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Crosstalk between TEMs and endothelial cells modulates angiogenesis and
metastasis via IGF1-IGF1R signalling in epithelial ovarian cancer
#MMPMID28898232
Wang X
; Zhu Q
; Lin Y
; Wu L
; Wu X
; Wang K
; He Q
; Xu C
; Wan X
; Wang X
Br J Cancer
2017[Oct]; 117
(9
): 1371-1382
PMID28898232
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BACKGROUND: Epithelial ovarian cancer (EOC) is the leading cause of death from
gynaecologic malignancies and has a poor prognosis due to metastasis. Drugs
targeting the angiogenesis pathway significantly improve patient outcome.
However, the key factors linking angiogenesis and metastasis have not been
elucidated. In this study, we found Tie2 expressing monocytes (CD14(+)Tie2(+),
TEMs) as key contributors to angiogenesis and metastasis of EOC. METHODS: Tissue
slides were evaluated by immunofluorescence for the presence of total tissue
macrophages and TEMs. The correlation between microvascular density (MVD) values
and the TEMs number or ratio was calculated in both ovarian cancer tissues and
peritoneum. The rate of TEMs in monocytes was evaluated in the peripheral blood
of female healthy donors, benign cysts patients, and EOC patients using flow
cytometry. The TEMs rate in ascites from EOC patients was also evaluated by flow
cytometry. The concentration of Ang2, as the ligand of Tie2, was examined by
ELISA in serum samples of EOC patients, benign cysts patients, and ascites
samples of EOC patients. The effects of Ang2 on the migration and the cytokine
expression of TEMs were further examined. The pro- angiogenesis activity of TEMs
via IGF1 was performed in both in vivo and in vitro. And the IGF1 blocking test
was performed using neutralising antibody. RESULTS: TEMs were significantly
higher in tumour foci, peripheral blood and ascites in EOC patients. The
proportion of TEMs among total tissue macrophages was positively correlated with
tumour MVD. In vivo animal results showed that TEMs promoted EOC angiogenesis and
metastasis. Further functional and mechanisms studies revealed that concentration
of angiopoietin 2 (Ang2), a ligand of Tie2, was elevated in EOC ascites which
further recruit TEMs in a dose-dependent manner as a powerful chemokine to TEMs.
Recruited TEMs promoted endothelial cell function through IGF1-activated
downstream signalling. Blocking secreted IGF1 using inhibiting antibody reduced
TEMs mediated angiogenesis and metastasis. CONCLUSIONS: TEMs significantly
increased in EOC patients and were recruited to tumour loci by the increased
Ang2. The increased TEMs have diagnostic value in ovarian cancer and were
positively correlated with the MVD in ovarian cancer tissue. Furthermore, TEMs
promote angiogenesis via IGF1 in both in vivo and in vitro experimental systems
after stimulation by Ang2. Altogether, this study paves the way to develop novel
therapy targets as the axis of Ang2-TEMs-IGF1 in EOC.
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