High ACE2 Expression Research Articles

Abstract P42: Construction of a risk map to understand the vulnerability of various types of cancer patients to COVID-19 infection

Abstract COVID-19 is leading to a global pandemic and invades human cells via ACE2. ACE2 was found to abundantly expressed in many organs and cells. However, there is no evidence about the potential risk of various types of cancer patients vulnerable to the infection of COVID-19. To obtain a risk map which indicating the novel coronavirus vulnerability of different types of cancer, so in this work we analyzed the RNA sequencing datasets of cancer patient. By interrogating the datasets, we not only identified the cancer types which vulnerable to COVID-19 attacks, but also we reported that variations in the mRNA expression level of ACE2 correlate to various prognosis phenomenon in different types of cancer cohorts and illustrated the underlying mechanism involved in may be related to lymphocytes infiltration. From these discoveries, we constructed an infection risk map which indicate the vulnerability of different types of cancer to COVID-19 infection, also elucidated the correlationship between ACE2 and the prognosis of cancer. We found that high ACE2 expression levels leading high risk of COVID-19 infection and poor prognosis of BRCA while better prognosis in OV patient cohorts. Moreover, our study demonstrated that this different pattern may correlate with the immune infiltration level. Note: This abstract was not presented at the conference. Citation Format: Jian He, Mei Meng, Yiyang Zhao. Construction of a risk map to understand the vulnerability of various types of cancer patients to COVID-19 infection [abstract]. In: Proceedings of the AACR Virtual Meeting: COVID-19 and Cancer; 2021 Feb 3-5. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(6_Suppl):Abstract nr P42.

Cross Talk between COVID-19 and Breast Cancer.

Cancer patients are more susceptible to COVID-19; however, the prevalence of COVID-19 in different types of cancer is still inconsistent and inconclusive. Here, we delineate the intricate relationship between breast cancer and COVID-19. Breast cancer and COVID-19 share the involvement of common comorbidities, hormonal signalling pathways, gender differences, rennin- angiotensin system (RAS), angiotensin-converting enzyme-2 (ACE-2), transmembrane protease serine 2 (TMPRSS2) and dipeptidyl peptidase-IV (DPP-IV). We also shed light on the possible effects of therapeutic modalities of COVID-19 on breast cancer outcomes. Briefly, we conclude that breast cancer patients are more susceptible to COVID-19 in comparison with their normal counterparts. Women are more resistant to the occurrence and severity of COVID-19. Increased expressions of ACE2 and TMPRSS2 are correlated with occurrence and severity of COVID-19, but higher expression of ACE2 and lower expression of TMPRSS2 are prognostic markers for overall disease free survival in breast cancer. The ACE2 inhibitors and ibuprofen therapies for COVID-19 treatment may aggravate the clinical condition of breast cancer patients through chemo-resistance and metastasis. Most of the available therapeutic modalities for COVID-19 were also found to exert positive effects on breast cancer outcomes. Besides drugs in clinical trend, TMPRSS2 inhibitors, estrogen supplementation, androgen deprivation and DPP-IV inhibitors may also be used to treat breast cancer patients infected with SARS-CoV-2. However, drug-drug interactions suggest that some of the drugs used for the treatment of COVID-19 may modulate the drug metabolism of anticancer therapies which may lead to adverse drug reaction events.

High expression of ACE2 and TMPRSS2 and clinical characteristics of COVID-19 in colorectal cancer patients

Little is known of the patterns of expression of ACE2 and TMPRSS2 or the clinical characteristics of COVID-19 in patients with COVID-19 and colorectal cancer. We found in both bulk and single-cell RNA-seq profiles that ACE2 and TMPRSS2 were expressed at high levels on tumor and normal colorectal epithelial tissues. Clinically, patients with colorectal cancer and COVID-19 were more likely to have lymphopenia, higher respiratory rate, and high hypersensitive C-reactive protein levels than matched patients with COVID-19 but without cancer. These results suggest that patients with colorectal cancer may be particularly susceptible to SARS-CoV-2 infection. Further mechanistic studies are needed to support our findings.

Construction of a risk map to understand the vulnerability of various types of cancer patients to COVID-19 infection.

