Tumor-associated universal inhibitors and free plasmin in adenocarcinoma of stomach and pancreatic head
Authors: E. Frantsiyants, O. Kit, L. Kozlova, A. Maslov, E. Kolesnikov, S. Ilchenko
Journal: Annals of Oncology (2018)

Introduction: Plasminogen, plasmin, α1 proteinase inhibitor (α1PI), and α2 macroglobulin (α2M) are mainly products of gastrobiliopancreatoduodenal organs (the liver, pancreas), so they are directly involved in the pathology of these organs. Plasmin provides the autolysis initiation both indirectly (through the activation of growth factor zymogens and matrix metalloproteinases) and directly, by participating in the hydrolysis of proteins and in the lysis of membrane and cellular structures. Physiological processes require a strict balance between the precursor, the enzyme and the inhibitors, as overactive proteolysis will lead to the destruction of the intercellular matrix and cells. The purpose of the study was to determine the levels of plasminogen, plasmin, α1PI and α2M in adenocarcinoma of the stomach (AS) and pancreatic head (APH) and in adjacent tissues. Methods: Tumor, perifocal and resection line tissues were studied by spectrophotometry in 84 patients aged 43-72 years with AS (n = 38, G2, T2-3N0-1M0) and APH (n = 46, G2, Т2-4N0M0) with calculation per 1 mg of protein. Statistical processing of the results was performed using the Statistica 10 program. Results: Plasminogen levels were maximal in AS tumor tissues, an order of magnitude lower in its perifocal zone and two orders of magnitude lower in resection line tissues (p < 0.001). In APH, maximal levels of plasminogen were observed in perifocal tissues; plasminogen was 1.3 times lower in resection line tissues, and 1.7 times lower in tumor tissues than in the resection line (p < 0.01). Distribution of plasmin in AS was similar to that of plasminogen, and in APH the highest level of plasmin was registered in the resection line tissues, while in tumor and perifocal tissues the values were almost twice lower. The activity of α1PI and α2M was maximal in all tumor tissues, lower in perifocal tissues and even lower in resection line tissues (p < 0.001). The plasminogen/plasmin ratios decreased in AS from the tumor to the resection line tissues (p < 0.001); in APH - perifocal zone>tumor>resection line (p < 0.001). The α1PI/plasmin and α2M/plasmin ratios in APH decreased from the tumor to the resection line tissues (p < 0.001); in AS - resection line>tumor>perifocal zone (p < 0.001). Conclusion: The possibility of the secretion of all studied proteins by AS is obvious and does not require proof. APH has such a potential (which was demonstrated by the distribution of the activity of both inhibitors), but the results on plasminogen and plasmin confirm a more complex relationship between the tumor and surrounding tissues. In the perifocal zone, the predominant level of plasminogen can also provide an increased content of plasmin, but instead plasmin "evades" even further into the area of intact tissues. The phenomenon of "evasion" of enzymes to surrounding tissues in APH and its rapid growth have long been known. Plasmin in intact tissues has a tumor origin, and this was confirmed by the ratios. An increase in the plasmin-antiplasmin complex in adenocarcinoma of the rectum was reported, in contrast to benign polyps. Perhaps, some amount of plasmin is bound with α2antiplasmin in tissues of gastrointestinal adenocarcinoma. The study demonstrated the production of tumor-associated α1PI, α2M and plasmin in AS and APH.