Human angiotensin-converting enzyme 2 (ACE2) regulates the renin-angiotensin (RAS) system by cleaving angiotensin (Ang) I to 1–9 and Ang II peptide to Ang 1–7 (1–3), reactions that promote vasodilation and lead to the inhibition of smooth muscle cell proliferation and hypertrophy (4,5) (Fig. 1). The emergence of the corona virus disease 2019 (COVID-19) augmented the interest in studies on ACE2, as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the β coronavirus that is responsible for the infection, uses ACE2 as functional receptor for cellular entry (1,2). The overall heritability of the ACE2 expression is ~16% among Europeans, of which 30% is linked to 10 protein quantitative trait loci (6). ACE2 is primarily expressed in endothelial cells as a cell-surface non-raft protein with little intracellular localization (7). High expression of ACE2 in the heart, kidney and lungs has been implicated in the pathophysiology of these organs (8–13). Moreover, ACE2 has been detected in a wide range of organs and tissue (14–23) (Fig. 2). In addition to organ-regulated ACE2 expression, demographic data have shown that the expression and activity of ACE2 are both sex- and age-regulated (6,24–27). In addition, androgens are associated with ACE2 upregulation; blocking androgens has the effect of decreasing ACE2 levels (28,29). Exercising has also been shown to affect ACE2 levels (30). Furthermore, high plasma ACE2 levels are observed in patients with type 2 diabetes mellitus, in male smokers, and patients diagnosed with hypertension, atherosclerosis, cardiopathy, respiratory system disorder, pulmonary arterial hypertension, cirrhosis, non-alcoholic steatohepatitis, chronic kidney and inflammatory bowel disease (6,24,31–40). Moreover, hypoxia, cell stress and treatment with IL-1 increase ACE2 levels (41). ACE2 levels are positively associated with cathepsin L1, body mass index, triglycerides and usage of calcium channel blockers (6).

The differential expression of ACE2 in tumors compared with controls has been revealed by epidemiological studies using microarray analysis and bioinformatics (14,18–20,27,33,42–47). Moreover, methylation disturbance and microsatellite instability are associated with ACE2 levels in different types of tumors (18,19). Additionally, ACE2 expression, being positively associated with immune cell infiltration in tumor tissue, may affect tumor prognosis through cancer immunity (19,43,47). Previous studies have also suggested that the ACE2/Ang-(1–7)/Mas receptor axis exerts a pivotal role in tumorigenesis (48,49). The possible antitumor effects of RAS have already been documented in breast and colorectal cancer, although these findings require further validation (50,51). Upregulation of ACE2 is associated with favorable anti-programmed cell death protein 1/programmed-death ligand-1/cytotoxic T lymphocyte-associated protein 4 immunotherapy responses, and inversely associated with tumor proliferation and epithelial-mesenchymal transition tumor properties (52). In addition, angiotensin I-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers improve disease-free survival rates in patients with urinary tract, colorectal, pancreatic and prostate cancer, with subsequent decreases in cancer mortality and recurrence (53). The present review discusses ACE2 expression in human tissue and their tumor counterparts. Furthermore, ACE2 prognostic and predictive value in human tumors is summarized (Table I).

ACE2 expression has been detected in the human brain, wherein low levels of ACE2 mRNA have been reported (54). ACE2 expression in the human brain is localized in neurons, astrocytes, oligodendrocytes and brain endothelial cells (55,56). Furthermore, ACE2 expression is not age-dependent in astrocytoma and brain endothelial cells (26). Human-induced pluripotent stem cell-derived neural stem/progenitor cells exhibit ACE2 expression (57). The amygdala, the cerebral cortex and brainstem are rich in ACE2, although the highest ACE2 expression levels are identified in the pons and medulla oblongata, mainly in the medullary cardiorespiratory centers (58,59). ACE2 expression is also detected in the cerebellum (55,60,61). ACE2 was found to be expressed in vascular smooth muscle cells (62) and pericytes of the brain (63). Moreover, in mice with neurospecific expression of ACE2, ACE2 may protect the brain against ischemic injury by regulating NADPH oxidase levels (64).

ACE2 expression has been demonstrated in the neuroblastoma cell lines SH-SY5Y and SK-N-BE, as well as in the glioblastoma cell lines U87 and U-373 (65–67). High levels of ACE2 are associated with poor prognosis in patients with neuroblastoma (68). Similarly, ACE2 expression is upregulated in glioblastoma multiforme compared with normal brain, and this upregulation decreases survival rates (19,69). Moreover, ACE2 expression is upregulated in low-grade glioma of the brain, and this differential expression is associated with poor prognosis (19,47). In addition, bioinformatics analysis revealed that ACE2 and cathepsin B, which, along with cathepsin L, act as the entry-associated proteases of SARS-CoV-2, both predicted poor prognosis in brain low-grade glioma (45). In a different bioinformatics study (60), ACE2 expression in glioblastoma multiforme compared with normal brain was upregulated, although differences in the expression pattern were not identified by immunohistochemical analysis, potentially due to the small sample size. In the same study, ACE2 levels in glioblastoma multiforme tissue were shown to be associated with monocyte immune infiltration rates, which were increased in patients aged <60 years (60). However, in a transcriptomic analysis, ACE2 gene expression was found not to be significantly different between brain tumors (glioblastoma multiforme and lower-grade glioma) and normal brain (33). ACE2 co-localization with CD31, CD73, and nestin is detected in endothelial cells, bone marrow mesenchymal and neural precursor cells from glioblastoma multiforme samples (70). In a study by Lei et al (71), significantly higher immunohistochemical expression of ACE2 was reported in glioblastoma multiforme tissue (adjacent, peritumor and core) from a patient with COVID-19 compared with glioblastoma tissues from a patient without COVID-19 history. Additionally, ACE2, along with transmembrane serine protease 2 (TMPRSS2) and neuropilin-1 (NRP1) factors, has been detected in glioblastoma multiforme tissue (72).

