Plasma Kallikrein-Activated TGF-beta Is Prognostic for Poor Overall Survival in Patients with Pancreatic Ductal Adenocarcinoma and Associates with Increased Fibrogenesis

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-beta). TGF-beta is produced in an inactive complex with a latency-associated protein (LAP) that can be cleaved by plasma kallikrein (PLK), hereby releasing active TGF-beta. 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-beta 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-beta was higher in patients with PDAC compared to healthy individuals (p < 0.0001). High levels (> median) of PLK-cleaved LAP-TGF-beta 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-beta were associated with high PRO-C3 and PRO-C6, indicating a relationship between the PLK-cleaved LAP-TGF-beta fragment, TGF-beta activity, and tumor fibrosis. If these preliminary results are validated, circulating PLK-cleaved LAP-TGF-beta may be a biomarker for future clinical trials.