Article ; Online: Plasma Kallikrein-Activated TGF-β Is Prognostic for Poor Overall Survival in Patients with Pancreatic Ductal Adenocarcinoma and Associates with Increased Fibrogenesis.
2022 Volume 12, Issue 9
Abstract: Pancreatic ductal adenocarcinoma (PDAC) is a hard-to-treat cancer due to the collagen-rich (fibrotic) and immune-suppressed microenvironment. A major driver of this phenomenon is transforming growth factor beta (TGF-β). TGF-β is produced in an inactive ... ...
| Abstract | Pancreatic ductal adenocarcinoma (PDAC) is a hard-to-treat cancer due to the collagen-rich (fibrotic) and immune-suppressed microenvironment. A major driver of this phenomenon is transforming growth factor beta (TGF-β). TGF-β is produced in an inactive complex with a latency-associated protein (LAP) that can be cleaved by plasma kallikrein (PLK), hereby releasing active TGF-β. The aim of this study was to evaluate LAP cleaved by PLK as a non-invasive biomarker for PDAC and tumor fibrosis. An ELISA was developed for the quantification of PLK-cleaved LAP-TGF-β in the serum of 34 patients with PDAC (stage 1−4) and 20 healthy individuals. Biomarker levels were correlated with overall survival (OS) and compared to serum type III collagen (PRO-C3) and type VI collagen (PRO-C6) pro-peptides. PLK-cleaved LAP-TGF-β was higher in patients with PDAC compared to healthy individuals (p < 0.0001). High levels (>median) of PLK-cleaved LAP-TGF-β were associated with poor OS in patients with PDAC independent of age and stage (HR 2.57, 95% CI: 1.22−5.44, p = 0.0135). High levels of PLK-cleaved LAP-TGF-β were associated with high PRO-C3 and PRO-C6, indicating a relationship between the PLK-cleaved LAP-TGF-β fragment, TGF-β activity, and tumor fibrosis. If these preliminary results are validated, circulating PLK-cleaved LAP-TGF-β may be a biomarker for future clinical trials. |
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| MeSH term(s) | Biomarkers/metabolism ; Carcinoma, Pancreatic Ductal/metabolism ; Collagen Type III ; Collagen Type VI ; Complement C3 ; Fibrosis ; Humans ; Pancreatic Neoplasms/metabolism ; Plasma Kallikrein ; Prognosis ; Transforming Growth Factor beta/metabolism ; Tumor Microenvironment ; Pancreatic Neoplasms |
| Chemical Substances | Biomarkers ; Collagen Type III ; Collagen Type VI ; Complement C3 ; Transforming Growth Factor beta ; Plasma Kallikrein (EC 3.4.21.34) |
| Language | English |
| Publishing date | 2022-09-17 |
| Publishing country | Switzerland |
| Document type | Journal Article ; Research Support, Non-U.S. Gov't |
| ZDB-ID | 2701262-1 |
| ISSN | 2218-273X ; 2218-273X |
| ISSN (online) | 2218-273X |
| ISSN | 2218-273X |
| DOI | 10.3390/biom12091315 |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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