Neuroendocrine differentiation in the 12T-10 transgenic prostate mouse model mimics endocrine differentiation of pancreatic beta cells.
BACKGROUND
Neuroendocrine (NE) prostate cancer develops as an aggressive disease that does not respond to androgen ablation therapy. It has been demonstrated that the paracrine action of NE cells facilitates the progression of androgen dependent adenocarcinoma to an androgen independent state, suggesting a significant role for NE cells during failure of androgen ablation therapy.


METHODS
To investigate the pathways that are involved in NE differentiation of prostate cancer, we have looked at the expression of genes known to be involved in endocrine differentiation of beta-cells in the pancreas. This study has been performed using the NE prostate cancer mouse model (12T-10) and the derivative allograft model (NE-10).


RESULTS
Immunohistochemical studies have shown that the neuroendocrine prostate tumors express the transcription factors Foxa2, mouse achaete-scute homolog-1 (mash-1), neurogenin3 (Ngn3) and Nkx2.2. These tumors show a loss of hairy/enhancer of split (Hes-1), a gene that inhibits NE differentiation. Human NE prostate cancers also express Foxa2 and human achaete-scute homolog-1 (HASH-1). These genes are expressed in NE prostate tumors in the similar sequential manner as they appear in a pancreatic beta-cell endocrine differentiation. Foxa2 expression is detected in early prostatic intraepithelial neoplasia (PIN). Mash-1 expression is detected in a few clusters within low grade PIN lesions and Nkx2.2 expression is rarely detected in individual scattered cells within the PIN lesion. Ngn3 and Nkx2.2 frequently appear in the invasive NE cancer. Subsequent NE metastasis to lung and liver show a distinct gene expression pattern. The lung metastasis expresses Ngn3 but does not express Nkx2.2 whereas liver metastases do not express Ngn3 but express Nkx2.2.


CONCLUSIONS
These results suggest that Ngn3 and Nkx2.2 expression are markers for site-specific metastasis and/or transcriptionally regulated genes that are required for organ-specific metastasis. This study indicates that a pathway similar to pancreatic beta-cell differentiation is involved in NE differentiation of prostate cancer.
Gupta
Aparna
A
Department of Urologic Surgery, Vanderbilt University Medical Center, Nashville, Tennessee 37232-2765, USA.
Wang
Yongqing
Y
Browne
Christopher
C
Kim
Susan
S
Case
Tom
T
Paul
Manik
M
Wills
Marcia L
ML
Matusik
Robert J
RJ
D000230:Adenocarcinoma / Q000473:pathology / Q000503:physiopathology; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism; D014408:Biomarkers, Tumor / Q000235:genetics; D018278:Carcinoma, Neuroendocrine / Q000503:physiopathology / Q000556:secondary*; D018288:Carcinoma, Small Cell / Q000503:physiopathology / Q000556:secondary*; D002454:Cell Differentiation / Q000502:physiology; D004195:Disease Models, Animal; D015972:Gene Expression Regulation, Neoplastic; D051542:Hepatocyte Nuclear Factor 3-beta / Q000235:genetics / Q000378:metabolism; D000090322:Homeobox Protein Nkx-2.2; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000166:cytology*; D008114:Liver Neoplasms, Experimental / Q000503:physiopathology / Q000556:secondary; D008175:Lung Neoplasms / Q000503:physiopathology / Q000556:secondary; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008822:Mice, Transgenic; D009368:Neoplasm Transplantation; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009687:Nuclear Proteins; D011471:Prostatic Neoplasms / Q000473:pathology* / Q000503:physiopathology; D000072056:Transcription Factor HES-1; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D029961:Zebrafish Proteins
D051792:Basic Helix-Loop-Helix Proteins; D014408:Biomarkers, Tumor; D051542:Hepatocyte Nuclear Factor 3-beta; D000090322:Homeobox Protein Nkx-2.2; D018398:Homeodomain Proteins; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D000072056:Transcription Factor HES-1; D014157:Transcription Factors; D029961:Zebrafish Proteins; C499317:Ascl1 protein, mouse; C496503:Foxa2 protein, mouse; C489734:Hes1 protein, mouse; C000715631:NKX2-2 protein, human; C407737:Neurog3 protein, mouse; C000715627:Nkx2-2 protein, mouse; C000715630:nkx2.2b protein, zebrafish