Expression of the TPα and TPβ isoforms of the thromboxane prostanoid receptor (TP) in prostate cancer: clinical significance and diagnostic potential

Abstract

The prostanoid thromboxane (TX) A2 plays a central role in haemostasis and is increasingly implicated in cancer progression. TXA2 signals through two T Prostanoid receptor (TP) isoforms termed TPα and TPβ, with both encoded by the TBXA2R gene. Despite exhibiting several functional and regulatory differences, the role of the individual TP isoforms in neoplastic diseases is largely unknown.This study evaluated expression of the TPα and TPβ isoforms in tumour microarrays of the benign prostate and different pathological (Gleason) grades of prostate cancer (PCa). Expression of TPβ was significantly increased in PCa relative to benign tissue and strongly correlated with increasing Gleason grade. Furthermore, higher TPβ expression was associated with increased risk of biochemical recurrence (BCR) and significantly shorter disease-free survival time in patients post-surgery. While TPα was more variably expressed than TPβ in PCa, increased/high TPα expression within the tumour also trended toward increased BCR and shorter disease-free survival time. Comparative genomic CpG DNA methylation analysis revealed substantial differences in the extent of methylation of the promoter regions of the TBXA2R that specifically regulate expression of TPα and TPβ, respectively, both in benign prostate and in clinically-derived tissue representative of precursor lesions and progressive stages of PCa. Collectively, TPα and TPβ expression is differentially regulated both in the benign and tumourigenic prostate, and coincides with clinical pathology and altered CpG methylation of the TBXA2R gene. Analysis of TPβ, or a combination of TPα/TPβ, expression levels may have significant clinical potential as a diagnostic biomarker and predictor of PCa disease recurrence.

Scavenging of Labile Heme by Hemopexin Is a Key Checkpoint in Cancer Growth and Metastases

“…We detected significantly higher levels of labile heme ( Figure 1A ) and lower levels of its scavenger Hx ( Figure 1B ) in the plasma of patients with cancer (low- or high-grade tumors) compared with healthy controls. Second, we validated the relevance of these findings in a larger cohort of PCa, including malignant and benign prostatectomy specimens from 341 patients ( Mulvaney et al, 2016 ) and analyzed Hx expression in a tissue microarray (TMA) by immunohistochemistry. The Hx staining in the stroma was significantly weaker in moderately (Gleason score [GS] ≤ 7) and poorly differentiated (GS > 7) tumors as compared with benign tissues ( Figures 1C and 1D ), similar to what we observed in the plasma samples ( Figure 1B ).…”

“…Tissues from radical prostatectomies of 341 prostate cancer patients, operated between 1998 and 2006 at Skåne University Hospital, Malmö, Sweden was used to construct a tissue microarray (TMA) as previously described in ( Tassidis et al, 2013 ). Clinical follow-up data of minimum 10 years and pathological staging was available for most of the patients and the clinical characteristics have been previously described in Mulvaney et al (2016) . Plasma samples were from patients undergoing a PSA test at the Malmö University Hospital between 2004 and 2010 (ethical permit number 2016/1030).…”

NTP42, a novel antagonist of the thromboxane receptor, attenuates experimentally induced pulmonary arterial hypertension

“…Hence, imbalances in the levels of TXA 2 , or of TXA 2 S or of the TP have been implicated in a range of cardiovascular, renal and pulmonary diseases, including in PAH [2][3][4][5]. The TXA 2 -TP axis also regulates key mitogenic/ERK and RhoA-mediated signalling cascades, explaining, at least in part, the role of TXA 2 in increasing cell proliferation and migration such as occurs in restenosis, vascular remodelling, and in a range of cancers in which the TXA 2 -TP axis is increasingly implicated [2][3][4][5][6][7][8].…”

NTP42, a novel antagonist of the thromboxane receptor, attenuates experimentally induced pulmonary arterial hypertension

“…(2)(3)(4)(5) The TXA 2 -TP axis also regulates key mitogenic/ERK and RhoA-mediated signalling cascades, explaining, at least in part, the role of TXA 2 in increasing cell proliferation and migration such as occurs in restenosis, vascular remodelling, and in a range of cancers in which the TXA 2 -TP axis is increasingly implicated. (2)(3)(4)(5)(6)(7)(8) Moreover, and also critically, the TP not only mediates the actions of TXA 2 but also those of the isoprostane 8-iso-prostaglandin (PG) F 2α (also termed 15-F2t-isoprostane), a non-enzymatic-, freeradical-derived product of arachidonic acid produced in abundance during oxidative injury/hypoxia, including in various cardiovascular and pulmonary diseases. (9) Significantly in the context of PAH, 8iso-PGF 2α is increased over 3-fold in PAH patients and correlates with PAH status and disease progression.…”