Angiotensin-2 receptors (AT1-R and AT2-R), new prognostic factors for renal clear-cell carcinoma?

Abstract

Background:The growth factor Angiotensin-2 signals through Angiotensin receptor type 1 (AT1-R) in a broad range of cell types and tumours and through the type-2 receptor (AT2-R) in a more restricted group of cell types. Although numerous forms of cancer have been shown to overexpress AT1-R, expression of AT1-R and AT2-R by human renal clear-cell carcinoma (RCCC) is not well understood. In this study, the expression of both angiotensin receptors was quantified in a retrospective series of RCCC and correlated with prognostic factors.Methods:Angiotensin receptor type 1 and AT2-R expressions were quantified on tumour tissues by immunohistochemistry (IHC), western blot and quantitative reverse transcriptase PCR (qRT–PCR). IHC results were correlated to Fuhrman's grade and patient progression-free survival (PFS).Results:A total of 84 RCCC were analysed. By IHC, AT1-R and AT2-R were expressed to a greater level in high-grade tumours (AT1-R: P<0.001, AT2-R: P<0.001). Univariate analysis showed a correlation between PFS and AT1-R or AT2-R expression (P=0.001). By multivariate analysis, only AT2-R expression correlated with PFS (HR 1.021, P=0.006) and cancer stage (P<0.001). By western blot, AT1-R and AT1-R were also found to be overexpressed in higher Fuhrman's grade (P<0.01 and P=0.001 respectively). By qRT–PCR, AT1-R but not AT2-R mRNA were downregulated (P=0.001 and P=0.118, respectively).Conclusion:Our results show that AT1-R and AT2-R proteins are overexpressed in the most aggressive forms of RCCC and that AT2-R expression correlates with PFS. AT1-R or AT2-R blockage could, therefore, offer novel directions for anti-RCCC therapy.

The renin-angiotensin system meets the hallmarks of cancer

“…When signalling through the AT1R, AngII facilitates cellular proliferation and angiogenesis, whereas AngII signalling through AT2R has antiproliferative properties. 9 In most tissues, the proportion of AT1R and AT2R changes dramatically during the postnatal period. In foetal tissues, AT2R expression is dominant, and in adult animals, it is the AT1R that is more abundant.…”

GPCRs and cancer

“…As it concerns the renin-angiotensin system, an abundant generation of Ang-II stimulated by the angiotensin-converting enzyme (ACE) and the up-regulation of AT1R have been demonstrated in various tumors [110,116] . In this respect, ACE inhibitors and angiotensin II receptor blockers (ARBs) have recently acquired an increasing interest as chemopreventive agents [110,117,118] .…”

ACE and ACE2 expression in normal and malignant skin lesions

“…The authors speculated about the possibility of using these enzymes as prognostic and diagnostic factors, although this hypothesis remains to be clarified [37]. The role of RAS in cancer pathogenesis has also been supported by the study of Dolley-Hitze et al, which was performed on renal clear-cell cancer and recognized the expression of AT1R and AT2R as negative prognostic and predictive factors [38]. Thus, on the basis of our findings of the lower immunoreactivity of ACE in more malignant skin lesions as compared with the premalignant AK and normal skin, one could hypothesize a tumor-suppressing role of ACE.…”