To the best of our knowledge, in the endocrine system, ACE2 has not been investigated in detail. A study on patients with SARS have revealed that ACE2 is expressed in the pituitary gland, thyroid, parathyroid, endocrine pancreas, adrenal glands and testis (73). Low expression of ACE is detected in pituitary neuroendocrine tumors, whereas higher expression of ACE2 is identified in gonadotropic adenomas compared with other pituitary tumors and normal pituitary specimens (74). By contrast, transcriptomic analysis revealed that ACE2 gene expression is similar in adrenocortical carcinomas and normal pituitary tissue (33). High ACE2 levels are associated with an improved prognosis of adrenocortical carcinoma (19).

ACE2 expression is low in the thyroid gland (22). In a transcriptomic analysis (33), ACE2 levels significantly differed in thyroid tissue carcinomas compared with controls. Cytoplasmic expression of ACE2 is significantly increased in papillary thyroid carcinoma and follicular adenomas and thyroid carcinomas as compared with goiters. Furthermore, in a study by Narayan et al (75), ACE2 expression was increased according to tumor size enlargement and the presence of node or remote metastasis, suggesting that ACE2 expression may serve as a biomarker for thyroid carcinoma. In the same study, ACE2 levels were found to be lower in well-differentiated thyroid carcinoma and in samples from patients aged >50 years. Furthermore, downregulation of ACE2 expression in thyroid carcinoma has been reported in a pan-cancer analysis (19). ACE2-positive staining in small vessels is associated with earlier tumor stages in papillary thyroid carcinomas (14). Similarly, ACE2 expression in capillaries is associated with lower tumor staging in low-grade neuroendocrine neoplasms (14). Cox regression analyses using data from The Cancer Genome Atlas revealed that ACE2 may affect the survival rates of patients with thyroid carcinoma (69).

ACE2 is expressed at low levels in the cytoplasm of α-, β- and δ-pancreatic cells, whereas ACE2 staining is stronger in islets, vasculature and duct system cells (14,76–81). In patients with COVID-19, ACE2 was expressed in ~70% of the pancreatic vasculature and in 30% of β-cells (82,83). Pericytes around the exocrine ducts and endocrine islets express ACE2 (63,80). The transcription factor hepatocyte nuclear factor-1 α (HNF1A) regulates ACE2 expression in pancreatic tissue (84). According to bioinformatics studies, ACE2 gene expression is higher in pancreatic adenocarcinoma compared with normal tissue (19,33,44,76), and ACE2 downregulation is associated with tumor progression (85). Moreover, these tumors present with decreased DNA methylation levels of ACE2 (44). However, immunohistochemical expression of ACE2 is not associated with the survival of patients with pancreatic cancer (76). ACE2 levels have been positively associated with immune cell infiltration in pancreatic adenocarcinoma (86). Previous data have provided evidence for ACE2 as a promising candidate biomarker for pancreatic cancer treatment (87). Restoration of the levels of ACE2 suppress the cell proliferative and migratory properties of BxPC3 and SW1990 pancreatic adenocarcinoma cell lines; moreover, the sensitivity to gemcitabine in a pancreatic cancer mouse model is increased with ACE2 overexpression (87). Lau and Leung (88) demonstrated that Ang II type 1 receptor (AT1R) blockers (ARBs) and ACEIs may exert therapeutic properties against pancreatic cancer. Finally, analyses of transcriptomic datasets have shown that the gene expression of ACE2 is similar in adrenocortical carcinoma, pheochromocytoma and paraganglioma compared with normal tissue (33), although the thymus gland contains no ACE2-expressing cells (22).

ACE2 is highly expressed in the heart, and its expression is further increased under stress conditions, such as myocardial infarction (89,90). An enhanced expression of ACE2 is implicated in the pathogenesis of heart failure, atrial fibrillation, coronary artery disease and thoracic aneurysm formation (91–97). Single-cell RNA sequencing (scRNA-seq) suggested that myocardial cells express ACE2 (98) independently of the age of the patients (26). Additionally, cardiofibroblasts, cardiovascular progenitor and endothelial cells, as well as epicardial adipose cells, express ACE2 (21,22,34). Nearly 30% of pericytes in the heart express ACE2 (97,99).

In the upper respiratory tract, ACE2 is detected in the olfactory and respiratory epithelium cells (100,101). According to a single-cell transcriptomic study (102), nasal secretory cells express ACE2. However, ACE2 expression has not been detected in secretory goblet cells of the airway (103). The proportion of nasal epithelial cells express ACE2 was 8.4% (22). Olfactory receptor neurons do not exhibit ACE2 expression, even though the olfactory bulb is ACE2-immunopositive (100). In addition, expression of ACE2 increases with age in the olfactory epithelium of the experimental mice (104). Epithelial cells of the tongue and lymphocytes within the normal oral mucosa are rich in ACE2 (105). ACE2 protein and mRNA expression levels are similar comparing among normal and oral dysplastic and squamous cell carcinoma (106,107). By contrast, a previous study suggested that ACE and ACE2 are promising targets for oral squamous cell carcinoma therapy (108). As Ang-(1–7) may have an important role in oral carcinogenesis, Ang-(1–7) and AT1R antagonists have already been introduced as therapeutic agents for head and neck squamous cell carcinoma (109). Moreover, treatment with the Ang-(1–7) complex decreases the progression of human nasopharyngeal carcinoma via autophagy, cell proliferation and angiogenesis inhibition, illustrating a possible role for ACE2 in the treatment of nasopharyngeal carcinoma (110,111).

High levels of ACE2 are associated with an improved prognosis in patients with operable laryngeal cancer (112). A total of ~2% of epithelial cells of the lower respiratory tract express ACE2 (98), whereas the bronchus and trachea express low levels of ACE2 (22,98). In terms of subcellular localization, ACE2 has been shown to be concentrated in the cilia organelle (103). Human alveolar type II (ATII) cells exhibit high ACE2 expression (23,113,114). According to previous findings based on scRNA-seq expression profiling analysis, ATII cells express ACE2 at low levels (22). ACE2 has also been detected in ATII progenitor and in alveolar stem-like cells (115). By contrast, ACE2 is expressed at lower levels in ATI and bronchial epithelial cells, fibroblasts, pericytes, endothelial cells and macrophages of the respiratory system (63,113). ACE2 is co-expressed with key elements of the bradykinin, angiotensin and coagulation systems in alveolar cells, and is associated with the differentiation dynamics of these systems (116). ACE2 expression is also associated with androgen expression in lung epithelial cells (117). Smoking was associated with higher ACE2 protein levels in alveolar and bronchial lung epithelial cells (117), and this association is independent of age and sex (118). ACE2 was found to be expressed in goblet cells in smokers (119,120); however, in a single-cell sequencing study, smoking did not affect ACE2 expression levels in lung cells (121). Similarly, in a bioinformatics study, the ACE2 levels of bronchial epithelial cells were similar between smokers and non-smokers (122). By contrast, recent data have shown that hypercapnia increases ACE2 expression in human bronchial epithelial cells (123). These conflicting data concerning smoking and ACE2 expression may reflect differences in the susceptibility of patients to inflammation, and structural changes in the lung parenchyma leading to the development of chronic obstructive pulmonary disease.

