Fibroblast Activation Protein (FAP) Is Essential for the Migration of Bone Marrow Mesenchymal Stem Cells through RhoA Activation

Chung, Kuei‐Min; Hsu, Shu-Shong; Chu, Yue-Ru; Lin, Meng-Hsuan; Jiaang, Weir-Tong; Chen, Ruey‐Hwa; Chen, Xin

doi:10.1371/journal.pone.0088772

Cited by 65 publications

(52 citation statements)

References 62 publications

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“…FAP belongs to the post‐proline dipeptidyl aminopeptidase family, which have activities of dipeptidyl peptidase and gelatinase and can cleave amino‐terminal dipeptides between proline and other amino acids through formation of 170‐kDa by homodimerization . FAP is only expressed in bone marrow mesenchymal stem cells in normal adult tissues, but it plays an important role in cancers and fibroblasts during embryonic development, chronic inflammation and matrix remodeling (such as wound healing and fibrosis) . However, FAP was best known for its critical function in stromal cancer‐associated fibroblasts (CAFs), which showed high expression in over 90% of epithelial tumors including breast cancer, ovarian cancer, lung cancer, colorectal cancer, gastric cancer, pancreatic cancer and skin melanoma .…”

Section: Discussionmentioning

confidence: 99%

“…16 FAP is only expressed in bone marrow mesenchymal stem cells in normal adult tissues, but it plays an important role in cancers and fibroblasts during embryonic development, chronic inflammation and matrix remodeling (such as wound healing and fibrosis). 17 However, FAP was best known for its critical function in stromal cancerassociated fibroblasts (CAFs), which showed high expression in over 90% of epithelial tumors including breast cancer, ovarian cancer, lung cancer, colorectal cancer, gastric cancer, pancreatic cancer and skin melanoma. 16,18,19 Moreover, FAP was found to associated with tumor stage, metastasis status and poor prognosis in various cancers.…”

Section: Discussionmentioning

confidence: 99%

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Transcripto‐based network analysis reveals a model of gene activation in tongue squamous cell carcinomas

Zeng

Zhao

et al. 2019

Head & Neck

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Background Tongue squamous cell carcinoma (TSCC) is the most common malignant tumor derived from the oral cavity, yet its specific molecular mechanisms have not been fully clarified. The aim of this study was to evaluate the association between potential genes and clinical features through constructing gene co‐expression networks. Methods The weighted gene co‐expression network analysis was used to construct gene co‐expression networks and to identify candidate key modules and hub genes. The gene expression profiles of GSE31056 obtained from the Gene Expression Omnibus (GEO) database was used to construct co‐expression networks. Results Five hub genes (FAP, AGTRAP, PLOD1, POSTN, and TSHZ3) were identified and validated at transcriptional levels. Moreover, the protein levels of these five hub genes were also found significantly higher in tumor tissues. Among them, FAP was most associated with immune infiltration. Conclusions These five candidate biomarkers and therapeutic targets are worthy of further investigation and discussion.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Transcripto‐based network analysis reveals a model of gene activation in tongue squamous cell carcinomas

Zeng

Zhao

et al. 2019

Head & Neck

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“…By means of integrins, cells are able to “sense” concomitant physical and biochemical cues, which via downstream molecules such as FAK and Rho-ROCK [74, 75] both react to ECM and further prompt additional ECM changes [71, 72, 73]. Interestingly, Rho-ROCK activation is known to be regulated by many of the same CAFs expressed stromal signaling proteins such as Cav-1 [76], FAP [77], and YAP [78], known to promote matrix alignment. Moreover, Rho-ROCK activation is also triggered by mechanical forces, such as the ones imparted by desmoplastic ECMs, and transmitted to cells via integrins [79].…”

Section: Dynamic Reciprocity Between Biochemistry and Mechanics Affecmentioning

confidence: 99%

Biomechanical and biochemical remodeling of stromal extracellular matrix in cancer

Malik

Lelkes

Cukierman

2015

Trends in Biotechnology

284

235

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The extracellular matrix (ECM) provides structural and biochemical signals that regulate cell function. A well-controlled balance between cells and surroundings (i.e., Dynamic Reciprocity) is crucial for regulating ECM architecture. During cancer progression, epithelial cells undergo genetic alterations, which together with stromal changes, including ECM remodeling, disturb the homeostatic dynamics of the epithelium. A parallel organization of stromal ECM fibrils is associated with tumorigenic responses. In an emerging paradigm, continuous and progressive regulation via mechanical forces and aberrant signaling are believed to be responsible for tumor-associated ECM remodeling. In this review, we discuss the discrete biomechanical and biochemical mechanisms that underlie these architectural changes and highlight their particular relevance to the regulation of the alignment of ECM in the mesenchymal stroma.

