Adrenomedullin promotes the growth of pancreatic ductal adenocarcinoma through
recruitment of myelomonocytic cells
#MMPMID27391260
Xu M
; Qi F
; Zhang S
; Ma X
; Wang S
; Wang C
; Fu Y
; Luo Y
Oncotarget
2016[Aug]; 7
(34
): 55043-55056
PMID27391260
show ga
Stromal infiltration of myelomonocytic cells is a hallmark of pancreatic ductal
adenocarcinoma (PDAC) and is related to a poor prognosis. However, the detailed
mechanism for the recruitment of myelomonocytic cells to pancreatic cancer tissue
remains unclear. In the present study, pancreatic cancer cells secreted high
levels of adrenomedullin (ADM), and CD11b+ myelomonocytic cells expressed all
components of ADM receptors, including GPR182, CRLR, RAMP2 and RAMP3. ADM
enhanced the migration and invasion of myelomonocytic cells through activation of
the MAPK, PI3K/Akt and eNOS signaling pathways, as well as the expression and
activity of MMP-2. ADM also promoted the adhesion and trans-endothelial migration
of myelomonocytic cells by increasing expression of VCAM-1 and ICAM-1 in
endothelial cells. In addition, ADM induced macrophages and myeloid-derived
suppressor cells (MDSCs) to express pro-tumor phenotypes. ADM knockdown in
tumor-bearing mice or administration of AMA, an ADM antagonist, significantly
inhibited the recruitment of myelomonocytic cells and tumor angiogenesis.
Moreover, in vivo depletion of myelomonocytic cells using clodronate liposomes
suppressed the progression of PDAC. These results reveal a novel function of ADM
in PDAC, and suggest ADM is a promising target in the treatment of PDAC.
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