ACE2 is strongly expressed in lung adenocarcinoma and squamous cell carcinoma compared with normal tissues according to database analysis studies (19,44,124). In the study by Chai et al (44), decreased levels of ACE2 DNA methylation are associated with high expression of ACE2 in lung adenocarcinomas Similarly, in a bioinformatics study by Zhang et al (125), the expression of ACE2 was shown to be significantly increased in lung adenocarcinoma and squamous cell carcinoma compared with normal tissue, without any variations being observed with respect to the stage of the tumor, whereas ACE2 upregulation is associated with DNA methylation. According to another study (126), ACE2 upregulation in patients with lung adenocarcinoma is age-dependent. Moreover, in a retrospective cohort study on the outcomes of patients with COVID-19 and lung cancer, ACE2 expression was higher at the resection margins of lung cancer survivors compared with the normal tissue of non-cancerous individuals (127). Furthermore, in a single-cell transcriptomic small-scale analysis (128), the expression of ACE2 was predominantly found in cancer and alveolar cells of lung adenocarcinoma, and no differentiation of expression was observed between lung adenocarcinoma and lung squamous cell carcinoma in the cancer cells, irrespective of smoke exposure. On the other hand, in a study that used gene expression analyses of data obtained from the Gene Expression Profiling Interactive Analysis 2 (GEPIA2), The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) public databases (129), the upregulation of ACE2 in lung adenocarcinoma was not confirmed. Furthermore, in a study by Kong et al (130) on lung squamous cell carcinoma, ACE2 expression was shown to be similar between normal lung and the classical, secretory and basal subtypes of lung squamous cell carcinoma whereas the primitive subtype demonstrated lower ACE2 gene expression compared with normal lung tissue. In addition to these findings, another study that employed gene expression analysis suggested that the gene expression of ACE2 does not change in lung tumors compared with normal tissue (33). By contrast, in the bioinformatics study of Cui et al (18), lower levels of ACE2 expression were reported in lung adenocarcinoma compared with normal tissue. However, the aforementioned bioinformatics gene expression studies did not provide the clinicopathological characteristics of the patients, and, to the best of our knowledge, only one dataset has been published containing information on smoke exposure of the patients (128); therefore, the results may not be considered comprehensive. Additional clinical data will need to be analyzed in the future to clarify the association between ACE2 and clinical characteristics of cancer, including exposure of the patients to pollutants, a previous diagnosis of chronic obstructive pulmonary disease and daily prescriptions. It is worth noting that ACE2 expression in lung metastases derived from different cancer subtypes is higher compared with organ metastases of other sites (126). Additionally, ACE2 is expressed at higher levels in lung metastases from colorectal cancer compared with normal lung tissue (131). Moreover, the proportion of ACE2-positive cells is higher in the pulmonary metastatic areas of patients with high-grade serous ovarian cancer compared with normal alveolar and bronchiolar areas. Notably, ACE2 is expressed in alveolar epithelial stem and stem-like cells adjacent to ovarian cancer in lung metastasis (132).

In a bioinformatics study by Feng et al (43), it was reported that high expression of ACE2 is beneficial in lung adenocarcinoma, although this has a detrimental effect on prognosis in lung squamous cell carcinoma. However, in the bioinformatics study by Zhang et al (125), although ACE2 expression was not associated with disease-free and overall survival for patients with lung adenocarcinoma, higher ACE2 expression was associated with prolonged disease-free survival in patients with lung squamous cell carcinoma, suggesting a complex role for ACE2 in lung cancer. By contrast, in the bioinformatics study by Samad et al (133), high expression of ACE2 mRNA, irrespective of the age and sex of the patients, was associated with shorter overall and relapse-free survival rates in patients with lung adenocarcinoma and squamous carcinoma. In a study by Lazar et al (134), ACE2 expression in either normal lung tissue or tumor tissue derived from non-small cell lung cancer (NSCLC) was not associated with disease-free survival of the patients. In the same study, higher expression levels of ACE2 were identified in advanced stages of lung cancer (134). Moreover, a bioinformatics study by Dai et al (135) revealed that ACE2 expression is not associated with the prognosis of patients with lung cancer compared with ACE2 expression from resected normal lung tissue. Furthermore, decreased ACE2 expression was associated with poor overall survival in mesothelioma (135).

In the study by Deben et al (136), wherein membranous and soluble ACE2 expression was investigated in patients with NSCLC and focus was made on standard-of-care therapies, no association between ACE2 levels and the patient clinicopathological data was observed. Moreover, higher frequency of ACE2 expression was reported in patients with epidermal growth factor receptor (EGFR) mutations, whereas no increased ACE2 expression was observed in KRAS-mutant patients, and prior therapy did not cause increases in soluble ACE2 levels (136). ACE2 levels are increased in the EGFR-mutant lung adenocarcinoma HCC827 cell line, and an anti-ACE2 antibody has been developed against tumors resistant to EGFR inhibitors, although further testing of this antibody is required (137). On the other hand, in vitro data have suggested that ACE2 overexpression exerts a protective effect by inhibiting cell proliferation and the production of vascular endothelial growth factor A (VEGFA) in NSCLC cell lines (138). Treatment with cisplatin and gemcitabine upregulate ACE2 expression in A549 NSCLC cancer cells, demonstrating that standard chemotherapy regimens affect ACE2 expression levels in lung cancer cells in vitro (139). Nevertheless, ACE2 overexpression may inhibit cell proliferation and VEGF production in NSCLC lines following the development of acquired platinum resistance (140). Moreover, the overexpression of ACE2 decreases both the invasive properties of A549 lung cancer cells and the production of matrix metalloproteinase (MMP)-2 and MMP-9, whereas it decreases tumor angiogenesis in vivo by lowering VEGFΑ levels (141). Τhe addition of DX600, which serves as an ACE2 inhibitor, to the A549 lung cancer cell line leads to a recovery of the sensitivity of lung cancer cells to TGF-β1-mediated induction of epithelial-mesenchymal transition, suggesting that ACE2 enhances lung cancer cell metastasis (142). Furthermore, patients with advanced lung cancer who receive ARBs or ACEIs in addition to platinum-based first-line treatment demonstrate a 3.1-month longer median survival rate compared with non-recipients (143). In addition, Ang-(1–7) peptides decrease tumor size in a lung cancer mouse model, wherein mice were injected with A549 human lung cancer cells, indicating a RAS-inhibitory effect in lung cancer cell proliferation (144). Nevertheless, the use of ACEIs is associated with an increased risk of lung cancer (145). A recent study highlighted the interaction of SARS-CoV-2 with ACE2 as a possible mechanism in lung tumor therapy (146). ACE2 has also been proposed as a postoperative prognostic factor for patients with NSCLC (147).

