Human trypsinogens in the pancreas and in cancer

Abstract

ISBN 978-952-92-3963-4 (paperback) ISBN 978-952-10-4732-9 (pdf) http://ethesis.helsnki.fi Yliopistopaino Helsinki 20083

Intra-acinar Trypsinogen Activation Mediates Early Stages of Pancreatic Injury but Not Inflammation in Mice With Acute Pancreatitis

“…In conditions simulating colocalization compartments, activation of anionic trypsinogen was considerably inhibited relative to cationic trypsinogen while the autocatalytic degradation of anionic trypsinogen and trypsin derived from it was 10–20 folds higher (41) indicating that cationic trypsinogen and its trypsin are important players in pathological conditions. In fact, upregulation of anionic trypsinogen reported to occur in pancreatic diseases (45, 46, 60) could be a protective response to limit enzyme activation (41) although upregulation of anionic trypsinogen has also been cited to argue otherwise (52). Using knockout approach, we report that the absence of cationic trypsinogen abrogates pathologic trypsinogen activation, thus clearly establishing that cationic trypsinogen is the isoform that is involved in pathologic intra-acinar enzyme activation during pancreatitis.…”

Gelatinase B/MMP-9 in Tumour Pathogenesis and Progression

“…Furthermore, the myeloperoxidase/H 2 0 2 /hypochlorous acid (HOCl) system of inflammation induces the oxidative inactivation of TIMPs, whilst promoting the activation of MMPs, at concentrations found during inflammation [184,185], providing mechanisms through which the gelatinase B/MMP-9/TIMP equilibrium within tumours can be altered in favour of proteolytic activity even under conditions of high level TIMP expression [186]. TIMP MMP-inhibitory activity, furthermore, can be destroyed by neutrophil elastase, trypsin and α-chymotrypsin, all of which activate gelatinase B/MMP-9 [12,187,188], providing an additional mechanism for irreversible TIMP inhibition combined with gelatinase B/MMP-9 activation within inflammatory tumour environments and also environments such as the pancreas, in which trypsin and trypsin-like enzymes are expressed [189]. Finally, truncated gelatinase B/MMP-9 isoforms generated by enzymatic digestion or present on the cell surface of human leukemic cells have been shown to escape TIMP inhibition (see Section 3.4).…”

Trypsin-antitrypsin Imbalance in Immune Escape and Clonal Proliferation of Pancreatic Cancer

“…AAT can be synthesized by mononuclear cells, alveolar macrophages and epithelial cells and those synthesized by extrahepatic cells play an important role in the regulation of local tissue injury. Our previous work has demonstrated that trypsin can degrade extracellular matrix and basement membrane to promote the occurrence, invasion and metastasis of pancreatic cancer [15,17,21]. The principle of trypsin induces normal cells turning into cancerous ones is that; trypsin activates cell surface transmembrane receptor PAR-2 which promotes the formation of p-ERKI/2.…”

“…Pancreatic secretory trypsin inhibitor (PSTI) also known as serine protease inhibitor Kazal-type 1 (SPINK1) or tumor-associated trypsin inhibitor (TATI) (Account for 20%) and AAT (Account for about 80%) can antagonize against the activity of trypsin in the physiological state, but over expression of AAT can cause immune tolerance of mutant cells [19][20][21][22][23][24]. Therefore, it is necessary to analysis the relation between chain expression of PRSS1, PRSS2, AAT besides TCRVß and the occurrence, invasion and clinical outcome of pancreatic cancer.…”

“…So far it remains unclear that how the co-localization of TCRVß gene with PRSS1, PRSS2 and their homologous genes [5][6][7] (Figure 1) affect the maturation and function of lymphocytes. The relationship between trypsin, α1-antitypsin (AAT) and TCRVß genes' spatiotemporal expression and tumor besides tumor lymphatic invasion has not been clear [9][10][11]. Problems such as how PRSS1 gene mutations affect calcium binding loop or autolysis loop and the auto activation mechanism of trypsinogen being triggered are still…”