Is There a Trojan Horse to Aggressive Pancreatic Cancer Biology? A Review of the Trypsin-PAR2 Axis to Proliferation, Early Invasion, and Metastasis

Abstract

Purpose: Pancreatic cancer is one of the most lethal of solid tumors and is associated with aggressive cancer biology. The purpose is to review the role of trypsin and effect on molecular and cellular processes potentially explaining the aggressive biology in pancreatic cancer. Methods: A narrative literature review of studies investigating trypsin and its effect on protease systems in cancer, with special reference to pancreatic cancer biology. Results: Proteases, such as trypsin, provides a significant advantage to developing tumors through the ability to remodel the extracellular matrix, promote cell invasion and migration, and facilitate angiogenesis. Trypsin is a digestive enzyme produced by the exocrine pancreas that is also related to mechanisms of proliferation, invasion and metastasis. Several of these mechanisms may be co-regulated or influenced by activation of proteinaseactivated receptor 2 (PAR-2). The current role in pancreatic cancer is not clear but emerging data suggest several potential mechanisms. Trypsin may act as a Trojan horse in the pancreatic gland, facilitating several molecular pathways from the onset, which leads to rapid progression of the disease. Pancreatic cancer cell lines containing PAR-2 proliferate upon exposure to trypsin, whereas cancer cell lines not containing PAR-2 fail to proliferate upon trypsin expression. Several mechanisms of action include a proinflammatory environment, signals inducing proliferation and migration, and direct and indirect evidence for mechanisms promoting invasion and metastasis. Novel techniques (such as organoid models) and increased understanding of mechanisms (such as the microbiome) may yield improved understanding into the role of trypsin in pancreatic carcinogenesis. Conclusion: Trypsin is naturally present in the pancreatic gland and may experience pathological activation intracellularly and in the neoplastic environment, which speeds up molecular mechanisms of proliferation, invasion, and metastasis. Further investigation of these processes will provide important insights into how pancreatic cancer evolves, and suggest new ways for treatment.

Identification of Potential Serum Protein Biomarkers and Pathways for Pancreatic Cancer Cachexia Using an Aptamer-Based Discovery Platform

“…LYVE1 is reported to be elevated in urine of patients with PDAC, enough to be one of three biomarkers to stratify cancer risk [ 48 ], with no data on cachexia. PRSS1 aka trypsin/trypsinogen mutations increase risk of chronic pancreatitis and pancreatic cancer [ 49 ] and its pathological activation promotes neoplasia [ 50 ]. The ratio of PRSS1 and its inhibitor SERPINA1 or alpha-1-antitrypsin is elevated in patients with PDAC [ 51 ], and SERPINA1 deficiency is associated with pancreatitis and cachexia phenotypes [ 52 ].…”

Fisetin Inhibits Trypsin Activity and Suppresses the Growth of Colorectal Cancer in Vitro and in Vivo

“…Tumor-associated trypsin has been recognized as a significant factor in cancer progression and metastatic processes. 28 As the precursor of trypsin, PRSS2 seems to be strongly correlated with cancers in 4 trypsin isoforms. 29 Several studies revealed high trypsinogen expression in different CRC cell lines.…”

A high throughput blood-based assay for the early detection of pancreatic cancer

“…Effective FDA approved, early detection assays for PDAC detection are nonexistent, but are critically needed to transform survival from this deadly disease. The only FDA approved clinical biomarker for PDAC is carbohydrate antigen 19-9 (CA19-9), which is used predominantly for measure of disease burden across treatment and not as an early detection biomarker, due to its low positive predictive value (PPV) in this setting (1)(2)(3)(4)(5). Currently, our ability to screen the general population as well as monitor patients at high-risk for PDAC is limited by many factors including access, cost, and assay accuracy.…”