Trypsin in colorectal cancer: molecular biological mechanisms of proliferation, invasion, and metastasis

Abstract

Trypsin is involved in colorectal carcinogenesis and promotes proliferation, invasion, and metastasis. Although a well-known pancreatic digestive enzyme, trypsin has also been found in other tissues and various cancers, most importantly of the colorectum. Moreover, colorectal cancers with trypsin expression have a poor prognosis and shorter disease-free survival. Biological understanding of how trypsin causes cancer progression is emerging. It seems to act both directly and indirectly through a 'proteinase-antiproteinase-system', and by activation of other proteinase cascades. Invasion of the basal membrane by cancer cells may be promoted directly by trypsin digestion of type I collagen. Trypsin activates, and is co-expressed with matrix metalloproteinases (MMPs), which are known to facilitate invasion and metastasis. MMP-2, MMP-7, and MMP-9 are co-expressed together with trypsin and seem to be of particular importance in proliferation, progression, and invasion. MMPs may play a role in both conversion from adenoma to carcinoma, and in the initiation of invasion and metastasis. Co-segregation of trypsin and MMPs within the tumour environment is important for the activation of MMPs, and may explain the deleterious effect of trypsin on prognosis in colorectal cancer. Trypsin and proteinase-activated receptor 2 (PAR-2) act together in an autocrine loop that promotes proliferation, invasion, and metastasis through various mechanisms, of which prostaglandin synthesis is important. Stimulated by trypsin, both MMP and PAR-2 may activate the mitogenic MAPK-ERK pathway through activation of the epidermal growth factor receptor. Experimental trypsin inhibition is feasible but not very effective, and trypsin as a target for clinical therapy is unlikely to be successful owing to its universal distribution. However, as the pathways of trypsin and co-activated protein cascades emerge, biological understanding of colorectal carcinogenesis will be further illuminated and may pave the way for prognosticators, predictors, and novel targets of therapy.