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

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.