Possible implications of redox-sensitive tumour cell transformation; lessons from cell culture studies

It is generally accepted that chronic inflammatory disease, either local or generalized, is associated with higher incidence of cancer. Since inflammation is often accompanied by oxidative stress the latter was indicated as the foundation for progressive mutations leading to tumor development (proliferation, invasion, metastasis). Even though, it is very hard to demonstrate by in vitro studies the causal relationship between oxidative stress and cell transformations. From our studies it is clear that cells are more likely to stop divisions and they commit suicide by apoptosis. During last decade, a novel view on the origin of cancer emerged. The so called cancer stem cells (CSC) were found that form the side-population of stem cells (SC) and they are believed to initiate cancer. Are the SC ancestors for CSC? Do SC transform into CSC? These and other questions remain unanswered. We hypothesize that SC might undergo transformation into CSC during prolonged oxidative stress. We claim that several changes in cell biochemistry has to occur to start the molecular modifications leading to neoplasma. These include either hypoxia-promoted apoptosis signal inducing kinase 1 (ASK-1), hypoxia inducing factor 1 alpha (HIF-1alpha) and glycolysis, or normoxia-promoted activating protein-1 (AP-1) or hyperoxia-induced nuclear factor kappa B (NF-kappaB). Next, harsh microenvironment and heterogenous extracellular matrix (ECM) induced by oxidative stress accelerate the selection of clones of cells resistant to apoptogenic signal. HIF-1alpha, protein crucial for transcriptional activation of protooncogene met leads to the overexpression of c-Met receptor that in turn sensitizes cells to hepatocyte growth factor/scatter factor (HGF/SF) mitogen. Finally, both impaired function of mitochondria and hypoxia elevate fibrin protein level and amplify hemostasis as disseminated intracapillary coagulation (DIC). In any case, it is very interesting and remains to be answered whether imbalance in prooxidant-antioxidant homeostasis has causal relationship with transformation of SC to CSC.