Interplay of tissue microenvironment and cellular DNA damage response machinery in genome (in)stability and senescence in inflammation and cancer

Konference: 2013 The 9th Symposium & Workshop on Molecular Pathology and Histo(cyto)chemistry

Kategorie: Nádorová biologie/imunologie/genetika a buněčná terapie

Téma: Invited guests

Číslo abstraktu: 02

Autoři: Prof. MUDr. Jiří Bártek, Ph.D.

Recent advances in research on molecular mechanisms underlying major human pathologies such as chronic inflammation and cancer point to an intimate interplay between factors in tissue microenvironment and intracellular pathways including the genome maintenance machinery, often referred to as the DNA damage response (DDR). This lecture will summarize our most recently published and unpublished results that provide novel tools to assess the tissue pathology processes and the status of cellular senescence and DNA damage signaling, as well as unexpected mechanistic insights into the pathways and genes that are critical for suppression of chromosomal instability and cancer. Emphasis will be on the interplay of cytokine signaling, oxidative stress caused by reactive oxygen species and nitric oxide as factors important in inflammatory pathologies and senescence, in the interplay with cellular DNA damage response network governed by the ATM/ATR kinases and their many targets. In terms of disease focus, inflammatory bowel disease and colorectal cancer will be used as examples of human pathologies in which cytokine signaling, cellular senescence and genome/chromosome instability play key roles. Furthermore, given the focus of the conference, we will discuss our efforts to introduce and validate various markers of cellular senescence, with particular emphasis on attempts to optimize detection in routine formalin-fixed, paraffinembedded tissues. A new marker shared by cells undergoing all forms of senescence (replicative, oncogeneinduced and drug-induced senescence) that we believe to be superior to the classical beta-galactosidae marker and also suitable for detecting senescent cells in routinely processed, paraffin tissues. Cellular defences against oxidative DNA damage will also be discussed, with focus on differences between cancer stem cells and the bulk of tumour cells (here using human glioblastoma as an example), revealing stem cell vulnerability that could be exploited in targeted therapy.

Datum přednesení příspěvku: 26. 4. 2013