Fibroblast Activation Protein Activates Macrophages and Promotes Parenchymal Liver Inflammation and Fibrosis

Yang, Aiting; Kim, Yong-Ook; Yan, Xuzhen; Abé, Hiroyuki; Noor, Muhammad Aslam; Park, Kyoung-Sook; Zhao, Xinyan; Jia, Jidong; Klein, Thomas; You, Hong; Schuppan, Detlef

doi:10.1016/j.jcmgh.2022.12.005

Cited by 30 publications

(20 citation statements)

References 53 publications

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“…Prior studies have associated FAP with M2 macrophage infiltration. 16,44,[55][56][57] In the present study, the extent of FAP expression correlated with the extent of tumor infiltration by CD163 positive macrophages, which we verified were themselves higher in carcinoma than in normal appearing regions. 42 Since these CD163-positive M2 macrophages are generally considered immunosuppressive, these findings are consistent with the hypothesis that FAP may contribute to immune suppression in the prostate tumor microenvironment.…”

Section: Discussionsupporting

confidence: 77%

Overexpression of Fibroblast Activation Protein (FAP) in stroma of proliferative inflammatory atrophy (PIA) and primary adenocarcinoma of the prostate

Caramella-Pereira,

Zheng,

Hicks

et al. 2024

Preprint

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Fibroblast activation protein (FAP) is a serine protease upregulated at sites of tissue remodeling and cancer that represents a promising therapeutic and molecular imaging target. In prostate cancer, studies of FAP expression using tissue microarrays are conflicting, such that its clinical potential is unclear. Furthermore, little is known regarding FAP expression in benign prostatic tissues. Here we demonstrated, using a novel iterative multiplex IHC assay in standard tissue sections, that FAP was nearly absent in normal regions, but was increased consistently in regions of proliferative inflammatory atrophy (PIA). In carcinoma, FAP was expressed in all cases, but was highly heterogeneous. High FAP levels were associated with increased pathological stage and cribriform morphology. We verified that FAP levels in cancer correlated with CD163+ M2 macrophage density. In this first report to quantify FAP protein in benign prostate and primary tumors, using standard large tissue sections, we clarify that FAP is present in all primary prostatic carcinomas, supporting its potential clinical relevance. The finding of high levels of FAP within PIA supports the injury/regeneration model for its pathogenesis and suggests that it harbors a protumorigenic stroma. Yet, high levels of FAP in benign regions could lead to false positive FAP-based molecular imaging results in clinically localized prostate cancer.

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Section: Discussionsupporting

confidence: 77%

Overexpression of Fibroblast Activation Protein (FAP) in stroma of proliferative inflammatory atrophy (PIA) and primary adenocarcinoma of the prostate

Caramella-Pereira,

Zheng,

Hicks

et al. 2024

Preprint

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“…S10), FAP is absent in most tissues under basal conditions but is highly expressed on activated myofibroblasts 40, 41 ; and it is a well-established marker for activated fibroblasts 42 . The serine protease activity of FAP promotes liver fibrosis by activating HSC and promoting macrophage infiltration after liver injury 43 . Also, the pattern of expression of 9 mesenchyme and myofibroblast-specific genes in mesenchymal cells and myofibroblasts in human liver is retained in Mes2 and MyoF_T1 cells in microHOs ( Fig.…”

Section: Resultsmentioning

confidence: 99%

Characterization of Pro-Fibrotic Signaling Pathways using Human Hepatic Organoids

Guan

Fang

et al. 2023

Preprint

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Due to the limitations of available in vitro systems and animal models, we lack a detailed understanding of the pathogenetic mechanisms and have minimal treatment options for liver fibrosis. To overcome this barrier, we engineered a live cell imaging system that identifies collagen producing cells in a human multi-lineage hepatic organoid. This system was adapted for use as a microwell-based platform (i.e., microHOs) where exposure to PDGF or TGFb1 induced the formation of thick collagen fibers. Transcriptomic analysis revealed that TGFb1 exposure converted mesenchymal cells into myofibroblast-like cells with a significantly altered pattern of production of proteases and anti-proteases, which contribute to the development of liver fibrosis. When pro-fibrotic intracellular signaling pathways were examined using pharmacological probes, the anti-fibrotic effect of receptor-specific tyrosine kinase inhibitors was limited to the fibrosis induced by the corresponding growth factor, which indicates that their antifibrotic efficacy would be limited to fibrotic diseases that were solely mediated by that growth factor. In contrast, GSK3b or p38 MAPK inhibitors could prevent TGFb1- or PDGF-induced fibrosis in microHOs because they block intracellular signaling pathways that are commonly utilized by the TGFb1 and PDGF receptors. Hence, these studies identified GSK3b and p38 MAPK inhibitors as potential new broad-spectrum therapies for liver fibrosis, and it is likely that other new therapies could subsequently be identified using this microHO system.

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“…Through the later activity, FAP cleaves the collagen and remodels the ECM, modifying the bioactive signaling pathway in fibrosis 83 . Elevated levels of FAP expression significantly promotes the activity of macrophage and fibrogenic events in cancer 82 and other pathological fibrosis, 84 including liver and cardiac fibrosis 85 . Pharmacological inhibition of FAP attenuates cardiac fibrosis and is considered a potential target 76 …”

Section: Strategies Of Car‐t Cell Therapy In Cardiac Fibrosismentioning

confidence: 99%

CAR‐T cell therapeutic avenue for fighting cardiac fibrosis: Roadblocks and perspectives

Abdalla,

Miao,

Ahmed

et al. 2024

Cell Biochemistry & Function

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Heart diseases remain the primary cause of human mortality in the world. Although conventional therapeutic opportunities fail to halt or recover cardiac fibrosis, the promising clinical results and therapeutic efficacy of engineered chimeric antigen receptor (CAR) T cell therapy show several advancements. However, the current models of CAR‐T cells need further improvement since the T cells are associated with the triggering of excessive inflammatory cytokines that directly affect cardiac functions. Thus, the current study highlights the critical function of heart immune cells in tissue fibrosis and repair. The study also confirms CAR‐T cell as an emerging therapeutic for treating cardiac fibrosis, explores the current roadblocks to CAR‐T cell therapy, and considers future outlooks for research development.

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Fibroblast Activation Protein Activates Macrophages and Promotes Parenchymal Liver Inflammation and Fibrosis

Cited by 30 publications

References 53 publications

Overexpression of Fibroblast Activation Protein (FAP) in stroma of proliferative inflammatory atrophy (PIA) and primary adenocarcinoma of the prostate

Overexpression of Fibroblast Activation Protein (FAP) in stroma of proliferative inflammatory atrophy (PIA) and primary adenocarcinoma of the prostate

Characterization of Pro-Fibrotic Signaling Pathways using Human Hepatic Organoids

CAR‐T cell therapeutic avenue for fighting cardiac fibrosis: Roadblocks and perspectives

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