Intratumorska heterogenost ekspresije katepsina D, ciklina D1, nm23 i nm23 H1 gena u planocelularnom karcinomu grkljana [ Intratumoral heterogeneity of cathepsin D, cyclin D1, nm23 and nm23H1 gene expression in laryngeal squamous cell carcinoma ]

Intratumoral heterogeneity is defined as the parallel existence of diploid and aneuploid clones as well as different abnormal cell lines within a given tumor. This implies that different tumor parts express different behavior (e.g. propensity to invade or metastasize, resistance against chemo- or radiotherapy). One of the most important goals of different investigations is to predict the biological behavior of tumors. Current investigations mostly neglect intratumoral heterogeneity in general and completely ignore the possibility of regional intratumoral heterogeneity. The goals of my investigation, performed on a group of 170 patients with laryngeal cancer undergoing partial or complete laryngectomy were to define intratumoral heterogeneity of cyclin D1, cathepsin D and nm23 protein as well as nm23H1 gene in three different tumor regions (tumor center, invasive margin and transformation region), to establish potential prognostic significance of regional factors and to establish potential correlation between the investigated factors and classical prognostic factors (T, N, M, histological grade). Taken together the results of this study give some intriguing answers to the above questions. It was clearly shown that the intratumoral heterogeneity is not a diffuse, random event, but that there is a clear areal distribution of immunoreactivity to cathepsin D and cyclin D1, with the invasive margin expressing the strongest immunoreactivity followed by the tumor center. There is positive correlation for expression of cathepsin D in tumor cells with T (p=0,003), and negative correlation for stromal expression of cathepsin D with T (p=0,006), N (p=0,01) and histological grade (p=0,02). Areal expression of cathepsin D and cyclin D1 showed prognostic significance on Kaplan-Meier curves (cathepsin D (p=0,001) cyclin D1 (p=0,008)). Using RPART statistics the expression of cathepsin D in tumor stromal cells of tumor center was demonstrated as being a classificator equal to standard prognostic parameters.