title: Adrenomedullin promotes the growth of pancreatic ductal adenocarcinoma through recruitment of myelomonocytic cells.
abstract: 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.
authors.affiliation: The National Engineering Laboratory for Anti-Tumor Protein Therapeutics, School of Life Sciences, Tsinghua University, Beijing, China.|Beijing Key Laboratory for Protein Therapeutics, School of Life Sciences, Tsinghua University, Beijing, China.|Cancer Biology Laboratory, School of Life Sciences, Tsinghua University, Beijing, China.
authors.forename: Min
authors.initials: M
authors.lastname: Xu
authors.affiliation: The National Engineering Laboratory for Anti-Tumor Protein Therapeutics, School of Life Sciences, Tsinghua University, Beijing, China.|Beijing Key Laboratory for Protein Therapeutics, School of Life Sciences, Tsinghua University, Beijing, China.|Cancer Biology Laboratory, School of Life Sciences, Tsinghua University, Beijing, China.
authors.forename: Feifei
authors.initials: F
authors.lastname: Qi
authors.affiliation: The National Engineering Laboratory for Anti-Tumor Protein Therapeutics, School of Life Sciences, Tsinghua University, Beijing, China.|Beijing Key Laboratory for Protein Therapeutics, School of Life Sciences, Tsinghua University, Beijing, China.|Cancer Biology Laboratory, School of Life Sciences, Tsinghua University, Beijing, China.
authors.forename: Shaosen
authors.initials: S
authors.lastname: Zhang
authors.affiliation: The National Engineering Laboratory for Anti-Tumor Protein Therapeutics, School of Life Sciences, Tsinghua University, Beijing, China.|Beijing Key Laboratory for Protein Therapeutics, School of Life Sciences, Tsinghua University, Beijing, China.|Cancer Biology Laboratory, School of Life Sciences, Tsinghua University, Beijing, China.
authors.forename: Xuhui
authors.initials: X
authors.lastname: Ma
authors.affiliation: The National Engineering Laboratory for Anti-Tumor Protein Therapeutics, School of Life Sciences, Tsinghua University, Beijing, China.|Beijing Key Laboratory for Protein Therapeutics, School of Life Sciences, Tsinghua University, Beijing, China.|Cancer Biology Laboratory, School of Life Sciences, Tsinghua University, Beijing, China.
authors.forename: Shan
authors.initials: S
authors.lastname: Wang
authors.affiliation: The National Engineering Laboratory for Anti-Tumor Protein Therapeutics, School of Life Sciences, Tsinghua University, Beijing, China.|Beijing Key Laboratory for Protein Therapeutics, School of Life Sciences, Tsinghua University, Beijing, China.|Cancer Biology Laboratory, School of Life Sciences, Tsinghua University, Beijing, China.
authors.forename: Chunying
authors.initials: C
authors.lastname: Wang
authors.affiliation: The National Engineering Laboratory for Anti-Tumor Protein Therapeutics, School of Life Sciences, Tsinghua University, Beijing, China.|Beijing Key Laboratory for Protein Therapeutics, School of Life Sciences, Tsinghua University, Beijing, China.|Cancer Biology Laboratory, School of Life Sciences, Tsinghua University, Beijing, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Fu
authors.affiliation: The National Engineering Laboratory for Anti-Tumor Protein Therapeutics, School of Life Sciences, Tsinghua University, Beijing, China.|Beijing Key Laboratory for Protein Therapeutics, School of Life Sciences, Tsinghua University, Beijing, China.|Cancer Biology Laboratory, School of Life Sciences, Tsinghua University, Beijing, China.
authors.forename: Yongzhang
authors.initials: Y
authors.lastname: Luo
mesh_terms: D053607:Adrenomedullin / Q000235:genetics* / Q000378:metabolism; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D008875:Middle Aged; D009000:Monocytes / Q000378:metabolism* / Q000473:pathology; D000072737:Myeloid-Derived Suppressor Cells / Q000378:metabolism* / Q000473:pathology; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D034622:RNA Interference; D014183:Transplantation, Heterologous
chemical_list: D053607:Adrenomedullin
keywords: adrenomedullin; cell recruitment; myelomonocytic cells; pancreatic ductal adenocarcinoma; tumor angiogenesis