COVID‐19 is leading to a global pandemic and invades human cells via ACE2. ACE2 was found to be abundantly expressed in many organs and cells. However, there is no evidence about the potential risk of various types of cancer patients vulnerable to the infection of COVID‐19. To obtain a risk map that indicates the novel coronavirus vulnerability of different types of cancer, we analyzed in this work the RNA sequencing datasets of cancer patients. By interrogating the datasets, we not only identified the cancer types vulnerable to COVID‐19 attacks, but also we reported that variations in the mRNA expression level of ACE2 correlate to various prognosis phenomenon in different types of cancer cohorts, and illustrated the underlying mechanism involved or may be related to lymphocytes infiltration. From these discoveries, we constructed an infection risk map, which indicates the vulnerability of different types of cancer to COVID‐19 infection, also elucidated the correlationship between ACE2 and the prognosis of cancer. We found that high ACE2 expression levels lead to high risk of COVID‐19 infection and poor prognosis of breast invasive carcinoma (BRCA), while better prognosis in ovarian serous cystadenocarcinoma (OV) patient cohorts. Moreover, our study demonstrated that this different pattern may correlate with the immune infiltration level.

The Spatial and Cell-Type Distribution of SARS-CoV-2 Receptor ACE2 in the Human and Mouse Brains.

By engaging angiotensin-converting enzyme 2 (ACE2 or Ace2), the novel pathogenic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) invades host cells and affects many organs, including the brain. However, the distribution of ACE2 in the brain is still obscure. Here, we investigated the ACE2 expression in the brain by analyzing data from publicly available brain transcriptome databases. According to our spatial distribution analysis, ACE2 was relatively highly expressed in some brain locations, such as the choroid plexus and paraventricular nuclei of the thalamus. According to cell-type distribution analysis, nuclear expression of ACE2 was found in many neurons (both excitatory and inhibitory neurons) and some non-neuron cells (mainly astrocytes, oligodendrocytes, and endothelial cells) in the human middle temporal gyrus and posterior cingulate cortex. A few ACE2-expressing nuclei were found in a hippocampal dataset, and none were detected in the prefrontal cortex. Except for the additional high expression of Ace2 in the olfactory bulb areas for spatial distribution as well as in the pericytes and endothelial cells for cell-type distribution, the distribution of Ace2 in the mouse brain was similar to that in the human brain. Thus, our results reveal an outline of ACE2/Ace2 distribution in the human and mouse brains, which indicates that the brain infection of SARS-CoV-2 may be capable of inducing central nervous system symptoms in coronavirus disease 2019 (COVID-19) patients. Potential species differences should be considered when using mouse models to study the neurological effects of SARS-CoV-2 infection.

High expression of ACE2 in the human lung leads to the release of IL6 by suppressing cellular immunity: IL6 plays a key role in COVID-19.

The pathogenesis of coronavirus disease 2019 (COVID-19) remains clear, and no effective treatment exists. SARS-CoV-2 is the virus that causes COVID-19 and uses ACE2 as a cell receptor to invade human cells. Therefore, ACE2 is a key factor to analyze the SARS-CoV-2 infection mechanism. We included 9,783 sequencing results of different organs, analyzed the effects of different ACE2 expression patterns in organs and immune regulation. We found that ACE2 expression was significantly increased in the lungs and digestive tract. The cellular immunity of individuals with elevated ACE2 expression is activated, whereas humoral immunity is dampened, leading to the release of many inflammatory factors dominated by IL6. Furthermore, by studying the sequencing results of SARS-CoV-2-infected and uninfected cells, IL6 was found to be an indicator of a significant increase in the number of infected cells. However, although patients with high expression of ACE2 will release many inflammatory factors dominated by IL6, cellular immunity in the colorectum is significantly activated. This effect may explain why individuals with SARS-CoV-2 infection have severe lung symptoms and digestion issues, which are important causes of milder symptoms. This finding indicates that ACE2 and IL6 inhibitors have important value in COVID-19.