ACE2 expression is significantly decreased in breast cancer samples compared with normal tissue (18,148,149), with the exception of the basal-like subtype (148). In addition, decreased levels of ACE2 expression in the plasma of patients with breast cancer compared with healthy controls has been identified (150). DNA promoter methylation has been proposed as the primary mechanism underlying ACE2 downregulation in breast cancer (151). ACE2 expression is positively associated with immune cell infiltration (18). Jiang et al (148) suggested that ACE2 expression is associated with enhanced rates of neutrophil infiltration in basal-like breast cancer, whereas in the luminal subtype, ACE2 expression is associated with higher ratios of CD4⁺ and CD8⁺ T cells and neutrophil infiltration (47,148). ACE2 expression is also associated with both the inflammatory microenvironment of the tumors and estrogen receptor, progesterone receptor and HER2 negativity in breast cancer (149). Moreover, increased expression of ACE2 is associated with fewer disseminated foci, shorter metastatic distances, downregulation of VEGFA and suppression of the proliferation of MCF-7 cells in vitro (152).

In addition, bioinformatics studies have shown that patients with breast cancer with high ACE2 expression exhibit longer relapse-free survival rates and improved overall prognosis (151,152). Decreased expression of ACE2 are associated with poorer prognosis of luminal B breast cancer following SARS-CoV-2 infection (148). However, in breast invasive cancer, ACE2 expression is significantly higher compared with normal tissue (135), and the stronger ACE2 immunostaining was associated with high-tumor grade, HER2 overexpression and loss of estrogen and progesterone receptors (14). He et al (47) reported that high ACE2 expression is associated with poor prognosis of patients with breast invasive carcinoma. On the other hand, results obtained in vitro have demonstrated that ACE2 may inhibit the development of breast cancer (152), and downregulation of the ACE2/Ang-(1–7)/Mas axis increases breast cancer cell metastatic properties by enhancing calcium entry (153). Finally, in a bioinformatics study, ACE2 expression was positively associated with EGFR expression, whereas high levels of ACE2 are associated with decreased disease-free survival in the HER2-enriched subtype (154).

Regarding therapeutic intervention options, ACE2 levels, controlled by hypoxia-inducible factor-1 (HIF-1) and the concentration of reactive oxygen species (ROS), are elevated following chemotherapy in breast cancer cells (150). Moreover, increased ACE2 expression following chemotherapy is a poor prognostic factor for patients with breast cancer, as ACE2 upregulation is likely associated with the development of drug resistance in breast cancer (150); however, it has been reported that patients with high levels of ACE2 tend to be sensitive to a variety of therapeutic options, including immunotherapy and antiangiogenic therapy (149).

Liver, pancreas, stomach, small intestine and colon tissue express ACE2, primarily in mesenchymal and capillary endothelial cells (61,76,86). The highest levels of ACE2 expression are found in the goblet cells (13,22,61). Furthermore, ACE2 is highly expressed in epithelial basal cells, cholangiocytes and colonocytes, ileum and rectum enterocytes and in the epithelial stomach cells, as well as in progenitor, stem and transient amplifying cells of the ileum (23). ACE2 has been shown to be expressed in 30% of ileal cells (98), whereas ACE2 expression in the terminal ileum is 25-fold higher compared with that in the colon (155). In the ileum and colon, ACE2 levels are regulated by the HNF-4α) transcription factor (156). Additionally, ACE2 is highly expressed in the epithelial cells of the tongue and salivary gland (17,23,157).

ACE2 levels are also increased in esophageal carcinoma (42,43,47). However, database analyses have revealed that ACE2 expression does not differ in esophageal carcinoma tumors compared with normal tissue (19,33). In a study that utilized data from an scRNA-seq analysis, ACE2 expression increased with progression from chronic gastritis to metaplasia, reaching its highest levels in early gastric cancer (158). Additionally, gene expression analyses have confirmed a significant upregulation of ACE2 expression in stomach cancer samples compared with that in adjacent non-tumor gastric tissue (44,76,129). By contrast, other bioinformatics studies have shown both that ACE2 levels are lower in stomach adenocarcinomas compared with the adjacent normal tissue, and that ACE2 expression either tends to increase in conjunction with the stages of tumor progression (19,47) or does not differ between stomach adenocarcinoma and normal tissues (33). However, the aforementioned studies did not include clinical information about the patients. ACE2 expression was found not associated with the prognosis of patients with stomach adenocarcinomas (19).

