Pancreatic stromal Gremlin 1 expression during pancreatic tumorigenesis

Authors

Joy M. Davis, University of Texas Health Science Center at Houston
Binglu Cheng, University of Texas Health Science Center at Houston
Madeline M. Drake, University of Texas Health Science Center at Houston
Qiang Yu, University of Texas Health Science Center at Houston
Baibing Yang, University of Texas Health Science Center at Houston
Jing Li, University of Texas Health Science Center at Houston
Chunhui Liu, University of Texas Health Science Center at Houston
Mamoun Younes, University of Texas Health Science Center at Houston
Xiurong Zhao, University of Texas Health Science Center at Houston
Jennifer M. Bailey, University of Texas Health Science Center at Houston
Qiang Shen, LSU Health Sciences Center - New Orleans
Tien C. Ko, University of Texas Health Science Center at Houston
Yanna Cao, University of Texas Health Science Center at Houston

Document Type

Journal Article

Publication Date

1-1-2020

Journal

Genes and Diseases

DOI

10.1016/j.gendis.2020.05.001

Keywords

Fibroblasts; Gremlin 1; Macrophage migration inhibitory factor; Macrophages; Pancreatic ductal adenocarcinoma

Abstract

© 2020 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 FibroblastsGrem1+ marginally increased from CP to pancreatic intraepithelial neoplasia (PanIN) and PDAC. Within PDAC, FibroblastsGrem1+ increased with higher pathological tumor stages and in a majority of PDAC subtypes screened. Additionally, FibroblastsGrem1+ positively correlated with total macrophages (MacCD68+) and M2 macrophages (M2CD163+) in PDAC. To begin exploring potential molecular links between FibroblastsGrem1+ 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 M2CD163+ 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.

APA Citation

Davis, J., Cheng, B., Drake, M., Yu, Q., Yang, B., Li, J., Liu, C., Younes, M., Zhao, X., Bailey, J., Shen, Q., Ko, T., & Cao, Y. (2020). Pancreatic stromal Gremlin 1 expression during pancreatic tumorigenesis. Genes and Diseases, (). http://dx.doi.org/10.1016/j.gendis.2020.05.001