Castration Agitating Neurotensin Paracrine Network In Microenviroment Promotes Neuroendocrine Differentiation In Prostate Cancer

Prostate cancer(PCa)with neuroendocrine differentiation(NED)can develop into high aggression and androgen independence that identified as castration resistant prostate cancer with NED(NeCRPC).The mechanism of NED in the development of castration-resistant prostate cancer(CRPC)remains indistinct.Also,there is lack of predictive and clinical classifying marker for distinguishing NeCRPC from other types of CRPC.Additionally,there is no standard treatment for patients with NeCRPC accounted for in part by its poorly understood mechanism.We uncovered neurotensin network in tumor microenvironment that drove NED following androgen-deprivation therapy(ADT).Neurotensin(NTS)is a secreted tridecapeptide,which is detectable in serum and function as a neurotransmitter or a neuromodulator.Although killing sensitive prostate cancer cells,ADT also triggered a parallel reaction leading to increased NTS production in cancer associated stromal cells through direct inhibiting androgen/androgen receptor(A/AR)signaling.While,the excessive stromal NTS stimulates certain tumor cells,CK8~+/CK14~+intermediate epithelial population that accumulated following ADT,undergoing NED via neurotensin receptor 1(NTSR1)-PRKACB and receptor 3(NTSR3)-AHNAK axes.Furthermore,we found the NTSR1 blocker could prevent NED in castrated tumor,and impede tumor regrowth in vivo.More interestingly,serum NTS level was positively correlated with NED in CRPC tumors,thus had irreplaceable advantages in predicting NeCRPC over serum PSA.Therefore,NTS is not only looked as an early predictor but also a potential therapy target for NeCRPC.