The PI3K/AKT Pathway Is Activated by HGF in NT2D1 Non-Seminoma Cells and Has a Role in the Modulation of Their Malignant Behavior.

Overactivation of the c-MET/HGF system is a feature of many cancers. We previously reported that type II testicular germ cell tumor (TGCT) cells express the c-MET receptor, forming non-seminomatous lesions that are more positive compared with seminomatous ones. Notably, we also demonstrated that NT2D1 non-seminomatous cells (derived from an embryonal carcinoma lesion) increase their proliferation, migration, and invasion in response to HGF. Herein, we report that HGF immunoreactivity is more evident in the microenvironment of embryonal carcinoma biopsies with respect to seminomatous ones, indicating a tumor-dependent modulation of the testicular niche. PI3K/AKT is one of the signaling pathways triggered by HGF through the c-MET activation cascade. Herein, we demonstrated that phospho-AKT increases in NT2D1 cells after HGF stimulation. Moreover, we found that this pathway is involved in HGF-dependent NT2D1 cell proliferation, migration, and invasion, since the co-administration of the PI3K inhibitor LY294002 together with HGF abrogates these responses. Notably, the inhibition of endogenous PI3K affects collective cell migration but does not influence proliferation or chemotactic activity. Surprisingly, LY294002 administered without the co-administration of HGF increases cell invasion at levels comparable to the HGF-administered samples. This paradoxical result highlights the role of the testicular microenvironment in the modulation of cellular responses and stimulates the study of the testicular secretome in cancer lesions.

International journal of molecular sciences. 2020 Nov 17*** epublish ***

Luisa Gesualdi, Erica Leonetti, Alessandra Cucina, Bianca Maria Scicchitano, Silvia Sorrentino, Maria Grazia Tarsitano, Andrea Isidori, Mariano Bizzarri, Antonio Filippini, Anna Riccioli, Marcella Cammarota, Vincenzo Gigantino, Giulia Ricci, Angela Catizone

Section of Histology and Medical Embryology, Department of Anatomy, Histology, Forensic-Medicine and Orthopedics, "Sapienza" University of Rome, 00161 Rome, Italy., Department of Surgery "Pietro Valdoni", "Sapienza" University of Rome, 00161 Rome, Italy., Istituto di Istologia ed Embriologia, Dipartimento di Scienze della Vita e Sanità Pubblica, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy., Department of Experimental Medicine, "Sapienza" University of Rome, 00161 Rome, Italy., Department of Experimental Medicine, Università degli Studi della Campania "Luigi Vanvitelli", 80138 Naples, Italy., Istituto Nazionale Tumori IRCCS "Fondazione G. Pascale", 80131 Naples, Italy.

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