Hypoxic Prostate Cancer Research Articles

Androgen withdrawal improves tumor hypoxia in prostate cancer

Androgen withdrawal improves tumor hypoxia in prostate cancer

Androgen Withdrawal in Patients Reduces Prostate Cancer Hypoxia: Implications for Disease Progression and Radiation Response

Hypoxia is a feature of many human malignancies, and leads to aggressive clinical behavior and recurrence after treatment. Here, we show for the first time that androgen withdrawal reduces prostate cancer hypoxia in patients. Oxygen measurements were done in 248 patients with clinically localized prostate cancer prior to radiotherapy, and showed hypoxia of potential biological and clinical significance. In 22 of these patients, prostate oxygen levels were measured both before and after 30 to 145 days of the androgen antagonist bicalutamide. There was a significant reduction in tumor hypoxia with androgen withdrawal (P=0.005). The median pO(2) increased from 6.4 to 15 mm Hg, and the hypoxic proportion decreased from 40% to 31%. However, the response was heterogeneous, with improvement in 12 patients, stable oxygen readings in 9 patients and worsening hypoxia in 1 patient. Among the responding patients, the median pO(2) increased from 4.9 to 33 mm Hg, and the hypoxic proportion decreased from 51% to 23%. There was no apparent relationship between the change in oxygenation and baseline prostatic volume, T category, Gleason score, prostate-specific antigen levels, the duration of treatment with bicalutamide, or the change in prostate-specific antigen levels with bicalutamide. These results might, in part, explain the improved patient outcome that has been observed in clinical trials of radiotherapy and hormones, and suggest a role for novel therapeutic agents that block the molecular response to hypoxia in prostate cancer either alone or in combination with other established treatments.

Hypoxia in Prostate Cancer: Correlation of BOLD-MRI With Pimonidazole Immunohistochemistry—Initial Observations

To investigate the ability of blood oxygen level-dependent (BOLD) MRI to depict clinically significant prostate tumor hypoxia. Thirty-three patients with prostate carcinoma undergoing radical prostatectomy were studied preoperatively, using gradient echo sequences without and with contrast medium enhancement, to map relative tissue oxygenation according to relaxivity rates and relative blood volume (rBV). Pimonidazole was administered preoperatively, and whole-mount sections of selected tumor-bearing slices were stained for pimonidazole fixation and tumor and nontumor localization. Histologic and imaging parameters were independently mapped onto patient prostate outlines. Using 5-mm grids, 861 nontumor grid locations were compared with 237 tumor grids (with >50% tumor per location) using contingency table analysis with respect to the ability of imaging to predict pimonidazole staining. Twenty patients completed the imaging and histologic protocols. Pimonidazole staining was found in 33% of nontumor and in 70% of tumor grids. The sensitivity of the MR relaxivity parameter R(2)* in depicting tumor hypoxia was high (88%), improving with the addition of low rBV information (95%) without changing specificity (36% and 29%, respectively). High R(2)* increased the positive predictive value for hypoxia by 6% (70% to 76%); conversely, low R(2)* decreased the likelihood of hypoxia being present by 26% (70% to 44%) and by 41% (71% to 30%) when combined with rBV information. R(2)* maps from BOLD-MRI have high sensitivity but low specificity for defining intraprostatic tumor hypoxia. This together with the negative predictive value of 70% when combined with blood volume information makes BOLD-MRI a potential noninvasive technique for mapping prostatic tumor hypoxia.

HIF-1 and NF-κB-mediated upregulation of CXCR1 and CXCR2 expression promotes cell survival in hypoxic prostate cancer cells

Hypoxic cancer cells are resistant to treatment, leading to the selection of cells with a more malignant phenotype. The expression of interleukin-8 (IL-8) plays an important role in the tumorigenesis and metastasis of solid tumors including prostate cancer. Recently, we detected elevated expression of IL-8 and IL-8 receptors in human prostate cancer tissue. The objective of the current study was to determine whether hypoxia increases IL-8 and IL-8 receptor expression in prostate cancer cells and whether this contributes to a survival advantage in hypoxic cells. IL-8, CXCR1 and CXCR2 messenger RNA (mRNA) expression in PC3 cells was upregulated in response to hypoxia in a time-dependent manner. Elevated IL-8 secretion following hypoxia was detected by enzyme-linked immunosorbent assay, while immunoblotting confirmed elevated receptor expression. Attenuation of hypoxia-inducible factor (HIF-1) and nuclear factor-kappaB (NF-kappaB) transcriptional activity using small interfering RNA (siRNA), a HIF-1 dominant-negative and pharmacological inhibitors, abrogated hypoxia-induced transcription of CXCR1 and CXCR2 in PC3 cells. Furthermore, chromatin-IP analysis demonstrated binding of HIF-1 and NF-kappaB to CXCR1. Finally, inhibition of IL-8 signaling potentiated etoposide-induced cell death in hypoxic PC3 cells. These results suggest that IL-8 signaling confers a survival advantage to hypoxic prostate cancer cells, and therefore, strategies to inhibit IL-8 signaling may sensitize hypoxic tumor cells to conventional treatments.

