ATP7B IMMUNOREACTIVE IN MALIGNANT NEOPLASIA: A POSSIBLE PROGNOSTIC AND CHEMORESISTANCE MARKER

Cisplatin is one of the most potent antitumor agents known, displaying clinical activity against a wide variety of solid tumors. Its cytotoxic effect is a consequence of its interaction with DNA evidenced by the presence of DNA adducts and by the activation of several signal transduction pathways that culminate in the activation of apoptosis. DNA damage-mediated apoptotic signals, however, can be attenuated, and the resistance that ensues is the major limitation of cisplatin-based chemotherapy. Recent studies suggest that copper-transporting P-type adenosine triphosphatase protein (ATP7B), also known as Wilson’s disease protein, could be one of the possible mechanism responsible of this cisplatin-chemoresistance, preventing its toxic effect. This study aims at verifying this hypothesis in two type of malignant neoplasia in order to underline a possible uses of ATP7B as a chemoresistance marker. This research began studing the ATP7B immunoreactivity with polyclonal antibodies commercially available, in several selected cases of colon adenocarcinomas, which, as everyone knows, show an intrinsic resistance to cisplatin based chemotherapy. Our goal has been to identify ATP7B immunoreactivity in the most part (97%) of colon adenocarcinomas cases studied, so it could be conceivably that cisplatin resistance of colon adenocarcinoma is directly correlated with the presence of positive tumor cells percentage for ATP7B. These findings suggested that the ATP7B expression could be considered an intrinsic chemoresistance marker against cisplatin in patients with colon adenocarcinomas and its use in clinical practice might be directed to identify the 3% of negative cases, which could be sensitive to cisplatin based chemotherapy. The second part of the research investigated if ATP7B is expressed in head and neck squamous cell carcinoma, in which treatment cisplatin is one of chemotherapeutic drug of choice, and whether its expression correlates with reduced responsiveness to cisplatin treatment. This study was performed using a double-blind control procedure: with the collaboration of the oncologist, the cisplatin chemotherapy and the ATP7B immunohistochemistry was performed without to know before the cisplatin responsivity or the ATP7B response. A certain variability of ATP7B expression was observed in 21 cases and in 10 cases it was not detected. A very interesting evidence has stated that all patients with ATP7B-positive tumors had a significantly inferior response to cisplatin chemotherapy if compared to patients with ATP7B negative tumors. So our data suggest that cisplatin resistance of a part of head and neck squamous cell carcinomas is directly correlated with the presence of positive tumor cells percentage for ATP7B immunostaining. Therefore the ATP7B overexpression could be considered a chemoresistance marker against cisplatin in patients with head and neck squamous cell carcinomas. The data obtained suggest that the overexpression of ATP7B is correlated with cisplatin chemoresistance and that is another evidence to support the possibility to introduce ATP7B immunohistochemistry in clinical practice as a chemoresistance marker of head and neck squamous cell carcinoma. All together these informations should help the oncologist to plan a more customized polichemotherapy for each patient, reducing the toxic effects of unresponsive drugs.