Different profiles of neuroendocrine cell differentiation evolve in the PC-310 human prostate cancer model during long-term androgen deprivation.

Abstract

BACKGROUND:

Neuroendocrine (NE) cells are androgen-independent cells and secrete growth-modulating peptide hormones via a regulated secretory pathway (RSP). We studied NE differentiation after long-term androgen withdrawal in the androgen-dependent human prostate cancer xenograft PC-310.

METHODS:

Tumor-bearing nude mice were killed at 0, 2, 5, 7, 14, 21, 47, 84, and 154 days after castration. The half-life of the PC-310 tumor was 10 days, with a stable residual tumor volume of 30--40% after 21 days and longer periods of androgen deprivation.

RESULTS:

Proliferative activity and prostate-specific antigen serum levels decreased to zero after castration, whereas cell-cycle arrest was manifested by increased p27(kip1) expression. A temporary downregulation of androgen receptor (AR) expression was noted after androgen deprivation. The expression of chromogranin A, secretogranin III, and secretogranin V (7B2) increased 5 days after castration and later. Subsequently, pro-hormone convertase 1 and peptidyl alpha--amidating monooxygenase as well as vascular endothelial growth factor were expressed from 7 days after castration on. Finally, such growth factors as gastrin-releasing peptide and serotonin were expressed in a small part of the NE cells 21 days after castration, but strong expression was induced late during androgen deprivation, that is, 84 and 154 days after castration, respectively.

CONCLUSIONS:

Androgen deprivation of the NE-differentiated PC-310 model induced the formation of NE-differentiated AR(minus sign) and non-NE AR(+) tumor residues. The NE-differentiated cells actively produced growth factors via an RSP that may lead to hormone-refractory disease. The dormant non-NE AR(+) tumor cells were shown to remain androgen sensitive even after long-term androgen deprivation. In the PC-310 xenograft, time-dependent NE differentiation and subsequent maturation were induced after androgen depletion. The androgen-dependent PC-310 xenograft model constitutes an excellent model for studying the role of NE cells in the progression of clinical prostate cancer.

• Authors: Johan Jongsma, Monique H Oomen, Marinus A Noordzij, Wytske M Van Weerden, Gerard J M Martens, Theodorus H van der Kwast, Fritz H Schröder, Gert J van Steenbrugge
• Journal: The Prostate (Prostate) Vol. 50 Issue 4 Pg. 203-15 (Mar 01 2002) ISSN: 0270-4137 [Print] United States
• PMID: 11870798 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright 2002 Wiley-Liss, Inc.

Chemical References

• Androgens
• Antigens, Nuclear
• Cdkn1b protein, mouse
• Cell Cycle Proteins
• Chromogranin A
• Chromogranins
• Growth Substances
• Multienzyme Complexes
• Nuclear Proteins
• Proteins
• Receptors, Androgen
• Tumor Suppressor Proteins
• Cyclin-Dependent Kinase Inhibitor p27
• Mixed Function Oxygenases
• peptidylglycine monooxygenase
• Prostate-Specific Antigen

Topics

• Androgens (physiology)
• Animals
• Antigens, Nuclear
• Blotting, Western
• Cell Cycle Proteins (biosynthesis)
• Cell Differentiation (physiology)
• Chromogranin A
• Chromogranins (biosynthesis)
• Cyclin-Dependent Kinase Inhibitor p27
• Growth Substances (metabolism)
• Humans
• Immunohistochemistry
• Male
• Mice
• Mice, Nude
• Mixed Function Oxygenases (biosynthesis)
• Multienzyme Complexes (biosynthesis)
• Neurosecretory Systems (metabolism)
• Nuclear Proteins
• Orchiectomy
• Prostate-Specific Antigen (biosynthesis, blood)
• Prostatic Neoplasms (genetics, metabolism, pathology)
• Protein Biosynthesis
• Proteins
• Receptors, Androgen (biosynthesis)
• Tumor Cells, Cultured
• Tumor Suppressor Proteins (biosynthesis)