Aggressive variants of prostate cancer: underlying mechanisms of neuroendocrine transdifferentiation

Merkens, Lina; Sailer, Verena; Lessel, Davor; Janzen, Ella; Greimeier, Sarah; Kirfel, Jutta; Perner, Sven; Pantel, Klaus; Werner, Stefan; von Amsberg, Gunhild

doi:10.1186/s13046-022-02255-y

Journal of Experimental & Clinical Cancer Research

Table 1 Summary of factors involved in t-NEPC development

From: Aggressive variants of prostate cancer: underlying mechanisms of neuroendocrine transdifferentiation

Gene (Protein, if not identical)	Aberration in t-NEPC	Effects	Experimental Setting/ Source	Reference
Genetic aberrations
PTEN	Deletion	Survival and cell cycle progression	Patient tissue biopsies	[27, 28]
TP53	Mutation	Lineage plasticity	Patient tissue biopsies	[28]
RB1	Deletion	Lineage plasticity	Patient tissue biopsies	[28]
AURKA	Amplification	N-MYC stabilization, cell cycle progression	Patient tissue biopsies	[29]
MYCN	Amplification	Attenuation of AR signaling, NE differentiation, DDR activation	Patient tissue biopsies	[29,30,31]
Transcription factors
ASCL1	Induced expression	NE/pro-neural differentiation	Patient tissue biopsies	[32]
FOXA1	Reduced expression	Loss of Epithelial differentiation	Patient tissue biopsies	[33]
FOXA2	Upregulated expression	Pioneering transcription factor, promotion of NE differentiation	Patient tissue biopsies	[34]
FOXB2	Upregulated expression	Activation of WNT-signaling, NE marker expression	Patient tissue biopsies	[35]
NKX2-1 (TTF-1)	Upregulated expression	unknown	Patient tissue biopsies	[36]
NKX3-1	Reduced expression	Loss of Epithelial differentiation	Patient tissue biopsies	[37]
REST	Reduced expression, alternative splicing	De-repression of neuronal genes, NE differentiation	Patient tissue biopsies	[32]
ONECUT2	Upregulated expression	Attenuation of AR signaling, survival	Patient tissue biopsies	[38]
POU3F2 (BRN2)	Upregulated expression	NE differentiation, lineage plasticity	Patient tissue biopsies	[39]
POU3F4 (BRN4)	Upregulated expression	NE differentiation	Patient tissue biopsies, PDX	[40]
SOX2	Upregulated expression	Lineage plasticity	Patient tissue biopsies	[32]
ZBTB46	Upregulated expression	NE differentiation, EMT, inflammatory signaling	Patient tissue biopsies	[41]
Epigenetic factors
EZH2	Upregulated expression	Angiogenesis, NE differentiation	Patient tissue biopsies	[19]
PHF8	Upregulated expression	NE differentiation	Patient tissue biopsies, PDX	[42]
KDM1A (LSD1)	Alternative splicing	Cancer progression, therapy resistance, immune signaling	Patient tissue biopsies, PDX	[43]
MEAF6	Alternative splicing	Proliferation, anchorage-independent cell growth	Patient tissue biopsies, PDX	[44]
SMARCA4	Upregulated expression	Cell cycle progression, aggressiveness	Patient tissue biopsies	[45]
CBX5 (HP-1a)	Upregulated expression	Repression of luminal differentiation	Patient tissue biopsies, PDX	[46]
DNA repair pathways
PARP1	Upregulated expression	DDR	Patient tissue biopsies, PDX	[30]
SLFN11	Reduced expression	Cell cycle progression	Patient tissue biopsies	[47]
Other nuclear factors
CCND1	Upregulated expression	survival	Cell model	[48]
CCND1	Reduced expression	unknown	Patient tissue biopsies	[49]
LIN28B	Upregulated expression	Stemness and pluripotency/lineage plasticity	Patient tissue biopsies	[21]
PEG10	Upregulated expression	Cell cycle progression, EMT	Patient tissue biopsies	[32]
SRRM4	Upregulated expression	NE differentiation	Patient tissue biopsies	[50]
GIT1	Alternative splicing, GIT1-A upregulation	Neural differentiation, cell adhesion	Patient tissue biopsies, PDX	[51]
BIF1	Alternative splicing, BIF1b/c upregulation	Survival	Patient tissue biopsies, PDX	[52]
BHC80	Alternative splicing, BHC80-2 upregulation	Cell growth and invasion	Patient tissue biopsies, PDX	[53]
Signaling pathways
mTOR	Increased activity	NE differentiation, reduced growth, increased one-carbon pathway	NEPC cell model	[54]
PRKCI	Reduced expression	Cell proliferation, increased one-carbon pathway	Patient tissue biopsies	[55]
STAT3	Increased activity	NE differentiation, proliferation	Cell model	[23]
LIFR	Upregulated expression	NE differentiation, cell proliferation	Patient tissue biopsies	[56]
WNT7B	Upregulated expression	Tumor growth, stemness, drug resistance	Patient tissue biopsies	[35]
WNT11	Upregulated expression	Promotion of NE differentiation, survival migration	AR- independent Cell model and xenografts	[57, 58]
WLS	Upregulated expression	Promotion of Wnt signaling, proliferation, NE differentiation	Patient tissue biopsies	[59]
PCDH-PC	Upregulated expression	Wnt activation, NE differentiation	Patient tissue biopsies	[60, 61]
CREB1	Increased activation	NE differentiation, angiogenesis, epigenetic reprogramming	Cell model	[62]
RET	Upregulated expression	Tumor growth	Patient tissue biopsies	[63]
Tumor microenvironment
cAMP	Increased concentration	NE differentiation, angiogenesis, epigenetic reprogramming	Cell model	[64]
Glutamine	Increased concentration	ATP production, proliferation, NE differentiation	Cell model	[65]
IL-6	Increased concentration	NE differentiation, angiogenesis	Cell model	[64]
IL-8	Upregulated expression	Survival, proliferation	Cell model	[66]
GRPR/bombesin	Upregulated expression	Angiogenesis	Cell model	[67]
BIRC5 (Survivin)	Upregulated expression	Survival	Patient tissue biopsies	[68]
NTS (Neurotensin)	Upregulated expression	NE differentiation	Cell model and xenograft	[69]
PTHrH	Upregulated expression	Cell proliferation, treatment-resistance	Cell model	[70]
CALCA (Calcitonin)	Upregulated expression	Invasion	Cell model	[71]
QRFP (Neuropeptide 26RFa)	Upregulated expression	NE differentiation, migration	Patient tissue biopsies	[72]
ADM (Adrenomedullin)	Upregulated expression	NE differentiation	Cell model	[73]
ADCYAP1 (Pituitary adenylate cyclase activating polypeptide)	Upregulated expression	Cell proliferation, NE differentiation	Cell model	[74]
GABA	Upregulated expression	GRP release	Cell model	[75]

For genes and proteins presented in this review key information regarding their aberration in t-NEPC and the cellular effects of these aberrations are summed up. The experimental setting refers to the most reliable type of data in which the respective aberration has been found (Patient tissue biopsies > PDX > xenografts > cell model)

Back to article page

ISSN: 1756-9966

Contact us

Submission enquiries: Access here and click Contact Us
General enquiries: info@biomedcentral.com