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.
Highlights
Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy associated with desmoplasia and a marked infiltration of myeloid cells into the tumor stroma [1]
ADM is highly expressed in pancreatic cancer tissues and its level correlates with the abundance of CD11b+ myelomonocytic cells
ADM is highly expressed in pancreatic ductal adenocarcinoma (PDAC), and large numbers of myelomonocytic cells infiltrate the stromal compartment of PDAC
Summary
Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy associated with desmoplasia and a marked infiltration of myeloid cells into the tumor stroma [1]. The abundance of myelomonocytic cells, mainly monocyte-macrophage lineage, in tumor tissues correlates with inflammation and poor diagnosis [5, 6]. Tumorsecreted soluble factors, such as VEGF and GM-CSF, can stimulate these cells to differentiate into macrophages or result in the accumulation of myeloid-derived suppressor cells (MDSCs) [7, 8]. MDSCs reportedly promote tumor angiogenesis and growth through secretion of various cytokines, including VEGF and placental growth factor (PlGF), among others [9]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
