The pancreatic cancer secreted REG4 promotes macrophage polarization to M2 through EGFR/AKT/CREB pathway

Abstract

In the periphery of pancreatic ductal adenocarcinoma (PDAC), high accumulation of tumor-associated macrophages (TAMs), which exhibit M2 phenotype, has been shown to be correlated with extra-pancreatic invasion, lymph vessel invasion, lymph node involvement and shortened survival time. However, mechanisms by which tumor cells educate and reprogram TAMs remain largely unclear. The phenotype of TAMs in PDAC tissues was confirmed by immunofluoresence and confocal microscopy. Human CD14+ monocytes were incubated with recombinant human REG4 (rREG4) before being stimulated with LPS and IL-10 and IL-6 were measured with ELISA. A panel of M1 and M2 genes were measured by quantitative real-time PCR. Panc1, AsPC1 and BxPC3 cells were cultured in the conditioned medium (CM) and treated with REG4. The macrophages were infected with CREB shRNA or cultured by the CM of Panc1 cells infected with REG4 shRNA. The expression of CD163, CD206 and REG4 and the phosphorylation levels of epidermal growth factor receptor (EGFR), AKT and cAMP response element-binding protein (CREB) in cells were assessed with western blotting. Cell proliferation and invasiveness were also assessed. The rREG4 or the conditioned medium of Panc1 cells which secreted REG4 induced the polarization macrophages to M2 phenotype. Treatment of human macrophages with REG4 resulted in phosphorylation of EGFR, AKT and CREB. The latter was responsible for REG4-mediated macrophage polarization to M2. The conditioned medium of macrophages treated with rREG4 promoted the proliferation and invasion of pancreatic cancer cell lines. REG4, overexpressed in PDAC and secreted by cancer cells, promoted macrophage polarization to M2, through at least in part, activation of ERK1/2 and CREB and changed the microenvironment to facilitate cancer growth and metastasis.

RETRACTED: miR-181a Induces Macrophage Polarized to M2 Phenotype and Promotes M2 Macrophage-mediated Tumor Cell Metastasis by Targeting KLF6 and C/EBPα

“…Macrophages are recruited into tumor site by multiple cytokines expressed in the tumor microenvironment and become tumor-associated macrophages (TAMs). 7 TAMs coexist in tumors and function as an accomplice to promote tumor progression and metastasis, especially once polarized into M2 phenotype by the tumor microenvironment. 8 , 9 , 10 TAMs stimulate cancer cell invasion, motility, and migration, and that these effects can be impaired by inhibiting expression of epidermal growth factor.…”

Polarization of macrophages in the tumor microenvironment is influenced by EGFR signaling within colon cancer cells

“…In this study, we found cetuximab reduced both tumor growth in an AOM/DSS mouse model and F4/80 + /CD206 + macrophage populations. Experimental colitis colonic and peritoneal macrophages and human CD14 + monocytes have been reported to express EGFR [26, 31], but we did not detect EGFR expression in Ana-1 and THP-1 cells here (Figure 2A). Cetuximab might therefore modulate the secretion of various factors from tumor cells and thus inhibit macrophage accumulation and polarization.…”

Prognostic and diagnostic value of REG4 serum and tissue expression in pancreatic ductal adenocarcinoma

“…What animal models and cell cultures demonstrate is that pancreatic tumors tend to grow larger when REG4 expression is introduced. 12,[18][19][20] It is possible that negative or low-REG4expressing pancreatic tumors grow slower and are better differentiated also in humans. We show that positive tissue REG4 expression predicts better prognosis in PDAC patients with histological grade I disease.…”