Biological function and clinical implication of coagulation proteins during malignant transformation of pancreatic cells

The premalignant pancreatic cellular genotype can remain stable for years before rapid malignant transformation, often associated with inflammation. Tissue factor (TF) is an inflammatory modulator regulated by factor VIIa (fVIIa) for its levels and activity. The presence of TF in PDAC and its role in cell proliferation, angiogenesis, and metastasis suggests that TF may be a marker of the inflammatory microenvironment driving precursor lesions of pancreatic cancer. This study examined the in vitro influence of TF on pancreatic epithelial cells and its clinical value in detecting malignant transformation within pancreatic cyst fluid (PCyF). PCyF from 27 patients with pancreatic cystic lesions was analysed in a blinded fashion. TF and fVIIa levels were measured (ELISA), and the fVIIa:TF ratios were calculated. A cut-off value for TF concentration was determined and compared to the conventional assessment parameters (radiological features, CEA and amylase). Patients were categorised into four groups based on cytopathology and two groups based on indication for resection (‘resective’). Significant histological stage-dependent increases in TF levels were observed. Mean TF concentration was significantly higher (p=0.006) in the resective (high-grade dysplasia & malignant; 1.17 ng/ml, 95% CI 0.68, 1.67) vs non-resective group (benign & low-grade dysplasia; 0.27 ng/ml, 95% CI 0.1, 0.44), with a strong positive correlation (r= 0.746, p <0.001, TF cut-off 0.75 ng/ml, AUC 0.877, p=0.002). The fVIIa:TF ratio did not add further value. Incubation of pancreatic cells with recombinant TF resulted in increased expression of a marker of epithelial to mesenchymal transition (Vimentin). This influence was moderated by supplementation with fVIIa in benign (hTERT-HPNE) but not overtly malignant pancreatic cells (AsPC-1). Cyst-associated TF levels appear to correlate with cytological progression to the malignant phenotype and may allow better discrimination (specificity 94%) of the ‘resective’ lesion, reduce healthcare costs and offer a more nuanced tool for monitoring indeterminate cystic lesions.