title: Angiotensin-converting enzyme and the tumor microenvironment: mechanisms beyond angiogenesis.
abstract: The renin angiotensin system (RAS) is a network of enzymes and peptides that coalesce primarily on the angiotensin II type 1 receptor (AT1R) to induce cell proliferation, angiogenesis, fibrosis, and blood pressure control. Angiotensin-converting enzyme (ACE), the key peptidase of the RAS, is promiscuous in that it cleaves other substrates such as substance P and bradykinin. Accumulating evidence implicates ACE in the pathophysiology of carcinogenesis. While the role of ACE and its peptide network in modulating angiogenesis via the AT1R is well documented, its involvement in shaping other aspects of the tumor microenvironment remains largely unknown. Here, we review the role of ACE in modulating the immune compartment of the tumor microenvironment, which encompasses the immunosuppressive, cancer-promoting myeloid-derived suppressor cells, alternatively activated tumor-associated macrophages, and T regulatory cells. We also discuss the potential roles of peptides that accumulate in the setting of chronic ACE inhibitor use, such as bradykinin, substance P, and N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP), and how they may undercut the gains of anti-angiogenesis from ACE inhibition. These emerging mechanisms may harmonize the often-conflicting results on the role of ACE inhibitors and ACE polymorphisms in various cancers and call for further investigations into the potential benefit of ACE inhibitors in some neoplasms.
authors.affiliation: Department of Radiation Oncology, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors.forename: Derick
authors.initials: D
authors.lastname: Okwan-Duodu
authors.forename: Jerome
authors.initials: J
authors.lastname: Landry
authors.forename: Xiao Z
authors.initials: XZ
authors.lastname: Shen
authors.forename: Roberto
authors.initials: R
authors.lastname: Diaz
mesh_terms: D000818:Animals; D006801:Humans; D022423:Myeloid Cells / Q000502:physiology; D009369:Neoplasms / Q000201:enzymology* / Q000503:physiopathology*; D009389:Neovascularization, Pathologic / Q000503:physiopathology*; D018919:Neovascularization, Physiologic / Q000502:physiology; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism*; D012084:Renin-Angiotensin System / Q000502:physiology; D013601:T-Lymphocytes / Q000502:physiology; D059016:Tumor Microenvironment
chemical_list: D007703:Peptidyl-Dipeptidase A
keywords: T regulatory cells; angiogenesis; angiotensin-converting enzyme; cancer; macrophage polarization; myeloid-derived suppressor cells; tumor immunology