Adrenomedullin promotes the growth of pancreatic ductal adenocarcinoma through recruitment of myelomonocytic cells
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Min Xu1,2,3,*, Feifei Qi1,2,3,*, Shaosen Zhang1,2,3, Xuhui Ma1,2,3, Shan Wang1,2,3, Chunying Wang1,2,3, Yan Fu1,2,3, Yongzhang Luo1,2,3
1The National Engineering Laboratory for Anti-Tumor Protein Therapeutics, School of Life Sciences, Tsinghua University, Beijing, China
2Beijing Key Laboratory for Protein Therapeutics, School of Life Sciences, Tsinghua University, Beijing, China
3Cancer Biology Laboratory, School of Life Sciences, Tsinghua University, Beijing, China
*These authors have contributed equally to this work
Yongzhang Luo, email: [email protected]
Keywords: pancreatic ductal adenocarcinoma, adrenomedullin, myelomonocytic cells, cell recruitment, tumor angiogenesis
Received: March 24, 2016 Accepted: June 17, 2016 Published: July 04, 2016
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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