Supervisors: prof Enn Seppet ja prof Ants Peetsalu (TÜ kirurgiakliinik)
Opponent: professor Vilmantė Borutaitė (Lithuanian University of Health Sciences, Leedu)
Nowadays, gastric cancer (GC) represents one of the most challenging tumors due to the fact that its diagnosis is often late and, in the advanced stage, the therapeutic options are scarce with a consequent high rate of mortality. In fact, although a reduction in global incidence for GC is reported, it remains the second cause of cancer-related death (Ferlay et al., 2010; Forman and Burley, 2006). In general, survival rates of GC have been low. The EUROCARE study estimated average European survival for the cases diagnosed in the period 1995-1999 to be around 46% at 1 year and 25% at 5 years after diagnosis (Sant et al., 2009). These results indicate that the knowledge and data concerning the development of GC are still unclear. Additionally, the knowledge of precursor lesions for the development of GC could contribute to anticipating GC diagno- sis at an early stage when surgery or chemotherapy offers a better prognosis.
Based on extensive cohort studies conducted in Columbia, as well as on data gathered in Estonia, Finland and Japan, Pelayo Correa proposed a paradigm of gastric carcinogenesis that has become known as Correa's cascade. According to this, the biological model of gastric carcinogenesis can be displayed as an inflammation-atrophy-metaplasia-dysplasia-carcinoma sequence (Correa, 1992) that is based on three different intermingled processes. Firstly, chronic active inflammation caused by Helicobacter pylori (H. pylori) creates the background for geno- and phenotypic alterations. Secondly, disruption of the balance between apoptosis and cell proliferation results in mucosal atrophy. Thirdly, progressive loss of differentiation favors establishment of intestinal metaplasia characterized by replacement of intestine-type glands for normal glands (Correa, 2004).
It is conceivable that transition of the normal mucosal cell phenotype towards the cancer cell phenotype may be accompanied or even underlied by specific alterations in cellular energy metabolism, particularly at the level of mitochondrial functions. On the one hand, mitochondria support the function and viability of the cell by converting the energy released from substrate oxi- dation into adenosine triphosphate (ATP). On the other hand, mitochondria rep- resent the key organelles capable of initiating and controlling apoptotic cell death. Both mentioned functions are largely disturbed in cancer cells, which was first noted by Otto Warburg who proposed that development of cancer is causally related to suppression of oxidative phosphorylation (OXPHOS) and activation of aerobic glycolysis (Warburg, 1956). Later on, many studies have proved the correctness of the Warburg hypothesis. It has been proposed that alterations in the respiratory chain (RC) of mitochondria trigger reactive oxygen species (ROS) production, which in turn accelerates and aggravates the impair- ment of the mitochondrial structure. In parallel, the ROS dependent signalling pathways become activated, which eventually result in such bioenergetic re- arrangements that favor cancer development (reviewed in Seppet et al., 2009). Controversially, other investigations revealed contradictory modifications with
the upregulation of OXPHOS components and a larger dependency of cancer cells on oxidative energy substrates for anabolism and energy production (Jose et al., 2011; Moreno-Sánchez et al., 2007).
Today, however, there is only very limited information concerning the bioenergetic function of the mitochondria in the human normal gastric mucosa (GM) and GC in situ. In the present research, we used saponin treated (permeabilized) gastrobiopsy specimens of the antrum and corpus mucosa for studies of OXPHOS system in human GM. Our study addresses mainly the function of mitochondrial RC in three stages (chronic inflammation, atrophic gastritis (AG) and GC) of inflammationatrophycarcinoma sequence, to find out the possible markers of early changes in GM leading to GC.
Besides, the evidence confirming possible participation of creatine kinase (CK) and adenylate kinase (AK) isoforms in the energy transfer systems in human GM cells is still lacking. In many cells with intermittently high and fluctuating energy demands (cardiac muscle, brain and spermatozoa) the mito- chondria and ATPases are linked to each other by specialized phosphotransfer systems mediated by different CK) and AK isoforms. Thus we aimed to char- acterize energy transfer systems in human GM.