PRION PROTEIN EXPRESSION IN SURGICALLY RESECTED PANCREATIC DUCTAL ADENOCARCINOMA

Background Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal human cancers. The smoldering course of the disease and its severe propensity to spread along unconventional pathways call for establishing early biological markers. In particular a peculiar aspect of PDAC is its high neurotropism, highlighted by a notable rate of perineural invasion. Among the several possible new targets for the comprehension of the biology of PDAC, Prion proteins (PrP) deserve a particular mention. Prions are mainly known to be related to neurological disorders and neurodegenerative diseases thanks to their neurotropism, but evidences obtained in a variety of malignancy indicate that they could have a role also in tumorigenesis, in tumor stemness, invasiveness and resistance to chemotherapy. Some recent manuscripts investigated the molecular mechanisms which links the expression and abundance of PrP within tumor cells and the activation of genes involved in cell proliferation and migration. In particular, few in vitro studies in cell cultures showed the occurrence of PrP in PDAC cells, while it was absent in normal pancreatic cell lines; however, no study so far investigated in vivo the occurrence of PrP within PDAC. The aim of this study is to evaluate the presence of PrP in PDAC tissue as possible marker of specific biological behavior. Methods Samples from tumors of 16 patients undergone pancreatic resections from July 2018 to May 2019 at our institution were collected. Immunohistochemistry and western blotting of PDAC tissues were compared with control tissues, such as those of non-affected neighboring areas of the same patient. Immunohistochemistry was used also to evaluate the localization of PrP and of a tumoral stem-cell marker, CD155. Results All patients were affected by moderately differentiated PDAC. Perineural invasion was reported in 12/16 cases (75%). Both immunohistochemistry and western blotting revealed the exclusive staining of PrP on ductal cells, as a specific in situ marker of ductal compartment. According to the western-blot analysis, PrP was markedly expressed in tumor pancreatic tissues (438,61 ± 55,41 OD) respect to controls (100 ± 16,97 OD, p<0,001). Immunohistochemistry confirmed these findings: the linear staining of PrP in pancreatic ducts was 125±12.51 µm, while in controls it was 79,5±6,4 µm (p<0.001). Finally, we found a co-localization of PrP and CD155 in ductal tumoral cells, highlighting the possible relationship of PrP with cancer stemness and dedifferentiation. Conclusions PrP is markedly expressed in surgically resected PDAC tissues respect to control areas and it is found exclusively in the ductal compartment. Moreover, the labeling of PrP exactly overlapped with that of CD155, a stem cell marker which has been found to correlate with cancer cells dedifferentiation and aggressiveness. Given these results, PrP could be considered as a new potential marker for PDAC and might contribute to explain the biology of this disease, in particular some peculiar characteristics such as its marked neurotropism. Further studies are necessary to validate these findings and to investigate the possible clinical implications