Chronic pancreatitis (CP) is a major risk factor of pancreatic ductal adenocarcinoma (PDAC). How CP promotes pancreatic oncogenesis remains unclear. A characteristic feature of PDAC is its prominent desmoplasia in the tumor microenvironment, composed of activated fibroblasts and macrophages. Macrophages can be characterized as M1 or M2, with tumor-inhibiting or -promoting functions, respectively. We reported that Gremlin 1 (GREM1), a key pro-fibrogenic factor, is upregulated in the stroma of CP. The current study aimed to investigate the expression of GREM1 and correlation between GREM1 and macrophages within the pancreas during chronic inflammation and the development of PDAC. By mRNA in situ hybridization, we detected GREM1 mRNA expression within α-smooth muscle actin (SMA)-positive fibroblasts of the pancreatic stroma. These designated Fibroblasts^Grem1+ marginally increased from CP to pancreatic intraepithelial neoplasia (PanIN) and PDAC. Within PDAC, Fibroblasts^Grem1+ increased with higher pathological tumor stages and in a majority of PDAC subtypes screened. Additionally, Fibroblasts^Grem1+ positively correlated with total macrophages (Mac^CD68+) and M2 macrophages (M2^CD163+) in PDAC. To begin exploring potential molecular links between Fibroblasts^Grem1+ and macrophages in PDAC, we examined the expression of macrophage migration inhibitory factor (MIF), an endogenous counteracting molecule of GREM1 and an M1 macrophage promoting factor. By IHC staining of MIF, we found MIF to be expressed by tumor cells, positively correlated with GREM1; by IHC co-staining, we found MIF to be negatively correlated with M2^CD163+ expression. Our findings suggest that GREM1 expression by activated fibroblasts may promote PDAC development, and GREM1/MIF may play an important role in macrophage phenotype.

慢性胰腺炎（CP）是胰腺导管腺癌（PDAC）的主要危险因素。 CP 如何促进胰腺肿瘤发生仍不清楚。 PDAC 的一个特征是其在肿瘤微环境中显着的结缔组织增生，由活化的成纤维细胞和巨噬细胞组成。巨噬细胞可分为M1或M2，分别具有抑制肿瘤或促进肿瘤的功能。我们报道了 Gremlin 1 (GREM1)，一种关键的促纤维化因子，在 CP 基质中表达上调。本研究旨在探讨慢性炎症和 PDAC 发生过程中胰腺内 GREM1 的表达以及 GREM1 与巨噬细胞之间的相关性。通过 mRNA原位杂交，我们检测到胰腺基质的 α-平滑肌肌动蛋白 (SMA) 阳性成纤维细胞内 GREM1 mRNA 表达。这些指定的成纤维细胞^Grem1+从 CP 到胰腺上皮内瘤变 (PanIN) 和 PDAC 略有增加。在 PDAC 中，成纤维细胞^Grem1+随着病理肿瘤分期的升高而增加，并且在大多数筛选的 PDAC 亚型中。此外，成纤维细胞^Grem1+与 PDAC 中的总巨噬细胞 (Mac ^CD68+ ) 和 M2 巨噬细胞 (M2 ^CD163+ ) 呈正相关。为了开始探索 PDAC 中成纤维细胞^Grem1+和巨噬细胞之间潜在的分子联系，我们检测了巨噬细胞迁移抑制因子 (MIF)、GREM1 的内源性抵消分子和 M1 巨噬细胞促进因子的表达。通过MIF的IHC染色，我们发现MIF在肿瘤细胞中表达，与GREM1呈正相关；通过IHC共染色，我们发现MIF与M2 ^CD163+表达呈负相关。 我们的研究结果表明，活化的成纤维细胞表达 GREM1 可能促进 PDAC 发育，并且 GREM1/MIF 可能在巨噬细胞表型中发挥重要作用。