In normal liver tissue, ACE2 is expressed in the bile canaliculi of hepatocytes, biliary epithelium, sinusoidal and capillary endothelial cells (159). High ACE2 expression is observed at the apical surface of cholangiocytes (160). The hepatic expression of ACE2 is higher in adults compared with children, although it is augmented in pediatric patients with liver disease compared with normal subjects (160). ACE2 in hepatocytes limits fibrogenesis in mice, and ACEs are a negative glycolytic regulator for hepatocytes (161,162). ACE2 expression in hepatocytes is increased in inflammatory liver conditions and fibrotic/cirrhotic liver disease (163). ACE2 hepatic upregulation has been documented in a chronic liver injury rat model (164). In a different study (76), the immunohistochemical expression of ACE2 was found to be decreased in liver cancer tissue. A transcriptomic analysis by Facchiano et al (33) revealed no significant differences in ACE2 expression in liver hepatocellular carcinoma compared with normal liver. Moreover, increased mRNA and protein expression levels of ACE2 have been reported in well-to-moderately differentiated hepatocellular carcinoma tissue compared with poorly differentiated tumors (159). Furthermore, β-catenin mutations are associated with ACE2 DNA hypomethylation (159). In addition, higher levels of ACE2 are associated with improved overall and disease-free survival rates in patients with liver hepatocellular carcinoma (43,47,129,135), and ACE2 downregulation may serve as a predictor of poor prognosis in patients with hepatocellular cancer (162). An analysis using human using the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) databases revealed that ACE2 mRNA levels are gradually decreased with an increasing grade of hepatic disease severity, suggesting that low ACE2 expression levels are a poor prognosis indicator for hepatocellular carcinomas (165). Infection with hepatitis C has been shown to cause increases in the mRNA and protein levels of ACE2 in Huh7.5 cells and human liver tissue (166). In a patient-derived xenograft model (162), ACE2 overexpression impedes tumor growth via a decrease in ROS-HIF1α activity. Therefore, the ACE2/Ang-(1–7)/MasR/ROS/HIF-1α axis may be a promising target for therapeutic intervention in hepatocellular cancer (162).

ACE2 is highly expressed in the gallbladder, and ACE2 levels differ in cholangiocarcinoma compared with normal tissue (33). ACE2 levels are higher than normal in gallbladder carcinoma and cholangiocarcinoma tumors (19). Negative ACE2 expression is an independent poor prognostic factor for squamous cell carcinoma/adenosquamous carcinoma and adenocarcinoma of the gallbladder, as it is associated with larger tumor size, higher TNM stage, lymph node metastasis, invasive properties and increased levels of carbohydrate antigen 19-9 (167). In vitro and in vivo data have shown that genetic replenishment of ACE2 and the use of angiotensin receptor blockers restore the expression of ACE2, thereby mitigating gallbladder cancer (168).

ACE2 is present in enterocytes in the small intestine and colonocytes, primarily in the surface epithelium (76,169). Moreover, these cells exhibit the highest proportion of cells co-expressing ACE2 and TMPRSS2, which are required for SARS-CoV-2 entry into mammalian cells (169). ACE2 expression is continuous across the surface epithelium of the small intestine, and has also been detected on the crypt epithelium, whereas ACE2 expression in the colon is patchy (170). ACE2 serves as a mediator in intestinal homeostasis (171,172). Moreover, ACE2 regulates the gut-blood barrier; in ACE2^−/− Akita mice, the disrupted gut barrier was shown to be associated with lower levels of angiogenetic and hemopoietic cells and gut dysbiosis (34,173). ACE2 is a key player in the dopamine/trace amines metabolic pathway, as it supports the intestinal absorption of tyramine, tyrosine, phenylalanine, tryptophan and tryptamine (174). ACE2 knockdown induces the clinical and histological findings of dextran sodium sulfate-induced colitis in a mouse model (175). In addition, ACE2 expression is significantly decreased in the inflamed ileum of patients with Crohn's disease (155,156), whereas its expression is higher in the inflamed colon of patients with Crohn's disease or ulcerative colitis compared with control subjects (156). Furthermore, the mucosal expression of ACE2 is 50% higher in inflamed compared with non-inflamed colon sites in patients with ulcerative colitis (155). Serum ACE2 levels are also increased in patients with inflammatory bowel disease compared with controls (176). Finally, in a study by Potdar et al (177), decreased mRNA levels of ACE2 in the small bowel and increased levels of ACE2 in the colon were associated with demographic features, such as age and an elevated body mass index.

ACE2 expression is higher in rectum carcinomas (18,19,44) and colon cancer tissue compared with controls (18,19,33,42,47,76,129,178–182). The ACE2 expression increases moving from normal to adenoma samples, and colon cancer samples (183). ACE2 expression is associated with immune cell infiltration in both normal and cancerous stomach and colon tissue (87,184). Notably, colorectal tumors with upregulated ACE2 gene expression display decreased DNA methylation levels (44,179,184). In a study by Li et al (182), increased ACE2 gene mutation frequency, associated with decreased expression, was observed in the early-onset colorectal cancer group of patients compared with the late-onset group. However, according to bioinformatics studies, the upregulation of ACE2 expression is not associated with the survival outcomes of patients with colon adenocarcinoma (44,184). By contrast, higher expression levels of ACE2 are associated with a favorable prognosis and improved survival rates in patients with colon and colorectal adenocarcinoma, respectively (19,182). There are also data suggesting that decreased expression of ACE2 is associated with an unfavorable tumor phenotype in colorectal adenocarcinoma (14). Additionally, high mRNA levels of ACE2, along with high mRNA levels of bromodomain and extra terminal domain 4, are associated with reduced survival rates of patients with colorectal cancer (185).

ACE2 expression is downregulated in intestinal organoids following SARS-CoV-2 infection (186,187). Moreover, the radiological reduction of colon cancer metastasis in three patients following SARS-CoV-2 infection has been described; the potential mechanisms [a direct immune response, likely coordinated by natural killer (NK) cells and T lymphocytes, or cytokine release following SARS-CoV-2 infection in colorectal cells] merit further investigation as higher degranulation levels of NK cells has been documented in the presence of ACE-2/NRP-1-expressing cells (188,189). Ficin and bromelain, aqueous extracts derived from the fruits of Ficus carica and Ananas comosus plants, exert cytotoxic effects against human cholangiocarcinoma, breast, prostate, stomach and hypopharynx squamous carcinoma cells, respectively, inducing apoptosis and decreased ACE2 expression in Caco-2 cells (190). Higher ACE2 mRNA levels have also been associated with lower activity of the anti-cancer immune response in colorectal cancer (182).

ACE2 is highly expressed in proximal tubule cells and glomerular parietal epithelial cells of the kidney (14,23,46, 61,98,191–194). In addition, podocytes, endothelial and mesangial cells in the kidney also express ACE2 (22,61,195). ACE2 exerts renal protective properties against albuminuria and glomerular injury in diabetic mouse models (196,197). In a study by Vergara et al (198), the presence of ACE2 in the urine served as a prognostic indicator for acute kidney injury, and ACE2 tubular staining was 2-fold lower in the specimens of patients with COVID-19 compared with non-COVID-19 samples. ACE2 was not expressed in the ureter (22).

