Any disturbance of the balance between proteolytic enzymes and their inhibitors, or of the activation process, can result in pancreatits, where premature, intracellular activation of zymogens cause the autodigestion of the pancreas. During pancreatits, anionic trypsinogen becomes the predominant isoforms secreted from the pancreas, and there is an increased level of zymogen in serum. Anionic trypsinogen exhibits increased autocatalytic degradation over the cationic isoforms. Pancreatitis can occur as a hereditary, autodominant condition, as part of the pathogenesis of cystic fibrosis or as a result of alcohol toxicity.
Hereditary pancreatitis results in recurrent attacks of acute pancreatitis, progressing to chronic pancreatitis at a young age. Mutations in the cationinc trypsinogen I gene have been characterised from several patients. One of these mutations was shown to alter a trypsin recognition site, preventing the deactivation of trypsin within the pancreas, resulting in autodigestion. Hereditary pancreatitis can also result in patients with mutations in the trypsin/trypsinogen inhibitor SPINK1, which leads to the inappropriate activation of pancreatic zymogens. SPINK1 mutations appear to cause a more rapid progression of chronic pancreatitis than cationic trypsinogen mutations.
Cystic fibrosis (CF) is an autosomal recessive disorder caused by mutations in the CF transmembrane conductance regulator (CFTR) gene. Patients with CF often suffer from recurrent pancreatitis. CF is thought ot interfere with the negative feedback loop that helps regulate pancreatic zymogen secretion. A high concentration of protease in the duodenum inhibits cholecystokinin (CCK) secretion, thereby reducing pancreatic secretion of zymogens; a high concentration of inhibitors induces pancreatic zymogen secretion through CCK. In CF, it has been suggested that obstruction to pancreatic zymogen secretion could induce CCK release, which in turn stimulates pancreatic zymogen production. The blockage of zymogen secretion together with its continued synthesis could result in the built-up of digestive enzymes within lysosomes, which could then rupture into the cytoplasm.
Chronic alcohol consumption is known to increase the synthesis of several digestive enzymes in the pancreas, including trypsinogen. Progression to chronic pancreatitis can be rapid. As fewer than 10% of alcoholics develop chronic pancreatits, other genetic or environmental factors must be involved.
Hereditary pancreatitis carries a 40% risk of pancreatic cancer (5% risk for non-hereditary pancreatitis), a very invasive cancer with high mortality rates. Pancreatic inflammation promotes intensive cell proliferation to regenerate the damaged pancreas, during which the amplification of pathological changes in DNA can occur.
Elevated levels of trypsin have been found in a variety of other tumours, such as ovarian and colorectal carcinomas, where it may have a role in malignant tumour formation or metastasis. Trypsins appear to be necessary for cancer cells to invade normal tissue, and to enter the bloodstream and lymphatic channels. A critical step in cancer metastasis involves breaking down the extracellular matrix surrounding the malignant tumour, which allows it to invade and spread. Type I collagen degradation involves the action of matrix metalloproteases (MMP-1, -8 and -13), which are activated by MMP-3. Trypsin-2 can directly activate all four pro-MMP enzymes, and can degrade type I collagen, acting as a potent tumour-associated matrix serine protease. The inhibitor TATI (tumour-associated trypsin inhibitor) can inhibit trypsin activation of pro-MMPs and trypsin degradation of type I collagen. Not surprisingly, TATI has been detected at elevated levels in a variety of tumours and in the serum of cancer patients. Trypsin has also been shown to activate a G protein-coupled receptor PAR-2 (protease-activated receptor-2) in both colon and pancreatic cancer cell lines, where it appears to act as a potent mitogen in vitro, functioning as a growth factor.
Certain protease inhibitors appear to be capable of suppressing carcinogenesis in a variety of model systems, the most potent of which appear to inhibit chymotrypsin or chymotrypsin-like proteases. Both soybean-derived BBI (inhibits trypsin and chymotrypsin) and human alpha1-antichymotrypsin are potent inhibitors of chymotrypsin, are highly anti-inflammatory, and may be involved in defence of their respective organisms. BBI was found to help suppress a variety of tumours in different organisms, both in vitro and in vivo. Extracts high in proteolytic enzymes, especially trypsin, chymotrypsin and papain, have also been used in cancer studies. Enzyme therapy appears to be anti-inflammatory by its induction of protease inhibitors.