Prostate tumor neuroendocrine differentiation via EMT: The road less traveled

The long-standing challenge in the treatment of prostate cancer is to overcome therapeutic resistance during progression to lethal disease.Aberrant transforming-growth factor-b(TGF-b)signaling accelerates prostate tumor progression in a transgenic mouse model via effects on epithelial-mesenchymal transition(EMT),and neuroendocrine differentiation driving tumor progression to castration-resistant prostate cancer(CRPC).Neuroendocrine prostate cancer(NEPC)is highly aggressive exhibiting reactivation of developmental programs associated with EMT induction and stem cell-like characteristics.The androgen receptor(AR)is a critical driver of tumor progression as well as therapeutic response in patients with metastatic CRPC.The signaling interactions between the TGF-β mechanistic network and AR axis impact the EMT phenotypic conversions,and perturbation of epithelial homeostasis via EMT renders a critical venue for epithelial derived tumors to become invasive,acquire the neuroendocrine phenotype,and rapidly metastasize.Combinations of microtubule targeting taxane chemotherapy and androgen/AR targeting therapies have survival benefits in CRPC patients,but therapeutic resistance invariability develops,leading to mortality.Compelling evidence from our group recently demonstrated that chemotherapy(cabazitaxel,second line taxane chemotherapy),or TGF-β receptor signaling targeted therapy,caused reversion of EMT to mesenchymal-epithelial transition and tumor re-differentiation,in in vitro and in vivo prostate cancer models.In this review,we discuss the functional contribution of EMT dynamic changes to the development of the neuroendocrine phenotypedthe newly characterized pathological feature of prostate tumors in the context of the tumor microenvironment-navigated cell lineage changes and the role of this neuroendocrine phenotype in metastatic progression and therapeutic resistance.

Mechanisms navigating the TGF-βpathway in prostate cancer

Few pharmacotherapies are currently available to treat castration resistant prostate cancer(CRPC),with low impact on patient survival.Transforming growth factor-b(TGF-b)is a multi-functional peptide with opposite roles in prostate tumorigenesis as an inhibitor in normal growth and early stage disease and a promoter in advanced prostate cancer.Dysregulated TGF-b signaling leads to a cascade of events contributing to oncogenesis,including upregulated proliferation,decreased apoptosis,epithelial-to-mesenchymal transition(EMT)and evasion of immune surveillance.TGF-b signaling pathway presents an appropriate venue for establishing a therapeutic targeting platform in CRPC.Exploitation of TGF-b effectors and their cross talk with the androgen axis pathway will provide new insights into mechanisms of resistance of the current antiandrogen therapeutic strategies and lead to generation of new effective treatment modalities for CRPC.Points of functional convergence of TGF-b with key oncogenic pathways,including mitogen-activated protein kinase(MAPK)and androgen receptor(AR),are discussed as navigated within the EMT landscape in the tumor microenvironment.In this context the emerging anti-TGF-b pharmacotherapies for prostate cancer treatment are considered.Targeting the functional cross-talk between the TGF-b signaling effectors with the androgen axis supports the development of novel therapeutic strategies for treating CRPC with high specificity and efficacy in a personalized-medicine approach.