Genetic deletion of osteopontin in TRAMP mice skews prostate carcinogenesis from adenocarcinoma to aggressive human-like neuroendocrine cancers

// Giorgio Mauri 1 , Elena Jachetti 1 , Barbara Comuzzi 1 , Matteo Dugo 2 , Ivano Arioli 1 , Silvia Miotti 1 , Sabina Sangaletti 1 , Emma Di Carlo 3, 4 , Claudio Tripodo 5 , Mario P. Colombo 1 1 Molecular Immunology Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale Tumori, 20133, Milano, Italy 2 Functional Genomics and Bioinformatics, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale Tumori, 20133, Milano, Italy 3 Department of Medicine and Science of Aging, Section of Anatomic Pathology and Molecular Medicine, “G. d’Annunzio” University, 66100, Chieti, Italy 4 Ce.S.I. Aging Research Center, “G. d’Annunzio” University Foundation, 66100, Chieti, Italy 5 Tumor Immunology Unit, Department of Health Sciences, University of Palermo, 90127, Palermo, Italy Correspondence to: Mario P. Colombo, e-mail: mariopaolo.colombo@istitutotumori.mi.it Keywords: prostate cancer, extracellular matrix, osteopontin, neuroendocrine Received: November 18, 2015      Accepted: November 23, 2015      Published: December 19, 2015 ABSTRACT Osteopontin (OPN) is a secreted glycoprotein, that belongs to the non-structural extracellular matrix (ECM), and its over expression in human prostate cancer has been associated with disease progression, androgen independence and metastatic ability. Nevertheless, the pathophysiology of OPN in prostate tumorigenesis has never been studied. We crossed TRansgenic Adenocarcinoma of the Mouse Prostate (TRAMP) mice with OPN deficient (OPN −/− ) mice and followed tumor onset and progression in these double mutants. Ultrasound examination detected the early onset of a rapidly growing, homogeneous and spherical tumor in about 60% of OPN −/− TRAMP mice. Such neoplasms seldom occurred in parental TRAMP mice otherwise prone to adenocarcinomas and were characterized for being androgen receptor negative, highly proliferative and endowed with neuroendocrine (NE) features. Gene expression profiling showed up-regulation of genes involved in tumor progression, cell cycle and neuronal differentiation in OPN-deficient versus wild type TRAMP tumors. Down-regulated genes included key genes of TGFa pathway, including SMAD3 and Filamin, which were confirmed at the protein level. Furthermore, NE genes and particularly those characterizing early prostatic lesions of OPN-deficient mice were found to correlate with those of human prostate NE tumours. These data underscore a novel role of OPN in the early stages of prostate cancer growth, protecting against the development of aggressive NE tumors.