Research Paper Volume 13, Issue 3 pp 3386—3404
Tumor-associated macrophages promote pancreatic ductal adenocarcinoma progression by inducing epithelial-to-mesenchymal transition
- 1 Department of General Surgery, Pancreatic Disease Center, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
- 2 Research Institute of Pancreatic Diseases, Shanghai Jiaotong University School of Medicine, Shanghai, China
- 3 State Key Laboratory of Oncogenes and Related Genes, Shanghai, China
- 4 Institute of Translational Medicine, Shanghai Jiaotong University, Shanghai, China
Received: April 16, 2020 Accepted: September 28, 2020 Published: January 10, 2021
https://doi.org/10.18632/aging.202264How to Cite
Copyright: © 2021 Xiong et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Abstract
In this study, we investigated the role of tumor-associated macrophages (TAMs) in the progression of pancreatic ductal adenocarcinoma (PDAC). PDAC patients with higher levels of CD68+ TAMs exhibited shorter overall survival. In Transwell assays, PDAC cells incubated with TAMs or conditioned media from TAM cells (TAM-CM) showed higher migration and invasion rates than controls. PET/CT scan analysis of orthotopic PDAC model mice revealed greater primary tumor growth and liver metastasis in the TAM-CM treatment group than the controls. H&E staining of liver tissues showed significantly higher numbers of metastatic nodules in the TAM-CM treatment group. Heat inactivation of TAM-CM significantly reduced Transwell migration by PDAC cells, suggesting the involvement of one or more secreted proteins in PDAC progression. Transcriptome sequencing analysis of PDAC cells treated with TAM-CM revealed significant enrichment of transforming growth factor-β (TGF-β) signaling pathway genes. Western blot and qRT-PCR analysis showed that TAM-CM enhanced PDAC migration cells by inducing epithelial-to-mesenchymal transition through the TGF-β-Smad2/3/4-Snail signaling axis. The pro-tumorigenic effects of TAMs or TAM-CM were abolished by TGF-β signaling pathway inhibitors and neutralizing TGF-β antibody. These results demonstrate that TAMs promote PDAC progression through the TGF-β signaling pathway.
Abbreviations
TAM: Tumor-associated macrophage; TGF-β: transforming growth factor-β; TME: Tumor microenvironment; PDAC: Pancreatic ductal adenocarcinoma; IHC: immunohistochemistry; IF: immunofluorescence; EMT: Epithelial-to-mesenchymal transition; TAM-CM: Tumor-associated macrophage conditional medium; ECM: Extracellular matrix; PSC: Pancreatic stellate cell; MDSC: Myeloid-derived suppressor cell; PET/CT: Positron emission tomography/ computed tomography.