PMID26919098
show ga
The metastatic cascade describes the escape of primary tumour cells to distant
secondary sites. Cells at the leading tumour edge are thought to undergo
epithelial-mesenchymal transition (EMT), to enhance their motility and invasion
for spreading. Whether EMT cells directly promote tumour angiogenesis, and the
role of exosomes (30-150 nm extracellular vesicles) remains largely unknown. We
examined the functional effects of exosomes from MDCK cells, MDCK cells stably
expressing YBX1 (MDCKYBX1, intermediate EMT), and Ras-transformed MDCK cells
(21D1 cells, complete EMT). 2F-2B cell motility and tube formation (length and
branching) was significantly increased following supplementation with MDCKYBX1 or
21D1 exosomes, but not MDCK exosomes. Next, Matrigel? plugs containing
exosome-supplemented 2F-2B cells were subcutaneously injected into mice. Systemic
perfusion was only observed for plugs supplemented with MDCKYBX1 or 21D1
exosomes. Comparative proteomics revealed that 21D1 exosomes contained
VEGF-associated proteins, while MDCKYBX1 exosomes were enriched with activated
Rac1 and PAK2. To validate, 2F-2B cells and HUVECs were pre-treated with PAK
inhibitors prior to exosome supplementation. PAK inhibition nullified the effects
of MDCKYBX1 exosomes by reducing the tube length and branching to baseline
levels. By contrast, the effects of 21D1 exosomes were not significantly
decreased. Our results demonstrate for the first time that oncogenic cells
undergoing EMT can communicate with endothelial cells via exosomes, and establish
exosomal Rac1/PAK2 as angiogenic promoters that may function from early stages of
the metastatic cascade.
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