Table 2.

Secreted factors from neuroendocrine cells and potential roles in PC pathobiology.

Symbol	Name	Role	Reference
CgA	Chromogranin A	• Marker for NED • Elevated serum level is associated with poor prognosis and is inversely correlated with overall survival in men with CRPC.	(54, 55)
CgB	Chromogranin B	• Marker for NED • Involved in PC transdifferentiation	(56, 57)
SYP	Synaptophysin	• Marker for NED • Detected in circulating tumor cells of CRPC patients and the expression levels directly correlates with abiraterone and enzalutamide resistance.	(58)
ENO2	Enolase 2	• Isoenzyme of the glycolytic enzyme enolase. • Marker of NEPC; upregulated as a result of IL8 mediated downregulation of FOXA1	(59, 60)
SCGN	Secretagogin	• Neuroendocrine marker • Correlates with an increased risk of disease relapse after radical prostatectomy	(61, 62)
NPY	Neuropeptide Y	• Growth promoting factor in various malignancies. • Key regulator of energy metabolism in PC cells. • NPY neural axis regulates cancer cell survival, metabolism, and therapy resistance.	(63)
CGRP	Calcitonin-gene related peptide	• Increase invasiveness and promoting tumor growth in bone microenvironment.	(64, 65)
CT	Calcitonin	• Elevated in advanced prostate cancer along with calcitonin receptor (CTR). • CT-CTR axis promotes PC cell growth, invasion and epithelial-to-mesenchymal transition (EMT).	(8) (66, 67)
NTS	Neurotensin	• Expressed in LnCaP cells as a response to androgen-withdrawal. • Induces tumor cell transdifferentiation to NE-like cells through (NTSR1/3) signaling. • NTSR1 also has a frequently elevated expression in metastatic lymph nodes	(68)
AM	Adrenomedullin	• Expressed in LnCaP cells as a response to androgen withdrawal and maintains a NE phenotype. • Supports hormone independent tumor growth and neovascularization by supplying/amplifying signals for neoangiogenesis and lymphangiogenesis.	(69) (70)
IL8	Interleukin 8	• Expressed in both benign and malignant NE cells. • Increased expression associated with reduced FOXA1 expression in NEPC cells. • Paracrine and autocrine effects: cell survival and proliferation; NED.	(71) (72, 73)
GRP	Gastrin releasing peptide (mammalian homologue of bombesin)	• Increased expression as a response to androgen withdrawal, activates the GRP/GRP-receptor (GRP-R) pathway, in turn activating the NF-κB and increased levels of AR-splice variant (AR-V7). • GRPR expression also amplifies in CRPC.	(74) (75)
SS	Somatostatin	• Inhibits cytokine release from immune cells. • Somatostatin receptor scintigraphy (SRS) can identify NE features in prostate cancer and identify metastatic lesions.	(76–79)
VIP	Vasoactive intestinal peptide	• Increases expression of VEGF. • Induces NE differentiation in LnCaP cells through PKA, ERK1/2 and PI3K signaling.	(80, 81)
VEGF	Vascular endothelial growth factor	• Increased expression associated with a more aggressive phenotype by aiding in neovascularization of carcinomas. • Increased metastasis to lymph nodes	(82, 83)
PTHrP	Parathyroid hormone related protein	• Enhances proliferation of LnCaP cells at low levels of androgen, by stabilizing the AR protein through tyrosine phosphorylation and preventing ubiquitination. • Induces epithelial-to-mesenchymal transition (EMT) in prostate cancer cells along with promoting invasion, tumorigenicity and metastasis. • Protection of neighboring prostate cancer cells from Docetaxel (Doc) induced apoptosis. • Positively regulates bone marrow microenvironment, increasing the angiogenic potential and tumor growth.	(84) (85–87)
HCG	Human chorionic gonadotropin	• Associated with poor prognosis in PC patients. • Promotes cell migration and invasion via promoting ERK1/2 phosphorylation and MMP-2 upregulation in DU145 cells.	(88, 89)
5-HT	Serotonin	• Cell growth factor for PC cells. • Promotes dedifferentiation of LnCaP cells by maintaining an increased level of cAMP. • Activates MAPK/Erk and PI3K/Akt pathways to induce proliferation, migration, and differentiation.	(90, 91)
CCK	Cholecystokinin	• Induced by cysteine protease cathepsin B (CTSB) • Supports self-renewal of PC stem cells (CSCs)	(92)