High expression of ACE2 in HER2 subtype of breast cancer is a marker of poor prognosis

BackgroundACE2 a key molecule of the Renin-Angiotensin system has been identified as the receptor for SARS-CoV-2 entry into human cells. In the context of human cancers, there is evidence that ACE2 might function as a tumor suppressor. The expression levels of ACE2 among the different subtypes of breast cancer has not been investigated. MethodsWe have examined the differential expression of ACE2 and its correlation with prognosis in breast cancer subtypes using the METABRIC (n = 1898) and TCGA (n = 832) cohorts. Correlations were evaluated by Pearsons's correlation co-efficient and Kaplan-Meier analysis was used to estimate differences in disease-free survival between the ACE2 high and ACE2 low groups. ResultsThere is minimal expression of ACE2 in the luminal classes, but significantly higher levels in the Basal-like and HER2-enriched subclasses. Metastatic biopsies of these tumor types also show enhanced expression of ACE2. High levels of ACE2 correlated with decreased disease-free survival in the HER2-enriched subtype, and it was positively correlated with EGFR expression. ConclusionThese observations suggest ACE2 might function as a context dependent factor driving tumor progression in breast cancer and permit new opportunities for targeted therapy.

ACE2 Correlated With Immune Infiltration Serves As A Novel Prognostic Biomarker In Clear Cell Renal Cell Carcinoma: Implication For COVID-19.

The current severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a global infection, and is seriously threatening human life, especially cancer patients. Thus, we sought to determine the clinical roles of ACE2 (the cell entry receptor of SARS-CoV-2) in ccRCC (clear cell renal cell carcinoma). TCGA, GEO and TIP datasets, and immunohistochemistry and western blot results were used to determine the prognostic and clinicopathological characteristics of ACE2. ACE2 expression was down-regulated in ccRCC tissues and cell lines. The multivariate Cox regression analysis results indicated that increased ACE2 expression was independent predictor of longer OS (HR: 0.8259, 95%CI: 0.7734-0.8819, P<0.0001) and RFS (HR: 0.8023, 95%CI: 0.7375-0.8729, P<0.0001) in ccRCC patients. Lower ACE2 expression was also associated with advanced tumor stage, higher histological grade and pathological stage, and metastasis. Besides, ACE2 expression was significantly positively and negatively correlated with CD4 Naïve infiltration and CD4 Memory infiltration, respectively. Moreover, higher CD4 Naïve and lower CD4 Memory infiltration levels were associated with better pathological features and longer OS and RFS. Furthermore, high ACE2 expression group in decreased CD4 Naïve, enriched CD4 Naïve and enriched CD4 memory cohort had favorable prognosis. These findings identified that AEC2 was significantly reduced in ccRCC, and decreased ACE2 was related to worse pathological features and poor prognosis. Low ACE2 expression in ccRCC may partially affect the prognosis due to altered immune cells infiltration levels.

The War Against SARS-CoV-2: The Immune Giant Collapsing Under Its Own Rampaging Cytokine Storm

We examined SARS-CoV-2 (Covid-19) available treatments and prophylactic methods that included interventions associated with inhibiting the ‘type II transmembrane serine protease’ (TMPRSS2) to limit the fusion between the Covid-19 Spike proteins and ACE2 receptors, or newly developed therapeutics like Remdesivir that interferes with the viral RNA replication. We explored the dilemma of ACE2 receptors that have a protective function against high blood pressure associated disorders, yet, they serve as the viral points of entry, elevating the probability of infection. Human tissues’ analysis reveals a higher ACE2 expression in adipose tissue, placing obesity-related conditions in the eye of the pandemic storm. It primarily exposes males due to the surge of ACE2 receptors in the testes along with other tissues. Males manifest a relatively higher positive ACE2 correlation with certain immune cells in the lungs, thyroid, adrenals, liver and colon, while females evidence higher ACE2 correlations with immune cells in the heart. The remaining tissues’ ACE2/immunity expressions are equivalent in both sexes, indicating that despite its preference for males, the threat of Covid-19 can easily target females. Recent reports indicate that Covid-19 is empowered by hindering the critical process of viral recognition during the adaptive immune response leading to the “cytokine storm,” the aggravated immune response that indiscriminately perseveres, rampaging the host’s vital organs. Sedentary lifestyle, age-related hormonal imbalance, and adiposity induced inflammation predispose the body to the immune collapse following Covid-19 invasion, spotlighting the detrimental aftermath of metabolic dysfunction, and excess food consumption, provoked by elevated cortisol and dysregulated appetite hormones. ACE2 expression is suppressed in the skeletal muscle, rendering fitness and weight management an effective Covid-19 preventive intervention, along with social distancing, hygiene, and facial coverings. Physical activity, or exercise alternative methods have recently demonstrated statistically significant reductions of the inflammatory marker C-Reactive Protein (CRP), triglycerides, visceral fat, cortisol and the orexigenic hormone ghrelin, juxtaposed by optimal increases of IGF-1, skeletal muscle mass, Free T3, HDL, and the anorexic hormone leptin.

