Neuroendocrine differentiation in
prostate cancer correlates with overall prognosis and
disease progression after
androgen-deprivation
therapy, although its specific mechanisms are currently poorly understood. A role of Notch pathway has been reported in determining neuroendocrine phenotype of normal and neoplastic tissues. The aim of this study was to analyze whether this pathway might affect neuroendocrine differentiation in
prostate cancer. Human achaete-scute homolog 1 (hASH1), a pivotal member of the Notch pathway, was investigated in 80
prostate cancers selected and grouped according to
chromogranin A immunohistochemistry, as follows:
prostate cancers without neuroendocrine differentiation, untreated (25 cases);
prostate cancers with neuroendocrine differentiation, untreated (40 cases);
prostate cancers with previous
androgen-deprivation
therapy, all having neuroendocrine differentiation (15 cases). Human ASH1
protein was analyzed by immunohistochemistry, whereas the presence of hASH1
mRNA transcripts was investigated on
paraffin material by real-time PCR. By immunohistochemistry, hASH1 was colocalized with
chromogranin A in neuroendocrine cells of normal prostatic gland. It was absent in all but one
prostate cancers without neuroendocrine differentiation, whereas it was positive in 25% of
prostate cancers with neuroendocrine differentiation/untreated, with a significant correlation with the extent of neuroendocrine features (P=0.02). Moreover, comparing untreated and treated
prostate cancers with neuroendocrine differentiation, a positive association with
androgen-deprivation
therapy was observed (P=0.01). In
prostate cancers with neuroendocrine differentiation,
RNA analysis confirmed the association of higher transcript levels in
androgen deprivation-treated compared with untreated patients (P=0.01). In addition, hASH1
mRNA analysis in microdissected
chromogranin A-positive and
chromogranin A-negative areas within the same
tumor demonstrated a two- to sevenfold increase of hASH1
mRNA expression in
chromogranin A-positive
tumor cell populations.