Premium
Localization of immunoreactive HIF‐1α and HIF‐2α in neuroendocrine cells of both benign and malignant prostate glands
Author(s) -
Monsef Nastaran,
Helczynski Leszek,
Lundwall Åke,
Påhlman Sven
Publication year - 2007
Publication title -
the prostate
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.295
H-Index - 123
eISSN - 1097-0045
pISSN - 0270-4137
DOI - 10.1002/pros.20594
Subject(s) - chromogranin a , prostate cancer , neuroendocrine differentiation , prostate , lncap , medicine , pathology , hypoxia inducible factors , cancer research , immunohistochemistry , biology , cancer , biochemistry , gene
BACKGROUND Hypoxia induces increased tumor growth by promoting angiogenic and glycolytic pathways. Tumors expressing hypoxia‐inducible factor‐1α (HIF‐1α), an important transcriptional activator of oxygen‐regulated genes, are resistant to chemotherapy and radiotherapy. The major challenge in prostate cancer therapy today is to gain a better understanding of the development of hormone‐refractory tumors, which is often characterized by neuroendocrine differentiation. Here we studied the expression of HIF‐1α and HIF‐2α in neuroendocrine cells of the benign prostate and in prostate cancer. METHODS Tissue sections from 30 patients who underwent radical prostatectomy and from 21 patients operated by transurethral resection of the prostate were selected for immunohistochemical analysis for expression of HIF‐1α, HIF‐2α, androgen receptor (AR), neuroendocrine markers (chromogranin A, synaptophysin), and two gene products downstream of HIF‐1α: VEGF and GAPDH. RESULTS Immunoreactive HIF‐1α was detected in a subpopulation of AR‐negative neuroendocrine cells in benign and malignant prostate tissue. Analysis of serial sections showed that the levels of expression of GAPDH and VEGF proteins are increased in AR‐negative malignant neuroendocrine cells expressing HIF‐1α. In situ‐hybridization indicated that HIF‐1α mRNA levels are not higher in neuroendocrine prostate cancer cells relative to corresponding non‐neuroendocrine tumor cells. We also demonstrated induced stabilization of nuclear HIF‐1α in LNCaP cells by hypoxia and long‐term stimulation with interleukin‐6. Focal HIF‐2 expression was detected in benign neuroendocrine‐like cells and in malignant prostatic cells. CONCLUSIONS The expression of HIF‐1α and HIF‐2α in prostate cancer has been confirmed, but we also identified immunoreactive HIF‐1α and downstream gene products in benign and malignant prostate neuroendocrine cells. Prostate 67: 1219–1229, 2007. © 2007 Wiley‐Liss, Inc.