Targeting HIC1/TGF-β axis-shaped prostate cancer microenvironment restrains its progression

Prostate cancer (PCa) is a malignant tumor that seriously threatens men's health worldwide. Recently, stromal cells in the tumor microenvironment (TME) have been reported to contribute to the progression of PCa. However, the role and mechanism of how PCa cells interact with stromal cells to reshape the TME remain largely unknown. Here, using a spontaneous prostate adenocarcinoma (PRAD) model driven by the loss of Pten and Hic1, we found that M2 macrophages markedly infiltrated the stroma of Pten and Hic1 double conditional knockout (dCKO) mice compared with those in control (Ctrl) mice due to higher TGF-β levels secreted by HIC1-deleted PCa cells. Mechanistically, TGF-β in TME promoted the polarization of macrophages into "M2" status by activating the STAT3 pathway and modulating c-Myc to upregulate CXCR4 expression. Meanwhile, TGF-β activated the fibroblasts to form cancer-associated fibroblasts (CAFs) that secrete higher CXCL12 levels, which bound to its cognate receptor CXCR4 on M2 macrophages. Upon interaction with CAFs, M2 macrophages secreted more CXCL5, which promoted the epithelial-mesenchymal transition (EMT) of PCa via CXCR2. Moreover, using the TGF-β receptor I antagonist, galunisertib, significantly inhibited the tumor growth and progression of the TRAMP-C1 cell line-derived subcutaneous tumor model. Finally, we confirmed that the stromal microenvironment was shaped by TGF-β in HIC1-deficient PCa and was associated with the progression of PCa.

浏览次数：17 分享：

Tianqi Wu #, Wenfeng Wang #, Guohai Shi #, Mingang Hao, Yingying Wang, Mengfei Yao, Yongqiang Huang, Leilei Du, Xingming Zhang, Dingwei Ye, Xiaojie Bian, Jianhua Wang

期刊 Cell Death Dis
影响因子 9
起止号 2022 Jul 19;13(7):624.
种属 Human
技术平台抗体芯片
应用领域生殖系统
研究方向生殖系统
疾病类型前列腺癌
检测蛋白 Adiponectin/Acrp30,IFN-gamma,CCL2/MCP-1,Angiogenin,IGFBP-2,CCL7/MCP-3,Angiopoietin-1,IGFBP-3,M-CSF,Angiopoietin-2,IL-1 alpha/IL-1F1,MIF,Apolipoprotein A1,IL-1 beta/IL-1F2,CXCL9/MIG,BAFF/BLyS/TNFSF13B,IL-1ra/IL-1F3,CCL3/CCL4 MIP-1 alpha/beta,BDNF,IL-2,CCL20/MIP-3 alpha,CD14,IL-3,CCL19/MIP-3 beta,CD30,IL-4,MMP-9,CD31/PECAM-1,IL-5,Myeloperoxidase,CD40 Ligand/TNFSF5,IL-6,Osteopontin (OPN),Chitinase 3-like,IL-8,PDGF-AA,Complement Component C5/C5a,IL-10,PDGF-AB/BB,Complement Factor D,IL-11,Pentraxin 3/TSF-14,C-Reactive Protein/CRP,IL-12 p70,CXCL4/PF4,Cripto-1,IL-13,RAGE,Cystatin C,IL-15,CCL5/RANTES,Dkk-1,IL-16,RBP4,DPPIV/CD26,IL-17A,Relaxin-2,EGF,IL-18 BPa,Resistin,CXCL5/ENA-78,IL-19,CXCL12/SDF-1 alpha,Endoglin/CD105,IL-22,Serpin E1/PAI-1,EMMPRIN,IL-23,SHBG,Fas Ligand,IL-24,ST2/IL1 R4,FGF basic,IL-27,CCL17/TARC,KGF/FGF-7,IL-31,TFF3,FGF-19,IL-32 alpha/beta/gamma,TfR,Flt-3 Ligand,IL-33,TGF-alpha,G-CSF,IL-34,Thrombospondin-1,GDF-15,CXCL10/IP-10,TIM-1,GM-CSF,CXCL11/I-TAC,TNF-alpha,CXCL1/GRO alpha,Kallikrein 3/PSA,uPAR,Growth Hormone (GH),Leptin,VCAM-1,HGF,LIF,VEGF,ICAM-1/CD54,Lipocalin-2/NGAL,Vitamin D BP

Abstract

Prostate cancer (PCa) is a malignant tumor that seriously threatens men's health worldwide. Recently, stromal cells in the tumor microenvironment (TME) have been reported to contribute to the progression of PCa. However, the role and mechanism of how PCa cells interact with stromal cells to reshape the TME remain largely unknown. Here, using a spontaneous prostate adenocarcinoma (PRAD) model driven by the loss of Pten and Hic1, we found that M2 macrophages markedly infiltrated the stroma of Pten and Hic1 double conditional knockout (dCKO) mice compared with those in control (Ctrl) mice due to higher TGF-β levels secreted by HIC1-deleted PCa cells. Mechanistically, TGF-β in TME promoted the polarization of macrophages into "M2" status by activating the STAT3 pathway and modulating c-Myc to upregulate CXCR4 expression. Meanwhile, TGF-β activated the fibroblasts to form cancer-associated fibroblasts (CAFs) that secrete higher CXCL12 levels, which bound to its cognate receptor CXCR4 on M2 macrophages. Upon interaction with CAFs, M2 macrophages secreted more CXCL5, which promoted the epithelial-mesenchymal transition (EMT) of PCa via CXCR2. Moreover, using the TGF-β receptor I antagonist, galunisertib, significantly inhibited the tumor growth and progression of the TRAMP-C1 cell line-derived subcutaneous tumor model. Finally, we confirmed that the stromal microenvironment was shaped by TGF-β in HIC1-deficient PCa and was associated with the progression of PCa.

首页 >

技术资源 >

文献中心 >

相关货号

Abstract