Macrophage CD51 Promotes Cancer Stem Cell Properties via TGFβ1/smad2/3 Axis in Pancreatic Cancer

Abstract

Background: Targeting macrophage therapy offers new options for intractable pancreatic ductal adenocarcinoma (PDAC) with a low 5-year survival rate. However, the regulators of macrophages in PDAC are not fully understood. Methods: To investigate the relationship between CD51 and PDAC, survival analysis and immunohistochemistry (IHC) were performed. Furthermore, the biomarkers of macrophage polarization were tested to determine the relationship between CD51 and macrophage polarization. Finally, we studied the effects of macrophage CD51 on pancreatic cancer stem cells in vitro and in vivo using functional assays and a xenograft model. Findings: CD51 was positively associated with the poor prognosis of PDAC patients and highly expressed on macrophages, but not on cancer cells. Subsequently, by CD51 knockdown, we found that CD51 was a biomarker of macrophages, which promoted the stemness of pancreatic cancer. Furthermore, knockdown of CD51 in macrophages drove macrophages toward M1-like phenotype. Mechanistically, the CD51 on macrophage contributes to achievement of stemness traits of PDAC by regulating the TGF-β1 expression level. Interpretation: Our data demonstrate the central role that macrophage CD51 plays in the achievement of stemness traits of pancreatic cancer through paracrine induction of TGF-β1. We firstly proved the connection between the CD51/TGF-β1/smad2/3 axis and PDAC cancer stem cell properties and indicated that targeting CD51 therapy represents a new therapeutic modality for PDAC. Funding Statement: This research was supported by grants from the National Natural Science Foundation of China (grant number 81871945 81702951, 81672395, 81672807, 81370059, 81000917, 81702417, and 81402213, www.nsfc.gov.cn), the Guangdong Science and Technology Department (grant number S2012010008934,2014A030313044, 2014A030311047, 2016A030313340, 2016A030313296, and2017A030313880, 2017B030314026 http://pro.gdstc.gov.cn) and the Sun Yat-sen University Clinical Research Foundation of 5010 Project (grant number 2012007). Grant (2013)163 from Key Laboratory of Malignant Tumor Molecular Mechanism and Translational Medicine of Guangzhou Bureau of Science and Information Technology. Declaration of Interests: The authors declare no conflicts of interests. Ethics Approval Statement: The studies using human PDAC tissue samples were approved by the ethics committee of Sun Yat-sen Memorial Hospital of Sun Yat-sen University. The protocols for animal studies were approved by the Institutional Animal Care and Use Committee and Institutional Biosafety Committee of Sun Yat-sen University.