Dose escalation to combat hypoxia in prostate cancer: a radiobiological study on clinical data

Earlier studies have demonstrated that hypoxic regions exist in human prostate cancer and the degree of hypoxia correlates with the treatment outcome of radiotherapy. Using the concept of the clinical oxygen enhancement ratio (COER), the linear-quadratic (LQ) model was extended to account for the effect of tumour hypoxia. The clinical data collected at the Fox Chase Cancer Center for prostate cancer were analysed based on the LQ model as well as the tumour control probability (TCP) model. The LQ and TCP parameters (alpha = 0.15 Gy (-1), alpha/beta = 3.1 Gy and the number of clonogens K = 10(6) approximately 10(7) cells) determined in earlier studies were used to derive the COER for prostate cancer: COER = 1.4 with a standard confidence interval (CI) of (1.2, 1.8). The result is consistent with the in vitro OER measurements of human tumour cell lines under chronic hypoxia conditions. This implies that a higher dose is needed to overcome tumour hypoxia. For prostate tumours, the prescription dose required to overcome tumour hypoxia is 165 Gy (CI: 153 approximately 186 Gy) for permanent 125I implants and 88 Gy (CI: 74 approximately 118 Gy) in 2 Gy fractions for external-beam radiotherapy. The impact of LQ parameters on the calculations of COER and dose escalation was discussed. This study provides a preliminary estimate of the dose escalation needed to overcome tumour hypoxia based on clinical data. More clinical data with better statistics and longer follow-up time are required to further tune the radiobiological modelling of hypoxia for prostate cancer.

232: Activation of Androgen Receptor by Hypoxia in Prostate Cancer: Its Clinical and Biological Implications

You have accessJournal of UrologyDiscussed Poster, Sunday, May 22, 2005 8:00 am - 12:00 pm1 Apr 2005232: Activation of Androgen Receptor by Hypoxia in Prostate Cancer: Its Clinical and Biological Implications Young-Mee Park, Soo-Yeon Park, Yun-Jeong Kim, Allen Gao, James Mohler, Clement Ip, and Eun-Mi Park Young-Mee ParkYoung-Mee Park More articles by this author , Soo-Yeon ParkSoo-Yeon Park More articles by this author , Yun-Jeong KimYun-Jeong Kim More articles by this author , Allen GaoAllen Gao More articles by this author , James MohlerJames Mohler More articles by this author , Clement IpClement Ip More articles by this author , and Eun-Mi ParkEun-Mi Park More articles by this author View All Author Informationhttps://doi.org/10.1016/S0022-5347(18)34497-5AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail "232: Activation of Androgen Receptor by Hypoxia in Prostate Cancer: Its Clinical and Biological Implications." The Journal of Urology, 173(4S), p. 64 © 2016 by American Urological AssociationFiguresReferencesRelatedDetails Volume 173Issue 4SApril 2005Page: 64 Advertisement Copyright & Permissions© 2016 by American Urological AssociationMetricsAuthor Information Young-Mee Park More articles by this author Soo-Yeon Park More articles by this author Yun-Jeong Kim More articles by this author Allen Gao More articles by this author James Mohler More articles by this author Clement Ip More articles by this author Eun-Mi Park More articles by this author Expand All Advertisement PDF downloadLoading ...

Cyclooxygenase-2 Suppresses Hypoxia-induced Apoptosis via a Combination of Direct and Indirect Inhibition of p53 Activity in a Human Prostate Cancer Cell Line