ACE2 promotes epithelial-mesenchymal transition in renal tubular cells (199). According to TCGA, the Genotype-Tissue Expression the Gene Expression Omnibus database analyses that did not categorize patient characteristics (42,86), the mRNA and protein expression levels of ACE2 were higher in kidney renal clear and papillary cell carcinoma compared with the normal kidney. In a retrospective cohort study, chromophobe renal cell carcinoma specimens exhibited negative immunostaining for ACE2 (200). The downregulation of ACE2, as determined by immunohistochemical expression and enzyme activity in tumors from the distal nephron (chromophobe renal cell carcinoma and renal oncocytoma) with respect to normal tissues, was also reported by Larrinaga et al (201) and Errarte et al (202). In addition, higher levels of immunohistochemical expression and serum activity of ACE2 are noted in kidney renal clear and papillary cell carcinoma compared with healthy individuals (202). Therefore, ACE2 may be useful for identification of the renal subtype, as its low rates of immunopositivity in chromophobe renal cancer cells compared with the high levels of ACE2 positivity in clear and papillary renal tumor cells may be useful for assessing undifferentiated tissues (14). However, in the study by Facchiano et al (33) using data retrieved from GEPIA2 and GENT2 databases, there was no difference in expression in kidney renal clear cell carcinoma compared with controls. Other bioinformatics studies (18,203,204) have reported contradictory data, namely a significant downregulation of ACE2 expression at the mRNA and protein levels in kidney renal clear cell carcinoma compared with normal samples. Furthermore, in the study by Yang et al (204), ACE2 immunohistochemical analysis of 54 patients revealed that a lower expression of ACE2 in kidney renal clear carcinoma compared with adjacent normal tissue was associated with malignant characteristics and metastasis of the tumors. As ACE2 expression in the human kidney differs in various clinicopathological conditions, including diabetes, acute kidney injury and chronic renal failure (196–198), the contradictory results regarding ACE2 expression in kidney tumors require further investigation.

ACE2 is positively associated with immune cell infiltration in kidney renal clear and papillary cell carcinoma (43,86,203–206). In addition, several ACE2-associated kinases, microRNAs and transcription factors involved in regulating genomic stability, cell cycle and ribosomal activity have been identified in kidney renal clear cell carcinoma (203). Furthermore, decreased levels of ACE2 gene methylation in kidney renal clear and papillary cell carcinomas have been identified (18,44,205). Early-stage tumors express ACE2 at higher levels compared with advanced tumors in kidney renal clear and papillary cell carcinomas (86,206), whereas ACE2 expression is significantly reduced in stage IV kidney renal papillary carcinoma (18). ACE2 staining has been found in cancer stem cells (CSCs) in a limited sample of kidney renal clear cell carcinoma tissues (207), and the presence of CSCs in renal clear cell carcinoma has also been identified (208).

As ACE2 is differentially expressed in different renal tumor subtypes, conflicting data regarding its impact on patient outcome have also been reported (14,18,19,43,44,69,86, 202–205). Retrospective studies have not identified any significant association between the immunohistochemical expression of ACE2 and the survival rates of patients with kidney renal clear cell carcinoma (202,207), whereas the majority of bioinformatics data report that ACE2 expression is increased in kidney renal clear and papillary cell carcinoma, and this increased expression is associated with increased survival rates and improved disease-specific survival rates for these patients (19,43,44,69,86,206,209). In another bioinformatics study however, ACE2 is downregulated in kidney renal clear cell carcinoma at the mRNA and protein level, whereas the upregulation of ACE2 is associated with a favorable prognosis and improved overall survival of the patients (203). Decreased ACE2 levels have been associated with worse pathological features such as advanced tumor stage, higher histological grade and pathological stage and metastasis (18,204). However, the low expression of ACE2 in kidney renal clear cell carcinoma may affect the prognosis of patients since the prognostic role of ACE2 is differentiated according to infiltration levels of different types of immune cell in these tumors (204). In the study by Tang et al (206), ACE2 downregulation was associated with poor overall survival in kidney renal clear and papillary cell carcinomas and metabolic homeostasis of tumor cells. In other studies (14,209), decreased expression of ACE2 and its activity in kidney renal clear cell carcinoma is associated with advanced pathological features, poorer overall survival and different immune cell subtypes. According to Cui et al (18), ACE2 downregulation is associated with higher clinical stage and worse survival rate, whereas hypermethylation of ACE2 is linked to higher survival in kidney renal clear cell carcinoma.

ACE2 overexpression was reported by Khanna et al (210) to exert inhibitory effects on tumor proliferation in kidney renal clear cell carcinoma. Additionally, treatment of clear cell renal cell carcinoma xenografts with VEGF receptor-tyrosine kinase inhibitor (VEGFR-TKI) decreases ACE2 expression, whereas combinatorial treatment with VEGFR-TKI and Ang-(1–7) leads to further suppression of tumor growth, thereby improving survival outcomes (210). ACE2 expression, along with MMP24, solute carrier family 44 member 4, complement C1r, chromosome 1 open reading frame 194 and ADAM metallopeptidase with thrombospondin type 1 motif 15, are associated with TKI resistance in kidney renal clear cell carcinoma, which limits the therapeutic opportunities and worsens the prognosis for patients with metastatic disease (211). Furthermore, lower ACE2 levels are associated with increased drug resistance in renal cancer cell lines (206). In addition, Kim et al (69) demonstrated that prioritizing ACEIs for blood pressure control over other antihypertensives may increase survival rates of patients with kidney renal clear cell carcinoma.

