Angiotensin receptors: a new role in cancer?

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There is increasing evidence that Angiotensin II (AngII), a major regulator of blood pressure and cardiovascular homeostasis, is involved in the regulation of cell proliferation, angiogenesis, inflammation and tissue remodeling, which suggests that this peptide might also play a role in cancer. This review focuses on the expression and function of Angiotensin I-converting enzyme (ACE) and AngII receptors in various aspects of cancer. Recent experimental data suggests that ACE inhibitors and AngII type 1 receptor (AT1R) antagonists have beneficial effects on tumor progression, vascularization and metastasis, and that the AngII type 2 receptor (AT2R) subtype has a potential role in cancer. An overview of the major intracellular signaling pathways associated with AT1R and AT2R activation in cancer cells, as well as in endothelial and inflammatory cells, is presented here.

Introduction

Angiotensin II (AngII), the biologically active peptide of the renin–angiotensin system (RAS), is a major regulator of blood pressure and cardiovascular homeostasis, and is also recognized as a potent mitogen. AngII is an octapeptide produced by cleavage of the inactive decapeptide Angiotensin I (AngI) by Angiotensin I-converting enzyme (ACE) (Figure 1), a zinc metalloprotease found in the circulation or bound to the cell membrane. AngI itself is produced by enzymatic cleavage of the angiotensinogen precursor by renin (Figure 1). In addition to production of plasma AngII, a local RAS has been shown to be functional in various organs, leading to production of AngII that might have a paracrine or autocrine function. AngII mediates its biological effects through binding to two subtypes of receptors, AT1R and AT2R, that belong to the superfamily of G-protein-coupled receptors but have different tissue distribution and intracellular signaling pathways [1]. Most physiological effects of AngII have been attributed to stimulation of the AT1R – further subdivided into AT1aR and AT1bR in rodents – whereas AT2R often functions as a counter-regulatory receptor. In addition to its effects on blood pressure, AngII has been shown to play a role in various pathological situations involving tissue remodeling, such as wound healing, cardiac hypertrophy and development [1]. The role of AngII in cell proliferation and migration, as well as in several experimental models of angiogenesis, suggests that this peptide might also be involved in cancer. In this review, we summarize recent data suggesting that AngII has a potential role in various aspects of tumor progression, and discuss the possibility that widely used antihypertensive agents that target AngII production or actions could also prove useful in anticancer therapy.

Section snippets

Expression of the renin–angiotensin system in cancer

Recent studies have revealed local expression of several components of the RAS in various cancer cells and tissues, including brain, lung and pancreatic cancers, as well as breast, prostate, skin and cervix carcinomas (Table 1). All components of the RAS are present in human glioblastoma, ACE being mainly expressed in tumor blood vessels [2]. Expression of both AT1R and AT2R mRNA has also been detected on astrocytoma cell lines [3].

AT1R is overexpressed in breast hyperplasia and ductal in situ

ACE inhibitors as new anticancer drugs?

ACE inhibitors (ACEis) have been successfully used as potent antihypertensive drugs over the past 20 years; recent interest has focused on the possible role of these compounds in anticancer therapy [17].

The provocative hypothesis that ACEis might have a protective role in cancer was first suggested by Lever et al. [18], who observed a reduced incidence of breast and lung cancer in patients undergoing longterm treatment with the ACEis captopril, lisinopril or enalapril. By contrast, other

Role for the AT1R in tumor growth and angiogenesis?

The effects of TCV116 (candesartan), a potent and long-lasting AT1R antagonist, have been analyzed in experimental mouse models of tumor growth, angiogenesis and metastasis. Candesartan strongly reduces the size and vascularization of syngeneic sarcomas and reduces the number of lung metastases of 3LL carcinoma cells with the same efficacy as the ACEi lisinopril, suggesting that AT1R has a major role in these processes [34]. A significant reduction in tumor growth and vascularization have also

What could be the role of the AT2R in cancer?

The role of the AT2R in tumor growth and angiogenesis has not been directly addressed in the above studies. One report showed a significant reduction of azoxymethane-induced colon tumors in male AGTR2 null mice compared with those in WT mice [38], but this was related to an effect of the AT2R on azoxymethane metabolism rather than on growth of cancer cells themselves. However, it is important to assess the role of the AT2R in tumor progression and angiogenesis if AT1R blockers are to be used in

Role for AngII and AT1R in the tumor microenvironment?

It is well documented that neoplastic cells are influenced by their environment. Two recent studies have specifically raised the question of the role of the AT1R in the tumor microenvironment by comparing the growth and vascularization of syngeneic tumors injected subcutaneously into either WT or AT1aR knockout mice 35, 45. The results indicated that the AT1aR of host cells contributes to tumor growth and angiogenesis, and high levels of AT1aR were identified in the connective tissue

Angiotensin-receptor signaling pathways related to cancer

Signaling pathways associated with activation of AT1R and AT2R in various cell types have been the subject of extensive studies. The major intracellular pathways that might be involved in the potential effects of these receptors in cancer cell proliferation, angiogenesis and inflammation are summarized here (Figure 2).

Conclusion

Compounds such as ACEis and AT1R antagonists – that block AngII production or action – appear to have beneficial effects on various aspects of cancer, including tumor progression, vascularization and metastasis (Figure 3). AngII receptors, primarily of the AT1R subtype, are expressed on tumor and endothelial cells, and are upregulated in many cancer tissues. AT1R are also expressed at inflammatory sites and upregulate the levels of VEGF, suggesting a role for AngII in vascular permeability and

Acknowledgements

This work was supported by the Centre National de la Recherche Scientifique, the Institut National de la Santé et de la Recherche Médicale, the Université Paris V, the Association pour la Recherche sur le Cancer, the Ligue Contre le Cancer Comité Ile de France and the Fondation pour la Recherche Médicale. We thank S. Cazaubon and P.O. Couraud for critical reading of the manuscript.

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