Increased tissue and circulating levels of dipeptidyl peptidase-IV enzymatic activity in patients with pancreatic ductal adenocarcinoma

Bušek, Petr; Vaníčková, Zdislava; Hrabal, Petr; Brabec, Marek; Frič, Pavol; Zavoral, Miroslav; Škrha, J; Kmochová, Klára; Laclav, Martin; Bunganič, Bohuš; Augustyns, Koen; Veken, Pieter Van der; Šedo, Aleksi

doi:10.1016/j.pan.2016.06.001

Cited by 30 publications

(20 citation statements)

References 42 publications

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“…FAP immunopositivity was detectable by WB in most of the high-grade glioma samples, but was absent in the DPP-IV negative gliomas. This is consistent with ours as well as other authors' reports suggesting the coexpression and possible coregulation of DPP-IV and FAP in glioma cells and tissues 11,31 , human pancreatic alpha cells 37 and in some cancer cell lines 38 . The coexpression of DPP-IV and FAP was also described in endothelial cells, where both molecules are part of proteolytically active heteromeric aggregates with a molecular weight of 820 kDa, promoting cell migration and invasion 30 .…”

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confidence: 94%

Heterogeneity of molecular forms of dipeptidyl peptidase-IV and fibroblast activation protein in human glioblastomas

et al. 2017

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Background and Aims. Proteolytic enzymes contribute to the progression of various cancers. We previously reported increased expression of the proline specific peptidases dipeptidyl peptidase-IV (DPP-IV) and its closest paralogue fibroblast activation protein (FAP) in human glioblastomas. Here we analyze the molecular heterogeneity of DPP-IV and FAP in glioblastomas. Methods. ELISA, isoelectric focusing, 1D and 2D electrophoresis followed by WB or enzyme overlay assay were utilized to analyze DPP-IV and FAP isoforms. Cell fractionation using a Percoll gradient and deglycosylation with PNGase F were performed to analyze the possible basis of DPP-IV and FAP microheterogeneity. Results. Molecular forms of DPP-IV with an estimated molecular weight of 140-160 kDa and a pI predominantly 5.8 were detected in human glioblastoma; in some tumors additional isoforms with a more acidic (3.5-5.5) as well as alkaline (8.1) pI were revealed. Using 2D electrophoresis, two to three molecular forms of FAP with an alkaline (7.0-8.5) pI and an estimated MW of 120-140 kDa were identified in glioblastoma tissues. In glioma cell lines in vitro, several isoforms of both enzymes were expressed, however the alkalic forms present in glioblastoma tissues were not detected. Removal of N-linked oligosaccharides decreased the estimated molecular weight of both enzymes; the overall pattern of molecular forms nevertheless remained unchanged. Conclusion. Several isoforms of DPP-IV and FAP are present in glioblastoma tissue. The absence of alkaline isoforms of both enzymes in glioma cell lines however suggests that isoforms from other, most likely stromal, cell types contribute to the overall pattern seen in glioblastoma tissues.

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confidence: 94%

Heterogeneity of molecular forms of dipeptidyl peptidase-IV and fibroblast activation protein in human glioblastomas

et al. 2017

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“…In human tumor-adjacent tissues, FAP was detectable at the RNA level by RT-PCR in the context of esophageal squamous cell carcinoma (ESCC)( 19 ), lung carcinoma( 18 ), and glioma( 17 ). At the protein level, FAP was found in pancreatic ductal adenocarcinoma (PDAC) adjacent tissue( 20 , 21 ). However, data obtained from non-tumor-bearing subjects suggest that some of these instances of tumor-adjacent FAP expression are not reflective of FAP expression in healthy tissues.…”

Section: Patterns Of Fap Expression In Cancermentioning

confidence: 99%

“…In the pancreas, single cell RNA sequencing revealed that FAP expression is specific to alpha-cells within normal islets( 24 ). Though the cellular source is unknown, FAP can also be detected in the plasma of healthy donors( 20 , 25 ). These data suggest that, while FAP up-regulation in tumors does provide a potential therapeutic window, its expression in healthy tissues may not be as restricted as previously thought, and must be taken into consideration when evaluating the potential side effects of targeting FAP.…”

Section: Patterns Of Fap Expression In Cancermentioning

confidence: 99%

“…Using immunohistochemistry (IHC), apparent cytoplasmic FAP stain was observed in lung cancer( 31 ); unfortunately, this study appears to have relied on an antibody that—while marketed as targeting FAP—was actually generated against a peptide fragment of fas-associated phosphatase( 32 ); a protein with no relation to fibroblast activation protein. However, using different antibodies for IHC, FAP has been detected in lung( 33 ), breast( 34 – 36 ) and pancreatic tumor cells( 20 , 37 ). Using flow cytometry, FAP was detected on a subset of pancreatic tumor cells which also up-regulate Thy-1 (CD90), perhaps indicative of their undergoing EMT( 38 ).…”

Section: Patterns Of Fap Expression In Cancermentioning

confidence: 99%

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Pro-tumorigenic roles of fibroblast activation protein in cancer: back to the basics

2018

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“…Circulating FAPα levels were demonstrated significantly lower in cancer patients compared with healthy subjects and correlated inversely with survival in most types of cancer [6–9]. However, the circulating FAPα level in ESCC is still unclear.…”

Section: Introductionmentioning

confidence: 99%

Evaluation of the circulating level of fibroblast activation protein α for diagnosis of esophageal squamous cell carcinoma

Liao

Xing

et al. 2017

Oncotarget

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To evaluate whether circulating fibroblast activation protein α (FAPα) could serve as a biomarker for the diagnosis of esophageal squamous cell carcinoma (ESCC), enzyme-linked immunosorbent assay (ELISA) was used to detect plasma FAPα in 556 participants including ESCC group, benign esophageal disease group, healthy controls and other cancer controls group. The levels of plasma FAPα were significantly decreased in ESCC patients (P < 0.001) and showed a positive correlation with HDL-C levels (R = 0.372, P < 0.001). The sensitivity and specificity of plasma FAPα were 56.1% and 85.6% based on the optimal cut-off (49.04 ng/ml, AUC = 0.714). The combination of FAPα and the traditional biomarkers (CEA, CYFR211 and SCCA) improved the sensitivity (41.5%) without compromising the specificity (95.0%). Contradictorily, the immunohistochemical staining revealed the overexpression of FAPα in stroma of ESCC tissues. So the source of soluble FAPα was further explored by qRT-PCR, Western blotting, ELISA and immunoprecipitation in fibroblast cell lines and mouse xenograft models. We found that the plasma FAPα was not correlated with the FAPα expressed in tumor, and the multi-organ might contribute to the circulating levels of FAPα including skeletal muscle, liver and bone marrow. These results indicated that the low plasma FAPα level might due to the systemic reaction to the presence of tumor and circulating FAPα level might be a potential indicator for diagnosing ESCC.

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Increased tissue and circulating levels of dipeptidyl peptidase-IV enzymatic activity in patients with pancreatic ductal adenocarcinoma

Cited by 30 publications

References 42 publications

Heterogeneity of molecular forms of dipeptidyl peptidase-IV and fibroblast activation protein in human glioblastomas

Heterogeneity of molecular forms of dipeptidyl peptidase-IV and fibroblast activation protein in human glioblastomas

Pro-tumorigenic roles of fibroblast activation protein in cancer: back to the basics

Evaluation of the circulating level of fibroblast activation protein α for diagnosis of esophageal squamous cell carcinoma

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