Although p53-inactivating mutations have been described in the majority of human cancers, their role in prostate cancer is controversial as mutations are uncommon, particularly in early lesions. p53 is activated by hypoxia and other stressors and is primarily regulated by the Mdm2 protein. Cyclooxygenase (COX)-2, an inducible enzyme that catalyzes the conversion of arachidonic acid to prostaglandins and other eicosanoids, is also induced by hypoxia. COX-2 and resultant prostaglandins increase tumor cell proliferation, resistance to apoptosis, and angiogenesis. Previous reports indicate a complex, reciprocal relationship between p53 and COX-2. To elucidate the effects of COX-2 on p53 in response to hypoxia, we transfected the COX-2 gene into the p53-positive, COX-2-negative MDA-PCa-2b human prostate cancer cell line. The expression of functional p53 and Mdm2 was compared in COX-2+ versus COX-2- cells under normoxic and hypoxic conditions. Our results demonstrated that hypoxia increases both COX-2 protein levels and p53 transcriptional activity in these cells. Forced expression of COX-2 increased tumor cell viability and decreased apoptosis in response to hypoxia. COX-2+ cells had increased Mdm2 phosphorylation in either normoxic or hypoxic conditions. Overexpression of COX-2 abrogated hypoxia-induced p53 phosphorylation and promoted the binding of p53 to Mdm2 protein in hypoxic cells. In addition, COX-2-expressing cells exhibited decreased hypoxia-induced nuclear accumulation of p53 protein. Finally, forced expression of COX-2 suppressed both basal and hypoxia-induced p53 transcriptional activity, and this effect was mimicked by the addition of PGE2 to wild-type cells. These results demonstrated a role for COX-2 in the suppression of hypoxia-induced p53 activity via both direct effects and indirect modulation of Mdm2 activity. These data imply that COX-2-positive prostate cancer cells can have impaired p53 function even in the presence of wild-type p53 and that p53 activity can be restored in these cells via inhibition of COX-2 activity.

Prostate cancer hypoxia correlates with poor patient outcome following treatment with radiotherapy

Prostate cancer hypoxia correlates with poor patient outcome following treatment with radiotherapy

25 Prostate cancer hypoxia adversely influences outcome following treatment with radiotherapy

25 Prostate cancer hypoxia adversely influences outcome following treatment with radiotherapy

Prostate cancer hypoxia correlates with poor patient outcome following treatment with radiotherapy

Prostate cancer hypoxia correlates with poor patient outcome following treatment with radiotherapy

Tumor hypoxia and the progression of prostate cancer.

Tumor cell hypoxia is an innate environmental factor encountered during the development of many types of human tumors, including malignant prostate tumors. For prostate cancer, however, tumor cell hypoxia may be an even more critical element in tumor development and progression. Recent evidence suggests that androgenic steroids are important regulators of blood flow to prostate tumors and suppressors of tumor cell hypoxia. In addition, because prostate tumor cells are similar to other eukaryotic cells, they have the ability to respond to hypoxic conditions with drastic changes in gene expression mediated by the upregulation of a unique transcription factor, hypoxia-inducible factor-1. This response increases cancer cells' metabolic resistance to hypoxia, and also enhances the ability of prostate cancer cells to attract a more vigorous blood supply by upregulating the expression of pro-angiogenic factors. Because such changes would, in essence, increase the potential aggressiveness of affected prostate cancer cells, it is clear that tumor hypoxia has the potential for being a very important factor in prostate cancer cell biology. This review focuses on recent studies regarding the occurrence and potential role of hypoxia in prostate cancer, including hypoxia-inducible factor-1 and its related signaling pathways.

Analysis of hypoxia-associated gene expression in prostate cancer: lysyl oxidase and glucose transporter-1 expression correlate with Gleason score

Prostate cancer cells exist under hypoxic conditions. Hypoxia has a detrimental effect on the efficacy of treatment and final outcome in patients with prostate cancer. There have been a large number of endogenous markers of hypoxia described previously across a range of cancer types, both in vitro and in vivo. The aim of this study was to evaluate the expression of a range of hypoxia-associated genes within benign prostatic hypertrophy (BPH) and prostate cancer tissue. Messenger RNA was extracted from primary prostate tissue obtained from 67 men with benign prostatic hypertrophy or prostate cancer (Gleason score 5 to 10). Real-time polymerase chain reaction was performed to quantify the expression levels of 12 hypoxia-associated genes in these tissues. Expression of lysyl oxidase (LOX) and glucose transporter-1 (GLUT-1) genes were significantly higher in prostate cancer compared with BPH tissue (P<0.05) and correlated with Gleason score (LOX: R=0.297, P=0.015; GLUT-1: R=0.274, P=0.026). HIF-2alpha had a negative correlation with Gleason score (R= -0.309, P=0.012). The remaining hypoxia-associated genes did not show any specific pattern of expression in prostate tissue. Numerous molecules have been proposed as endogenous markers of hypoxia. The findings of this study illustrate that not all hypoxia-associated molecules are relevant to prostate cancer in vivo. However, LOX and GLUT-1 are candidate markers of hypoxia in prostate cancer and may prove useful in identifying patients with hypoxic prostate cancer. Not all hypoxia-associated molecules are relevant in prostate cancer in vivo.