Atlas of ACE2 gene expression reveals novel insights into transmission of SARS-CoV-2

The recent pandemic, COVID-19, is caused by a novel coronavirus, SARS-CoV-2, with elusive origin. SARS-CoV-2 infects mammalian cells via ACE2, a transmembrane protein. Therefore, the conservation and expression patterns of ACE2 may provide valuable insights into tracing the carriers of SARS-CoV-2. In this work, we analyzed the conservation of ACE2 and its expression pattern among various mammalian species that are close to human beings. We show that mammalian ACE2 gene is deeply conserved at both DNA and peptide levels, suggesting that a broad range of mammals can potentially host SARS-CoV-2. We further report that ACE2 expression in certain human tissues are consistent with clinical symptoms of COVID-19 patients. Furthermore, we have built the first atlas of ACE2 expression in various common mammals, which shows that ACE2 expresses in mammalian tissues in a species-specific manner. Most notably, we observe exceptionally high expression of ACE2 in external body parts of cats and dogs, suggesting that these household pet animals could be vulnerable to viral infections and/or may serve as intermediate hosts, thus yielding novel insights into the transmission of SARS-CoV-2.

ACE2 Receptor in the skin and Cutaneous Manifestations of SARS-Cov-2: A Review of the Literature

A B S T R A C TSevere Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) is a newlydiscovered coronavirus that causes Coronavirus Disease 2019 (COVID-19). Theinteraction of SARS-CoV-2 transmembrane spike (S) glycoprotein with the humanangiotensin-converting enzyme-2 (hACE2) is the primary method of virus entry tothe cell. ACE2 is a transmembrane enzyme involved in the renin-angiotensin-aldosterone system. This enzyme plays pivotal roles in blood pressure regulationsand also electrolyte homeostasis. The expression of ACE2 in various skin cells hasbeen demonstrated in previous studies. Keratinocytes in the epidermis show anexceptionally high expression of ACE2. In addition to human skin, ACE2 is alsofound in animals’ tissues and were exceptionally high in cats and dogs’ skin andeyes. This finding suggests their obscure role in COVID-19 transmission. Cutaneoussymptoms of COVID-19 in humans exist as the consequence of ACE2 presence inthe skin. The possible mechanisms of COVID-19 clinical manifestations in the skinare upregulated innate immune human response, hypercoagulable state, and non-structural proteins in SARS-CoV-2. These processes are presented as differentdermatologic manifestations, which are maculopapular rash, papulovesicular rash,and livedo reticularis. This review aims to link the theoretical framework andpublished findings to establish the connection between ACE2 expression in skin andcutaneous manifestations of COVID-19.

Heparan sulfate consumption as a potential mechanism of intra-cardiac thrombosis in SARS-CoV-2 infection

