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Localization of immunoreactive HIF-1alpha and HIF-2alpha in neuroendocrine cells of both benign and malignant prostate glands.

Monsef, Nastaran LU ; Helczynski, Leszek LU ; Lundwall, Åke LU and Påhlman, Sven LU (2007) In The Prostate 67(11). p.1219-1229
Abstract
BACKGROUND. Hypoxia induces increased tumor growth by promoting angiogenic and glycolytic pathways. Tumors expressing hypoxia-inducible factor-la (HIF-1 alpha), 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-1 alpha and HIF-2 alpha 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... (More)
BACKGROUND. Hypoxia induces increased tumor growth by promoting angiogenic and glycolytic pathways. Tumors expressing hypoxia-inducible factor-la (HIF-1 alpha), 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-1 alpha and HIF-2 alpha 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-l a, HIF-2a, androgen receptor (AR), neuroendocrine markers (chromogranin A, synaptophysin), and two gene products downstream of HIF-1a: VEGF and GAPDH. RESULTS. Immunoreactive HIF-1 alpha 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-1 alpha. in situ-hybridization indicated that HIF-1 alpha 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-1 alpha 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-1 alpha and HIF-2a in prostate cancer has been confirmed, but we also identified immunoreactive HIF-1 alpha and downstream gene products in benign and malignant prostate neuroendocrine cells. Prostate 67:1219-1229, 2007, (c) 2007 Wiley-Liss, Inc. (Less)
Please use this url to cite or link to this publication:
author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
The Prostate
volume
67
issue
11
pages
1219 - 1229
publisher
John Wiley & Sons
external identifiers
  • wos:000248537500009
  • scopus:34547700020
ISSN
0270-4137
DOI
10.1002/pros.20594
language
English
LU publication?
yes
id
47e6e247-5027-4643-b4eb-0e0eb10c3d87 (old id 539862)
alternative location
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=17562539&dopt=Abstract
date added to LUP
2007-12-18 12:06:45
date last changed
2017-01-01 04:37:14
@article{47e6e247-5027-4643-b4eb-0e0eb10c3d87,
  abstract     = {BACKGROUND. Hypoxia induces increased tumor growth by promoting angiogenic and glycolytic pathways. Tumors expressing hypoxia-inducible factor-la (HIF-1 alpha), 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-1 alpha and HIF-2 alpha 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-l a, HIF-2a, androgen receptor (AR), neuroendocrine markers (chromogranin A, synaptophysin), and two gene products downstream of HIF-1a: VEGF and GAPDH. RESULTS. Immunoreactive HIF-1 alpha 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-1 alpha. in situ-hybridization indicated that HIF-1 alpha 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-1 alpha 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-1 alpha and HIF-2a in prostate cancer has been confirmed, but we also identified immunoreactive HIF-1 alpha and downstream gene products in benign and malignant prostate neuroendocrine cells. Prostate 67:1219-1229, 2007, (c) 2007 Wiley-Liss, Inc.},
  author       = {Monsef, Nastaran and Helczynski, Leszek and Lundwall, Åke and Påhlman, Sven},
  issn         = {0270-4137},
  language     = {eng},
  number       = {11},
  pages        = {1219--1229},
  publisher    = {John Wiley & Sons},
  series       = {The Prostate},
  title        = {Localization of immunoreactive HIF-1alpha and HIF-2alpha in neuroendocrine cells of both benign and malignant prostate glands.},
  url          = {http://dx.doi.org/10.1002/pros.20594},
  volume       = {67},
  year         = {2007},
}