Testicular cells demonstrate high levels of ACE2 (22,46,61). ACE2 has been identified in both cytoplasmic and membranous regions of the testicular cells (13,192,212–214). Furthermore, male embryo primordial germ cells express ACE2 (215). In adulthood, ACE2 expression is negatively associated with age (215), and the age-associated expression of ACE2 in the testis is confirmed in other studies, with a peak occurring at ~30 years of age and the lowest expression occurring at ≥60 years (192,214,216). ACE2 in Leydig cells regulates steroidogenesis and vascular tone, and its expression is not affected by testosterone levels or downregulation of luteinizing hormone (212). Spermatogenesis is regulated by the RAS system (217). In particular, lower mRNA levels of ACE2 are found in testicular samples of patients diagnosed with non-obstructive azoospermia compared with patients with obstructive azoospermia (218). However, the activity of ACE2 is higher in infertile males compared with normal subjects following SARS-CoV-2 infection (216). Moreover, according to Fu et al (13), testis malignancy is associated with low expression rates of ACE2. In addition, a transcriptomic analysis revealed significantly higher levels of ACE2 in testicular germ cell tumors compared with healthy controls (33). Another bioinformatics study (86) identified lower levels of ACE2 in testicular germ cell tumors compared with the normal testis. In addition, Feng et al (43) showed that ACE2 may influence the tumor prognosis of testicular germ cell tumors via cancer immunity.

ACE2 is expressed in 0.32% of all prostate epithelial cells (219). Bioinformatics data show that ACE2 levels are lower in prostate adenocarcinomas compared with normal tissue (19,43,47). Contrary to these findings, however, results of studies that employed the same methodology (33,86) demonstrate ACE2 gene expression in prostate cancer tissue is not found significantly different from that of normal tissue. ACE2, as well as Ang-(1–7), has been shown to have a protective role against metastasis formation in prostate cancer (220,221). In addition, in the study by Huang et al (86), ACE2 was positively associated with immune cell infiltration in prostate cancer tissue. Since, as suggested by a study utilizing mice models, androgen inhibition augments ACE2 levels, ACE2 is a potential therapeutic target for patients with prostate cancer (222).

ACE2 is also expressed in the endometrium, although its expression is more pronounced in epithelial compared with stromal cells (223–226). The mRNA levels of ACE2 are increased in the endometrium of patients with polycystic ovaries (225). On the other hand, in another study (227), ACE2 was downregulated in the granulosa cells of patients with polycystic ovaries compared with controls. Other studies have demonstrated that ACE2 is expressed in syncytiotrophoblast, cytotrophoblast and trophoblastic cell lines, blastocysts, chorion cells of the placenta, endothelium and smooth muscle of the umbilical cord (12,226,228–230). High ACE2 mRNA levels have been confirmed in placental cells by Ren et al (61). ACE2 is expressed in the fallopian tube epithelium (22), although in primary oocytes, ACE2 expression is absent (230). However, ACE2 mRNA expression has been identified in tissue RNA from human ovarian samples (231). Moreover, high levels of ACE2 protein expression are identified using mass spectrometric analysis in ovarian cells, whereas immunohistochemical analyses did not detect the protein in either follicular or stromal ovarian cells (232).

The ACE2/Ang-(1–7)/Mas1 signaling axis may have both tumor-promoting and -inhibiting properties in ovarian cancer (233). ACE2 has been demonstrated to be a protective and independent prognostic factor in patients with ovarian cancer (19,43,47). High levels of ACE2 are associated with increased overall and disease-free survival rates in patients with ovarian cancer (19,43,47). High expression of ACE2 in patients with serous subtype ovarian cancer is associated with improved overall survival compared with the endometrioid subtype, and improved progression-free survival in the endometrioid subtype (47). High ACE2 expression is associated with poorer overall survival in patients with ovarian cancer without the TP53 mutation (47). In the study by Nagappan et al (234), ACE2 levels were increased in ovarian clear cell cancer carcinoma compared with normal tissue and this increase was associated with increased chemoresistance. According to the same study, ACE2 regulates caveolin-1-associated signaling pathways, thereby affecting the platinum-clearing enzyme cytochrome P450 3A4, and resistance to platinum-based drugs (234). Additionally, higher mRNA levels of ACE2 are detected in endometrium tumors compared with controls (235). ACE2 is upregulated in cervical squamous cell carcinoma, endocervical adenocarcinoma and uterine corpus endometrial carcinoma (19,42). In addition, higher expression of ACE2 in the uterine corpus and endometrial tumors is associated with both an enhanced infiltration of immune cells in the tumor environment and improved survival rates (205). By contrast, in the study by Facchiano et al (33), altered levels of ACE2 expression were not observed between ovarian serous cystadenomas and cervical squamous cell, endocervical and uterine carcinoma and normal tissue.

Low levels of ACE2 have been detected in bladder epithelial cells; 0.25 and 1.28% of intermediate and umbrella cells, respectively, express ACE2 (194). According to Zou et al (98), the proportion of ACE2-positive cells in bladder urothelial cells is ~2.4%; moreover, the levels of ACE2 were found not to differ in bladder urothelial cell carcinoma compared with normal tissue (19,33,86). However, ACE2 expression is associated with immune cell infiltration in bladder urothelial cell carcinoma and ACE2 gene mutations have been also observed (19). In addition, high expression of ACE2 is associated with improved prognosis for patients with uterine carcinosarcoma (19).

A previous study reported expression of ACE2 in basal epidermal layers and in the sebaceous gland cells in normal skin, whereas non-melanoma skin cancer, such as basal and squamous cell carcinoma, does not express ACE2 (236). The transcriptomic analysis by Facchiano et al (33) identified similar levels of ACE2 gene expression in skin cutaneous melanoma and in normal skin. Similarly, in the same study, ACE2 expression levels did not differ between head and neck squamous cell carcinomas and controls (33). However, ACE2 expression is positively associated with immune cell infiltration in skin cutaneous melanoma (19). Negative ACE2 immunostaining was reported in all head and neck metastatic malignant melanoma tissue samples included in the study by Siljee et al (237), although ACE2 mRNA was detectable in these tumors. Higher ACE2 levels are associated with improved overall survival for patients with uveal melanoma (19). According to Facchiano et al (33), ACE2 gene expression is significantly altered in sarcoma tissues compared with normal tissues. Ender et al (238) demonstrated the osteosarcoma cell lines U-2 OS and MNNG-HOS express ACE2, and therefore activation of the ACE2/Ang-(1–7)/Mas axis may be a promising therapeutic option for osteosarcoma.

