From normal to malignant phenotype: survival and cell death escaping mechanisms

Genetic damage acquisition, apoptosis inhibition, metabolic pathways shifting and growth signals self-sufficiency are the first steps in “survival mechanism” of the tumoral cell clone. Hence, the second important step is constituted by the proliferative advantage that leads to cooperation among tumor cells by an adaptative evolution of DNA repair and metabolic pathways to survival. Moreover, tumor progression implies immune escaping mimetism and trigger several processes that synergistically induce a cooperation among transformed cells that compete for space and resources such as oxygen and nutrients. Therefore in tumorigenesis the extra cellular milieu and tissue microenviroment heterotypic interactions cooperate to promote tumor growth, angiogenesis and cancer cell motility through elevated secretion of pleiotropic chemokines. In this view proteins involved in DNA repair , cell death induction and metabolism are inhibited or shifted towards other pathways by soluble mediators that orchestrate such change redirected towards the survival of malignant phenotype. In particular we focus our attention on defined pathways that underlie the promotion, initiation and progression of the tumor conferring resistance and aggressiveness to the neoplastic cells. We report the behaviour and the non conventional function of DNA repair proteins Ku70 and 80 and clusterin isoforms in tumorigenesis and the overexpression and non physiological distribution of the metabolic tumor suppressor FAS. In tumorigenesis Ku70 and Ku80, proteins involved in DNA repair and apoptosis induction, paradoxically translocate from the nucleus to the cytoplasm where they sterically inhibit cell death induction binding Bax by the cooperative interaction with the overproduced s-clusterin. In fact in tumor progression the pattern shift of the production of the two isoforms of clusterin that display different functions one antagonist of the other is observed. The nuclear pro-apoptotic form is inhibited during tumorigenesis and the over-production of cytoplasmic and secreted form is closely linked to metastasis invasion. Therefore the dynamic interaction among Ku70, Bax and Clusterin seems to have an import role in tumor insurgence as in its progression. Focusing on the regulating role of one member with respect to the activity of the others, the observation of their expression and relationship in tumor progression models could provide important information on their contribution to tumor behavior. Moreover biochemical studies have demonstrated that one of the multiple differences between tumoral cells and healthy counterparts resides in the metabolic pathway, the uptake of glucose and the glycolitic process. The altered metabolism of neoplasia would favor an increased cell survival, promoting tumor size increase and cancer aggressiveness. To prevent an accumulation of fatty acids, special alterations take place during tumor formation. One metabolic cause is the loss of cytosolic glycerol 3-P dehydrogenase. Glycerol 3-P is the backbone of triglycerides. In tumor cells, the strong reduction of glycerol 3-P dehydrogenase leads to an increase in fatty acid release. The accumulation of dihydroxyacetone-P leads to an increased ether-linked glycerolipid synthesis. The release of fatty acids, the over expression of FAS and the accumulation of ether-linked lipids may protect tumor cells from immune attack. Cooperation through the sharing of diffusible products and the redirection of some specific guardian pathways raises new questions about tumorigenesis and has implication on designing new therapeutic approaches.