Research ???Area
Department of Experimental Oncology
Transcriptional Control in Inflammation and Cancer Gioacchino Natoli, MD, PhD Director
STAFF Post-doctoral Fellows: Liv M. I. Austenaa PhD, Greta Caprara PhD, Francesca De Santa PhD, Serena Maria Luisa Ghisletti PhD, Luca Giorgetti PhD, Flore Mietton PhD PhD Students: Iros Giacomo Barozzi, Xuefen Chen, Agnese Collino, Betsabeh Khoramian Tusi, Samuele Notarbartolo Technician: Elena Prosperini Temporary Fellow: Sara Polletti
Activities 2011.
Chronic inflammation and cancer. Inflammation is a basic response to environmental and endogenous “danger signals” and serves an essential homeostatic and therefore beneficial role. At the same time, as demonstrated by a large body of epidemiological and experimental data, chronic and unresolved inflammation promotes the development of several types of epithelial cancers worldwide, including hepatocarcinomas, colon carcinomas, gastric and prostate cancer. Cancer development in chronically inflamed tissues is often preceded by specific alterations of tissue differentiation, as in the case of intestinal metaplasia of gastric mucosa in patients with chronic gastritis, and Barrett’s esophagus (squamous metaplasia) in patients with gastro-esophageal reflux disease. Such alterations of tissue differentiation are entirely reversible as their mechanistic basis is represented by epigenetic (non DNA sequence-based) alterations of chromatin and a subsequent change in the accessibility and usage of the underlying genome. Experimental data suggest that polyclonal epigenetic changes associated with chronic inflammation may lay the ground for the acquisition of clonal genetic changes leading to tumor development. Defining mechanisms that control inflammatory responses (and particularly sustained inflammation) may lead to the identification of novel cancer chemopreventive treatments, as suggested by the protective role of aspirin towards some tumor types. Research activity in the laboratory is mainly focused on the understanding at the molecular level the mechanisms that control inflammatory gene expression. Transcriptional control of inflammation. Inflammation entails the induction (or repression) of hundreds of genes whose products contribute to different aspects of the response, such as the recruitment of leukocytes, the induction of changes in vascular permeability, the activation of anti-bacterial responses, and in a
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subsequent step the induction of the repair response leading to reconstitution of tissue integrity. The first objective of the lab is the mechanistic understanding of transcriptional regulation of inflammatory genes both in inflammatory cells (like macrophages) and in bystander cells exposed to an inflammatory environment. An indepth understanding of such mechanisms may provide the molecular basis for therapeutic targeting of selected transcriptional events. To achieve these objectives, standard biochemical approaches to transcription are integrated with genomics, computational approaches, physics and in vivo studies.
Mechanisms controlling inflammatory gene expression in macrophages. Most of the research tackled by the laboratory relates to one of the most important cell types involved in inflammation, namely macrophages. Macrophages are highly specialized cells widely distributed in tissues and active both as immune effectors and as housekeeping phagocytes responsible for maintenance of tissue integrity. Macrophages display a striking heterogeneity that reflects a complex interplay between different micro-environmental signals provided by various tissues (as well as by microbial and endogenous stress signals), and a robust differentiation program that determines macrophage identity. The
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