The RAS system in the bone marrow controls myelopoiesis, erythropoiesis and thrombopoiesis (239,240). ACE2 serves an important role in myelopoiesis (241). Ang peptides accelerate the rate of hematopoietic recovery following radiation exposure in mice (242,243). The RAS system is expressed in hematopoietic stem cells and ACE2 is detected in very small embryonic-like stem cells (239,240,244–247). Notably, almost no cells of the peripheral blood, bone marrow and spleen exhibit high expression of ACE2 (22,23). However, through data analysis, high mRNA expression levels of ACE2 have been detected in the bone marrow (61). mRNA expression levels of RAS components have been reported in patients with myeloma, implying that the local RAS is implicated in the pathology of the hematopoietic system (247). In a study by Gomez Casares et al (248), renin expression was evaluated in hematological malignancies and in certain acute myeloid human leukemia cell lines, and the results showed that renin expression may have a role in the development of acute myeloid leukemia, and may be used as an aberrant marker of leukemia. High ACE2 mRNA expression levels have also been reported in leukemia (47), and ACE2 mutations are observed in acute myeloid leukemia (19). In the study by Alshareef (249), ACE2 gene expression levels were significantly higher in patients with chronic myeloid leukemia but did not differ significantly when comparing myelodysplastic syndrome and acute myeloid leukemia with normal samples. In addition, ACE2 expression was shown to be significantly associated with microsatellite instability in diffuse large B cell lymphoma (19). According to the transcriptomic analysis by Facchiano et al (33), ACE2 gene expression is not associated with acute myeloid leukemia or diffuse large B cell lymphoma. Finally, telmisartan, an Ang receptor blocker that functions via peroxisome proliferator-activated receptor and caspase activation, induces apoptosis in adult T cell leukemia cells (250).

As aforementioned, contradictory data for ACE2 expression and its association with prognosis have emerged, mainly in lung and kidney tumors. Although ACE2 may serve as a prognostic and therapeutic target in human tumors, in the majority of studies, the patient clinicopathological features such as age and sex, medical history of inflammatory conditions, diabetes, metabolic comorbidities, heart failure, hormonal status and previous therapies, which alter ACE2 expression (6,24–27,31–40), were not taken in consideration. Moreover, ACE2 polymorphisms and epigenetic factors affect ACE2 expression (251).

In the respiratory system, smoking, hypercapnia and hyperoxia influence ACE2 levels (117–123,252). In addition, increased immunoexpression levels of ACE2 following SARS-CoV-2 infection are reported in the lung autopsy tissues of patients with COVID-19 (253). With regard to the COVID-19 treatment options, it has been demonstrated that dexamethasone increases ACE2 levels, whereas remdesivir decreases ACE2 levels, in bronchial and alveolar cell cultures (254). Furthermore, ACE2 levels decrease following acute lung inflammation, although it is not known how long this decrease lasts (255). Therefore, the role of ACE2 in lung cancer should be evaluated in the context of the lung pathophysiological conditions and recent infection status of patients.

Similarly, according to a recent study (256), ACE2 is not expressed in the thyroid tissue of patients without COVID-19 infection, although a high proportion of positive ACE2-immunostained cells in the thyroid tissues of deceased patients with COVID-19 is documented, suggesting that the conflicting data regarding ACE2 expression in thyroid cancer should be re-evaluated after the pandemic. In addition, Bronowicka-Szydełko et al (257) demonstrated the interaction between SARS-CoV-2 and thyroid cells which may explain how carcinogenesis is initiated in this gland. SARS-CoV-2 may also affect the viability and migratory properties of colorectal and prostate cancer cell lines (258), thereby providing knowledge of how SARS-CoV-2 infection modulates human tumor biology.

Differences in the expression of ACE2 across kidney tissue in acute kidney injury were described by Shirazi et al (259), whereas ACE2 exerts protective effects against aging and albuminuria in kidney tissue (166,197,260). Therefore, the conflicting results on ACE2 expression in human kidney tumors may reflect differences in the underlying renal pathophysiological mechanisms. In addition, the oncolytic effects of COVID-19 in renal cancer cells should be evaluated according to recent data describing the consequences of SARS-CoV-2 infection in the kidney tissue (261).

Singh Parmar et al (262) reported that patients with breast cancer are more susceptible to COVID-19 compared with their normal counterparts, and ACE2 inhibitors and ibuprofen therapy for COVID-19 treatment may aggravate the clinical condition of patients with breast cancer through chemoresistance and metastasis. On the other hand, the therapeutic properties of ACE2 in intestinal cancer were presented in a study that reported that treatment with bromelain and ficin decreases ACE2 protein levels, thereby decreasing the viability of human colon cancer cells (190). Since numerous drugs modify ACE2 levels (263), data about medication usage should be considered in evaluation of ACE2 expression in various types of tumors.

Finally, the aforementioned studies integrated information from multiple public bioinformatics databases, which do not include associations with clinicopathological characteristics of the patients; moreover, there are variations in the numbers of samples for each type of cancer. Furthermore, there were discrepancies between databases regarding the comparisons made between tumor tissue and control samples; certain databases include matched healthy tissues whereas other databases include adjacent normal tissues. for control samples. Huang et al (86) reported that adjacent normal tissue expresses ACE2 in a different manner compared with healthy tissue; for example, both cancers and adjacent normal tissues were shown to express ACE2 at higher levels compared with healthy tissue in the colon, stomach, kidney and lung.

As conflicting results exist between databases, it is difficult to elucidate the role of ACE2 in the pathogenesis of cell-specific tumors. Further validation of the data in multicohort clinical analyses is warranted to identify the associations between ACE2 and the clinical characteristics of patients with cancer. Furthermore, additional functional studies, including in vivo and in vitro experiments, are required to clarify the role of ACE2 in oncogenesis, especially following the COVID-19 pandemic.

ACE2 expression may be implicated in tumor pathogenesis, and serve as a prognostic marker, despite the conflicting data for various types of cancer. The present study summarizes ACE2 expression in human tumors and the need for further investigations of the involvement of ACE2 in tumorigenesis. Furthermore, ACE2 expression should be evaluated with a multidisciplinary approach as the effects of SARS-CoV-2 on cancer cells may be cell type-dependent. Since the expression of ACE2 is regulated by chemical and mechanical signal transduction pathways (264) it is necessary to elucidate epigenetic profiling of ACE2 expression and its role in clinicopathological features of various types of tumors.