Cardiac injury occurs in up to 36% of hospitalized patients with COVID-19.1.Lala A. Johnson K.W. Januzzi J.L. et al.Prevalence and impact of myocardial injury in patients hospitalized with COVID-19 infection.J Am Coll Cardiol. 2020; 76 (533 LP - 546)https://doi.org/10.1016/j.jacc.2020.06.007Crossref Scopus (384) Google Scholar Exact mechanism of cardiac injury in COVID-19 is not well understood, but may relate to direct cardiomyocyte damage, coronary plaque destabilization, cytokine inflammatory response, and intracoronary microthrombi formation. Lindner et al.2.Lindner D. Fitzek A. Bräuninger H. et al.Association of cardiac infection with SARS-CoV-2 in confirmed COVID-19 autopsy cases.JAMA Cardiol. 2020; (Published online July 27)https://doi.org/10.1001/jamacardio.2020.3551Crossref PubMed Scopus (423) Google Scholar in an autopsy study identified SARS-CoV-2 RNA in the myocardium in 24 of 39 autopsy cases. However, none of the 39 patients had myocarditis. Plasma pro-inflammatory cytokine levels were increased in 16 patients, suggesting cytokine response as a plausible cause of cardiac injury in COVID-19. Early reports identified ACE2 as a receptor for the SARS-CoV-2. Clausen et al.3.Clausen T.M. Sandoval D.R. Spliid C.B. et al.SARS-CoV-2 infection depends on cellular heparan sulfate and ACE2.Cell. 2020; (Published online September 142020.07.14.201616)https://doi.org/10.1016/j.cell.2020.09.033Abstract Full Text Full Text PDF PubMed Scopus (531) Google Scholar have recently identified heparan sulfate as a co-receptor for ACE2, whereby SARS-CoV-2 binds to heparan sulfate, a negatively charged polymer, through a positively charged site adjacent to the ACE2 binding domain. Heparan sulfate is ubiquitously expressed in mammalian tissues, and ACE2 is broadly expressed in the arterial, capillary, and venous endothelial cells. Heparan sulfate also interacts with antithrombin, which subsequently undergoes conformation change, resulting in the generation of the active form of antithrombin. The active form of antithrombin inhibits the procoagulant factors Xa and thrombin (IIa) (Fig. 1). Additionally, Gue et al.4.Gue Y.X. Gorog D.A. Reduction in ACE2 may mediate the prothrombotic phenotype in COVID-19.Eur Heart J. 2020; 41: 3198-3199https://doi.org/10.1093/eurheartj/ehaa534Crossref PubMed Scopus (14) Google Scholar suggested that reduction in ACE2 activity may increase vascular permeability resulting in increased expression of tissue factor in subendothelial cells, leucocytes, and platelets with subsequent activation of coagulation and thrombosis. As SARS-CoV-2 binds heparan sulfate and ACE2 for cellular entry, it is possible that the high expression of ACE2 in the heart would facilitate an interaction between SARS-CoV-2 and heparan sulfate, leading to heparan sulfate consumption. A lower level of heparan sulfate would lead to a reduction in antithrombin activation creating a hypercoagulable state. Heparan sulfate also mediates antithrombin's anti-inflammatory activity.5.Liu J. Pedersen L.C. Anticoagulant heparan sulfate: structural specificity and biosynthesis.Appl Microbiol Biotechnol. 2007; 74: 263-272https://doi.org/10.1007/s00253-006-0722-xCrossref PubMed Scopus (108) Google Scholar Loss of antithrombin's anti-inflammatory activity can potentially lead to endothelialitis and subsequent endothelial injury and intra-cardiac thrombus formation. We believe that heparan sulfate consumption during SARS-CoV-2 cellular entry might play a role in the thrombotic events associated with COVID-19 infection.

Expression profiles revealed potential kidney injury caused by SARS-CoV-2: a systematic analysis of ACE2 and clinical lessons learned from this discovery.

