The gene for fibroblast activation protein α (FAP), a putative cell surface-bound serine protease expressed in cancer stroma and wound healing, maps to chromosome band 2q23

Mathew, Susan; Scanlan, Matthew J.; Raj, Bhaskara K. Mohan; Murty, V. V. V. S.; Garin‐Chesa, Pilar; Old, Lloyd J.; Rettig, Wolfgang; Chaganti, R. S. K.

doi:10.1016/0888-7543(95)80157-h

Cited by 69 publications

(54 citation statements)

References 13 publications

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“…Fibroblast activation protein-␣ (FAP) is a cell surface serine protease expressed at sites of tissue remodeling in embryonic development. FAP is not expressed by mature somatic tissues except activated melanocytes, tumor stroma, and fibroblasts in wound healing (13,15). Our study suggests that FAP is induced in the remodeling phase of ischemia-reperfused heart.…”

Section: Discussionmentioning

confidence: 73%

Transcriptome analysis of the ischemia-reperfused remodeling myocardium: temporal changes in inflammation and extracellular matrix

Roy

Khanna

Kuhn

et al. 2006

Physiological Genomics

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Transcriptome analysis of the ischemia-reperfused remodeling myocardium: temporal changes in inflammation and extracellular matrix. Physiol Genomics 25: 364 -374, 2006. First published March 22, 2006 doi:10.1152/physiolgenomics.00013.2006.-cDNA microarray analysis was performed to screen 15,000 genes and expressed sequence tags (ESTs) to identify changes in the ischemia-reperfused (I-R) rat myocardial transcriptome in the early (day 2) and late (day 7) inflammatory phases of acute myocardial infarction. Lists of candidate genes that were affected by I-R transiently (2 or 7 days only) or on a more sustained basis (2 and 7 days) were derived. The candidate genes represented three major functional categories: extracellular matrix, apoptosis, and inflammation. To expand on the findings from microarray studies that dealt with the two above-mentioned time points, tissues collected from days 0, 0.25, 2, 3, 5, and 7 after reperfusion were examined. Acute myocardial infarction resulted in upregulation of IL-6 and IL-18. Genes encoding extracellular matrix proteins such as types I and III collagen were upregulated in day 2, and that response progressively grew stronger until day 7 after I-R. Comparable response kinetics was exhibited by the candidate genes of the apoptosis category. Caspases-2, -3, and -8 were induced in response to acute infarction. Compared with the myocardial tissue from the sham-operated rats, tissue collected from the infarct region stained heavily positive for the presence of active caspase-3. Laser microdissection and pressure catapulting technology was applied to harvest infarct and adjacent noninfarct control tissue from a microscopically defined region in the rat myocardium. Taken together, this work presents the first evidence gained from the use of DNA microarrays to understand the molecular mechanisms implicated in the early and late inflammatory phases of the I-R heart. heart; oxygen; perceived hyperoxia; wound healing AN ACUTE MYOCARDIAL INFARCTION induces ventricular remodeling, a process that can influence ventricular functions and survival outcomes (22). Ventricular remodeling is directly implicated in postinfarction development of ventricular dilatation, a predictive sign of future congestive heart failure. Timedependent changes in ventricular architecture occur in the infarcted and noninfarcted regions, resulting in hypertrophy of the viable regions of the affected site (6). Cardiac remodeling after myocardial infarction depends on cellular responses, characterized by hypertrophy of myocytes and hyperplasia of interstitial fibroblasts (18). Animals that survive with large transmural infarctions develop heart failure without another ischemic event, as is typically seen in humans. A rat model of myocardial infarction has been extensively studied to understand the functional, structural, and molecular changes associated with clinical ischemic heart disease (23, 33). Substantial alterations in gene expression are needed to afford such profound changes within cells of the remodeling myocar...

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Section: Discussionmentioning

confidence: 73%

Transcriptome analysis of the ischemia-reperfused remodeling myocardium: temporal changes in inflammation and extracellular matrix

Roy

Khanna

Kuhn

et al. 2006

Physiological Genomics

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“…The proliferation indices of the CT26 tumors were determined based on Ki67 staining of sections of tumors from the 3 groups of CT26 tumor-bearing mice harvested at different time points (vehicle control, days 10-12; LAF237, days 11-14; and PT630, days [16][17][18][19][20] in order to analyze tumors of approximately the same size ( Figure 5, A and C). Proliferation was significantly reduced in tumor sections from animals treated with PT630 (P < 0.05) compared with tumors from animals treated with vehicle control or LAF237 (P < 0.01; Figure 5C).…”

Section: Lsl-k-rasmentioning

confidence: 99%

“…FAP is expressed selectively by TAFs and pericytes in more than 90% of human epithelial cancers examined (12)(13)(14)(15)(16). It is also expressed during embryonic development (17), in tissues of healing wounds (18), and in chronic inflammatory and fibrotic conditions such as liver cirrhosis (19,20) and idiopathic pulmonary fibrosis (21), as well as on bone and soft tissue sarcomas (16,22) and some melanoma (23). Expression of FAP is not however detected in benign lesions or normal adult tissues (23,24), while DPPIV is more widely expressed in a variety of cell types (reviewed in refs.…”

Section: Introductionmentioning

confidence: 99%

Targeting fibroblast activation protein inhibits tumor stromagenesis and growth in mice

Santos

Jung²,

Aziz³

et al. 2009

J. Clin. Invest.

370

357

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Membrane-bound proteases have recently emerged as critical mediators of tumorigenesis, angiogenesis, and metastasis. However, the mechanisms by which they regulate these processes remain unknown. As the cell surface serine protease fibroblast activation protein (FAP) is selectively expressed on tumor-associated fibroblasts and pericytes in epithelial tumors, we set out to investigate the role of FAP in mouse models of epithelialderived solid tumors. In this study, we demonstrate that genetic deletion and pharmacologic inhibition of FAP inhibited tumor growth in both an endogenous mouse model of lung cancer driven by the K-ras G12D mutant and a mouse model of colon cancer, in which CT26 mouse colon cancer cells were transplanted into immune competent syngeneic mice. Interestingly, growth of only the K-ras G12D -driven lung tumors was also attenuated by inhibition of the closely related protease dipeptidyl peptidase IV (DPPIV). Our results indicate that FAP depletion inhibits tumor cell proliferation indirectly, increases accumulation of collagen, decreases myofibroblast content, and decreases blood vessel density in tumors. These data provide proof of principle that targeting stromal cell-mediated modifications of the tumor microenvironment may be an effective approach to treating epithelial-derived solid tumors.

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“…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, 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).…”

mentioning

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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The gene for fibroblast activation protein α (FAP), a putative cell surface-bound serine protease expressed in cancer stroma and wound healing, maps to chromosome band 2q23

Cited by 69 publications

References 13 publications

Transcriptome analysis of the ischemia-reperfused remodeling myocardium: temporal changes in inflammation and extracellular matrix

Transcriptome analysis of the ischemia-reperfused remodeling myocardium: temporal changes in inflammation and extracellular matrix

Targeting fibroblast activation protein inhibits tumor stromagenesis and growth in mice

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

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