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confidence: 99%

“…In conditions associated with matrix remodeling, such as wound healing (11), fibrosis (6,12,13), and cancer (5, 14 -17), however, FAP expression is up-regulated on activated fibroblasts. FAP has also been detected on pericytes, bone marrow-derived mesenchymal stem cells (18,19), and a small population of macrophages (20,21 FAP's in vivo substrates remain unclear. Despite a lack of direct evidence, FAP is assumed to degrade ECM components, including type I collagen in vivo (9,22,23).…”

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confidence: 99%

Fibroblast Activation Protein (FAP) Accelerates Collagen Degradation and Clearance from Lungs in Mice

Fan

Zhu

et al. 2016

Journal of Biological Chemistry

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Idiopathic pulmonary fibrosis is a disease characterized by progressive, unrelenting lung scarring, with death from respiratory failure within 2-4 years unless lung transplantation is performed. New effective therapies are clearly needed. Fibroblast activation protein (FAP) is a cell surface-associated serine protease up-regulated in the lungs of patients with idiopathic pulmonary fibrosis as well as in wound healing and cancer. We postulate that FAP is not only a marker of disease but influences the development of pulmonary fibrosis after lung injury. In two different models of pulmonary fibrosis, intratracheal bleomycin instillation and thoracic irradiation, we find increased mortality and increased lung fibrosis in FAP-deficient mice compared with wild-type mice. Lung extracellular matrix analysis reveals accumulation of intermediate-sized collagen fragments in FAPdeficient mouse lungs, consistent with in vitro studies showing that FAP mediates ordered proteolytic processing of matrix metalloproteinase (MMP)-derived collagen cleavage products. FAP-mediated collagen processing leads to increased collagen internalization without altering expression of the endocytic collagen receptor, Endo180. Pharmacologic FAP inhibition decreases collagen internalization as expected. Conversely, restoration of FAP expression in the lungs of FAP-deficient mice decreases lung hydroxyproline content after intratracheal bleomycin to levels comparable with that of wild-type controls. Our findings indicate that FAP participates directly, in concert with MMPs, in collagen catabolism and clearance and is an important factor in resolving scar after injury and restoring lung homeostasis. Our study identifies FAP as a novel endogenous regulator of fibrosis and is the first to show FAP's protective effects in the lung.Idiopathic pulmonary fibrosis, the most common of the idiopathic interstitial pneumonias, is characterized by inexorable progressive lung injury and scarring, with eventual death within 2-4 years from the time of diagnosis in the absence of lung transplantation (1). The etiology of the disease is poorly understood, and current Food and Drug Administration-approved treatments have only limited impact on the course of the disease (2-4).Fibroblast activation protein (FAP, 2 also known as seprase) is a 95-kDa cell surface, type II integral serine protease belonging to the post-proline dipeptidyl aminopeptidase (DPP) family (5) that is specifically induced on lung fibroblasts in patients with idiopathic pulmonary fibrosis, in particular at the leading edge of fibrosis (6). The DPP family of serine proteases cleaves amino-terminal dipeptides from polypeptides with L-proline or L-alanine at the penultimate position. FAP is unique in that it displays additional in vitro endopeptidase (7), gelatinase, and potentially collagenase activity (8,9). FAP expression is restricted, occurring at high levels on mesenchymal cells during embryogenesis (10) and then is repressed shortly after birth. In conditions associated with matrix remodeling...

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Fibroblast Activation Protein (FAP) Is Essential for the Migration of Bone Marrow Mesenchymal Stem Cells through RhoA Activation

Cited by 65 publications

References 62 publications

Transcripto‐based network analysis reveals a model of gene activation in tongue squamous cell carcinomas

Transcripto‐based network analysis reveals a model of gene activation in tongue squamous cell carcinomas

Biomechanical and biochemical remodeling of stromal extracellular matrix in cancer

Fibroblast Activation Protein (FAP) Accelerates Collagen Degradation and Clearance from Lungs in Mice

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