Background: Novel Coronavirus disease 2019 (COVID-19) was first detected in pneumonia patients in Wuhan, China in December 2019. Based on the current understanding, COVID-19 has become a global issue. Presumably, numerous studies have found that SARS-CoV-2 also transpires in kidney tissue with permanent viral loads. However, it is elusive as to whether SARS-CoV-2 can directly damage the kidney or induce acute renal failure. Hence, to comprehensively understand the impact of COVID-19 on kidney damage, we conducted a retrospective series of case studies to assess kidney functions. Additionally, ACE2 distribution in kidney tissue was analyzed through RNAseq data in open-access databases.Results: According to the findings from transcriptome analysis, we revealed higher ACE2 expression levels in females than males. Similar results were more noticeable in the elderly than in young adults. Furthermore, single-cell RNA sequencing data analysis showed high ACE2 expression in kidney tubule and collecting duct principal cells as well as glomerular parietal epithelial cells. On their admission, the patient's serum creatinine and blood urea nitrogen (BUN) were elevated to between 36.13% and 16.80%, respectively. The estimated glomerular filtration rate (EGFR) of < 60 ml/min per 1.73 m2 was reported in 10.92 % of the patients. Notably, at admission, increased BUN time varied linearly following the generalized additive mixed model. Thus, the hourly-increase of BUN in patients was 0.495 (95%CI: 0.263, 0.726).Conclusion: Based on clinical findings, it was ascertained that COVID-19 can damage renal function, but it seldom causes acute renal failure. Coronavirus may directly bind to ACE2-positive cells and damage kidney tissue in the analysis of scRNA-seq data in kidney tissue. Therefore, this evidence suggests that kidney tissue act as the SARS-CoV-2 infection site and the findings could provide insight into the pathophysiology of kidney damage.Methods: We systematically analyzed ACE2 expression profiles in organs based on open-access datasets for healthy individuals. Meanwhile, single-cell sequencing data for kidney samples were collected and analyzed. Assessments on kidney functions were conducted on 119 selected COVID-19 positive patients admitted from 10th February – 18th March 2020, in hospital in Wuhan City, Hubei Province. Consequently, their clinical records and laboratory findings, such as the estimated glomerular filtration rate (eGFR), Blood Urea Nitrogen (BUN), Creatinine, and Comorbidities, were collected.

Dermatological aspects of SARS-CoV-2 infection: mechanisms and manifestations.

The human infection caused by the novel SARS-CoV-2 is a public health emergency of international concern. Although the disease associated to this virus, named COVID-19, mainly affects the lungs, the infection can spread to extrapulmonary tissues, causing multiorgan involvement in severely ill patients. The broad infective capacity of SARS-CoV-2 is related to the pattern of expression of the viral entry factors ACE2 and TMPRSS2 in human tissues. As such, the respiratory and gastrointestinal tracts are at high risk for SARS-CoV-2 infection due to their high expression of ACE2 and TMPRSS2, which explains the clinical phenotype described in the vast majority of infected patients that includes pneumonia and diarrhea. Recently, preoccupation about the potential of the virus to infect the skin has been raised by dermatologists due to the increasing observations of cutaneous manifestations in patients with SARS-CoV-2 infection. Although there is little evidence of the expression of ACE2 and TMPRSS2 in the normal skin, the dermatological findings observed among COVID-19 patients warrants further investigation to delineate the mechanisms of skin affection after SARS-CoV-2 infection. Here, we provide a summary of the dermatological findings observed among patients with laboratory-confirmed SARS-CoV-2 infection based on recent reports. In addition, we analyze possible mechanisms of skin injury in COVID-19 patients and discuss about the risk of individuals with chronic skin conditions for SARS-CoV-2 infection. The present review constitutes a useful informative tool to improve our understanding of the pathophysiological mechanisms of COVID-19 and the possible implications of the current pandemic in dermatology.

Blood clots in COVID-19 patients: Simplifying the curious mystery

The universal phenomenon of blood clotting is well known to be protective in external cellular/ tissue injury. However, the emergence of unusual thrombotic presentations in COVID-19 patients is the real concern. Interaction of the spike glycoprotein with ACE2 receptor present in the host cell surface mediates the entry of SARS-CoV-2 causing COVID-19 infection. New clinical findings of SARS-CoV-2 pathogenesis are coming out every day, and one such mystery is the formation of mysterious blood clots in the various tissues and organs of COVID-19 patients, which needs critical attention. To address this issue, we hypothesis that, high ACE2 expression in the endothelium of blood vessels facilitates the high-affinity binding of SARS-CoV-2 using spike protein, causing infection and internal injury inside the vascular wall of blood vessels. This viral associated injury may directly/indirectly initiate activation of coagulation and clotting cascades forming internal blood clots. However, the presence of these clots is undesirable as they are responsible for thrombosis and need to be treated with anti-thrombotic intervention.

Systematic Analysis of Coronavirus Disease 2019 (COVID-19) Receptor ACE2 in Malignant Tumors: Pan-Cancer Analysis.

