”CELLULAR SENESCENCE IN TUMORS AND REGENERATIVE PATHOLOGY”

Fibroproliferative wound healing represents a major pathology in elderly people shifting regular organ development into rogressive organ fibrosis with complete loss of organ function. RESOLVE is an European project that aims to create suitable treatment strategies to achieve healthy ageing in the elderly. In doing so, RESOLVE will create a significant impact on life quality of elderly people. The study proposal of this first part of work was assess the fibrotic process in two different experimental lung mice models: (1) fibrosis from hypersensitivity, (2) fibrosis induced by bleomycin, and to assess two different models of liver regeneration: (1) “regular wound healing”of the liver as provided by two-third partial hepatectomy (2/3 PH) (2) the “fibroproliferative wound healing” after inducing hepatic fibrosis by CCl4 treatment. Furthermore we know that cells are exposed to various types of stress, such as oncogenic events. Several cell-intrinsic mechanisms, however, are in place to limit the expansion of cancer cells. In addition to cell death programmes such as apoptosis and autophagy, oncogeneinduced senescence (OIS) is increasingly recognized as a potent barrier against oncogenic transformation, suppressing the uncontrolled proliferation of neoplastic cells. OIS is considered a premature form of cellular senescence, which is unresponsive to growth factors. It’s has been hypotized that OIS is triggered by a number of “counting mechanisms,”such as telomere shortening, which have been investigated at molecular level. Notably, the mechanisms underlying cellular senescence are involved in protection against cancer and also may be involved in organismal aging. OIS comprises the activation of tumour suppressor pathways, including the cytostatic INK4A–retinoblastoma (RB) and ARF–p53 signalling cascades. In the light of these notions, our aim was to investigate first the relations between fibrosis and senescence in mice tissue and than to investigate senescence and autophagy in human tissues focusing on chronic inflammatory and fibrogenetic diseases (idiopathic pulmonary fibrosis, IPF) and neoplastic processes (hodgkin's lymphoma (HD), histiocytosis x and angiomyolipoma of the kidney (AML)). Finally we investigated markers for autophagy and senescence in angiomyolipome to assess if autophagy and senescence can be connacted.