The Grand Challenges in GI Tract Cancers

StochaStic Modeling of tuMor ProgreSSion: gi tract cancerS aS a ParadigM Historically, the founding paradigm has been that cancers of the gastrointestinal tract are preceded by a pre-invasive stage of intraepithelial neoplasia. From the morphological standpoint the term “dysplasia” has been conventionally applied to the collection of changes in cellular morphology and tissue architecture that define intraepithelial neoplasia. Although morphologically different according to the specific GI tract anatomic location (Barrett-associated, gastritisand non-gastritis-associated, adenomatous and serrated dysplasia; Odze et al., 2010) the severity of intraepithelial neoplasia is estimated from the degree of deviation from the normal tissue of origin, and the neoplastic process has been thought to progress univocally toward carcinoma through dysplasia of increasing severity. There now exists evidence to construe the natural history of tumor progression in GI tract in accordance with a stochastic model, in which each stage is probabilistically linked with different evolutive pathways (progression, stabilization, regression) rather than deterministically associated with the onset of carcinoma (Risio, 2010). Moreover, even if biological reasons support dysplasia as the most predictive marker of the cancerization risk, the links between non-morphological features of precursors and their malignant transformation is greater than the one linking dysplasia and malignancy, at least in the colonic carcinogenesis. New biomarkers are therefore needed, to define the magnitude of risk and the times of progression for each step of tumorigenesis, in order to rationally schedule surveillance and follow-up of patients with diagnosed GI tract neoplasia and to plan suitable population-based cancer prevention interventions.