M2 Macrophage-Derived Exosomes Promote Angiogenesis and Growth of Pancreatic Ductal Adenocarcinoma by Targeting E2F2

Abstract

Pancreatic ductal adenocarcinoma (PDAC), one of the most aggressive tumors all over the world, has a generally poor prognosis, and its progression is positively correlated with the density of blood vessels. Recently, tumor-associated macrophages (TAMs) were proven to be beneficial for angiogenesis, but their mechanism of action remains unclear. Our study indicated that M2 macrophages were positively correlated with the microvessel density (MVD) of PDAC tissues, and M2 macrophage-derived exosomes (MDEs) could promote the angiogenesis of mouse aortic endothelial cells (MAECs) in vitro. At the same time, the M2 MDEs could also promote the growth of subcutaneous tumors and increase the vascular density of mice. Moreover, we also found that miR-155-5p and miR-221-5p levels in the M2 MDEs were higher than those in M0 MDEs, and they could be transferred into MAECs, as demonstrated by RNA sequencing (RNA-seq) and qPCR analysis. Our data confirmed the interaction between TAMs and the angiogenesis of PDAC by exosomes. Additionally, targeting the exosomal miRNAs derived from TAMs might provide diagnostic and therapeutic strategies for PDAC.

Effects of Ipriflavone-Loaded Mesoporous Nanospheres on the Differentiation of Endothelial Progenitor Cells and Their Modulation by Macrophages

“…As can be observed in Figure 6 , the coculture of EPCs with control RAW macrophages or M2d angiogenic macrophages produced a decrease or increase in VEGFR2 expression, respectively, when compared to monocultured EPCs. Although these changes were not statistically significant, they are in line with previous results by other authors who demonstrated that anti-inflammatory M2, but not proinflammatory M1 macrophages, promote angiogenesis in vivo [ 50 , 51 ].…”

Small extracellular vesicle non-coding RNAs in pancreatic cancer: molecular mechanisms and clinical implications

“…Horizontal transfer of miRNAs results in enhanced tube formation ability of mouse aortic endothelial cells, mediated through downregulation of transcription factor E2F2. Interestingly, injection of TAM sEVs also promotes angiogenesis in vivo, as reflected in a significant increase in microvascular density of pancreatic tumors in a murine PDAC xenograft [113].…”

“…Incubation of human microvascular endothelial cells with TAM sEVs promotes angiogenesis as reflected in (1) protein levels of VEGFA, VEGFR2, ANG2, and PlGF, and (2) enhanced angiogenic ability of human microvascular endothelial cells in vitro [82]. TAM sEVs also overexpress miRNAs 155-5p and 221-5p [113]. Horizontal transfer of miRNAs results in enhanced tube formation ability of mouse aortic endothelial cells, mediated through downregulation of transcription factor E2F2.…”

Pancreatic Cancer Small Extracellular Vesicles (Exosomes): A Tale of Short- and Long-Distance Communication

“…Moreover, sEVs derived from M2-macrophages containing miR-155-5p and miR-221-5p further promoted angiogenesis in vitro by targeting the E2F transcription factor 2 (E2F2). Uptake of the respective sEVs in mice additionally enhanced vascular density and growth of subcutaneous tumors [ 126 ]. Transfer of M2-macrophage-sEVs with miR-365 reduced sensitivity of PDAC cells to gemcitabine in vitro and in vivo, enhancing migration and invasion of PDAC cells by targeting B-cell translocation gene 2 (BTG2) and activating FAK/AKT signaling [ 127 ].…”