title: Neuroendocrine Transdifferentiation in Human Prostate Cancer Cells: An Integrated Approach.
abstract: Prostate cancer is highly sensitive to hormone therapy because androgens are essential for prostate cancer cell growth. However, with the nearly invariable progression of this disease to androgen independence, endocrine therapy ultimately fails to control prostate cancer in most patients. Androgen-independent acquisition may involve neuroendocrine transdifferentiation, but there is little knowledge about this process, which is presently controversial. In this study, we investigated this question in a novel model of human androgen-dependent LNCaP cells cultured for long periods in hormone-deprived conditions. Strikingly, characterization of the neuroendocrine phenotype by transcriptomic, metabolomic, and other statistically integrated analyses showed how hormone-deprived LNCaP cells could transdifferentiate to a nonmalignantneuroendocrine phenotype. Notably, conditioned media from neuroendocrine-like cells affected LNCaP cell proliferation. Predictive in silico models illustrated how after an initial period, when LNCaP cell survival was compromised by an arising population of neuroendocrine-like cells, a sudden trend reversal occurred in which the neuroendocrine-like cells functioned to sustain the remaining androgen-dependent LNCaP cells. Our findings provide direct biologic and molecular support for the concept that neuroendocrine transdifferentiation in prostate cancer cell populations influences the progression to androgen independence.
authors.affiliation: University of Portsmouth, Department of Mathematics, Hampshire, United Kingdom.
authors.forename: Marianna
authors.initials: M
authors.lastname: Cerasuolo
authors.affiliation: Endocannabinoid Research Group, Institute of Biomolecular Chemistry, National Research Council of Italy, Pozzuoli, Italy.
authors.forename: Debora
authors.initials: D
authors.lastname: Paris
authors.affiliation: Endocannabinoid Research Group, Institute of Biomolecular Chemistry, National Research Council of Italy, Pozzuoli, Italy.
authors.forename: Fabio A
authors.initials: FA
authors.lastname: Iannotti
authors.affiliation: Endocannabinoid Research Group, Institute of Biomolecular Chemistry, National Research Council of Italy, Pozzuoli, Italy.
authors.forename: Dominique
authors.initials: D
authors.lastname: Melck
authors.affiliation: Endocannabinoid Research Group, Institute of Biomolecular Chemistry, National Research Council of Italy, Pozzuoli, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Verde
authors.affiliation: Endocannabinoid Research Group, Institute of Biomolecular Chemistry, National Research Council of Italy, Pozzuoli, Italy.
authors.forename: Enrico
authors.initials: E
authors.lastname: Mazzarella
authors.affiliation: Endocannabinoid Research Group, Institute of Biomolecular Chemistry, National Research Council of Italy, Pozzuoli, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Motta
authors.affiliation: Endocannabinoid Research Group, Institute of Biomolecular Chemistry, National Research Council of Italy, Pozzuoli, Italy. aligresti@icb.cnr.it.
authors.forename: Alessia
authors.initials: A
authors.lastname: Ligresti
mesh_terms: D000465:Algorithms; D000728:Androgens / Q000378:metabolism; D054338:Cell Transdifferentiation / Q000187:drug effects; D016000:Cluster Analysis; D017077:Culture Media, Conditioned / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008962:Models, Theoretical; D010641:Phenotype; D016133:Polymerase Chain Reaction; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D014407:Tumor Cells, Cultured
chemical_list: D000728:Androgens; D017077:Culture Media, Conditioned