BackgroundCoronavirus disease 2019 (COVID-19) was first detected in patients with pneumonia in December 2019 in China and it spread rapidly to the rest of the world becoming a global pandemic. Several observational studies have reported that cancer is a risk factor for COVID-19. On the other hand, ACE2, a receptor for the SARS-CoV-2 virus, was found to be aberrantly expressed in many tumors. However, the characterization of aberrant ACE2 expression in malignant tumors has not been elucidated. Here, we conducted a systematic analysis of the ACE2 expression profile across 31 types of tumors.MethodsDistribution of ACE2 expression was analyzed using the GTEx, CCLE, TCGA pan-cancer databases. We evaluated the effect of ACE2 on clinical prognosis using the Kaplan-Meier survival plot and COX regression analysis. Correlation between ACE2 and immune infiltration levels was investigated in various cancer types. Additionally, the correlation between ACE2 and immune neoantigen, TMB, microsatellite instability, Mismatch Repair Genes (MMRs), HLA gene members, and DNA Methyltransferase (DNMT) was investigated. The frequency of ACE2 gene mutation in various tumors was analyzed. Functional enrichment analysis was conducted in various cancer types using the GSEA method.ResultsIn normal tissues, ACE2 was highly expressed in almost all 31 organs tested. In cancer cell lines, the expression level of ACE2 was low to medium. Although aberrant expression was observed in most cancer types, high expression of ACE2 was not linked to OS, DFS, RFS, and DFI in most tumors in TCGA pan-cancer data. We found that ACE2 expression was significantly correlated with the infiltrating levels of macrophages and dendritic cells, CD4+ T cells, CD8+ T cells, and B cells in multiple tumors. A positive correlation between ACE2 expression and immune neoantigen, TMB, and microsatellite instability was found in multiple cancers. GSEA analysis which was carried out to determine the effect of ACE2 on tumors indicated that several cancer-associated pathways and immune-related pathways were hyperactivated in the high ACE2 expression group of most tumors.ConclusionThese findings suggest that ACE2 is not correlated with prognosis in most cancer types. However, elevated ACE2 is significantly correlated with immune infiltrating levels, including those of CD8+ T cells, CD4+ T cells, macrophages, neutrophils, and DCs in multiple cancers, especially in lung and breast cancer patients. These findings suggest that ACE2 may affect the tumor environment in cancer patients with COVID-19.

Obesity and diabetes as comorbidities for COVID-19: Underlying mechanisms and the role of viral-bacterial interactions.

Obesity and diabetes are established comorbidities for COVID-19. Adipose tissue demonstrates high expression of ACE2 which SARS- CoV-2 exploits to enter host cells. This makes adipose tissue a reservoir for SARS-CoV-2 viruses and thus increases the integral viral load. Acute viral infection results in ACE2 downregulation. This relative deficiency can lead to disturbances in other systems controlled by ACE2, including the renin-angiotensin system. This will be further increased in the case of pre-conditions with already compromised functioning of these systems, such as in patients with obesity and diabetes. Here, we propose that interactions of virally-induced ACE2 deficiency with obesity and/or diabetes leads to a synergistic further impairment of endothelial and gut barrier function. The appearance of bacteria and/or their products in the lungs of obese and diabetic patients promotes interactions between viral and bacterial pathogens, resulting in a more severe lung injury in COVID-19.

Abstract S01-03: A prediction of prostate cancer deaths spiking by SARS-CoV-2 infection

Abstract COVID-19 is a global issue, with over 6.25 million cases in 213 countries and territories on June 1, 2020. Although this virus infects all groups, data indicate that the risk for severe disease and death is much higher in older men, which coincides with the same group of patients at risk for prostate cancer. A recent Italian study investigated the prevalence and severity of COVID-19 in men with prostate cancer. This study indicated that of a total of 4,532 men with COVID-19, from the Veneto region of Italy, 9.5% (n=430) had cancer and out of those around 30% (n=118) had prostate cancer. Data also indicated that male cancer patients had a 1.8-fold increased risk of COVID-19 infection and developed a more severe disease. Interestingly, they observed that the prostate cancer patients (n=4) treated with androgen-deprivation therapy (ADT) were less likely to develop COVID-19, and in those who were infected, the disease was less severe. In this current study, we focused on determining the genetic basis of the higher COVID-19 prevalence and severity in male patients and particularly for prostate cancer patients. Researchers found two genes that are essential for severe acute respiratory syndrome Coronavirus 2 (SARS-CoV-2). ACE2 is a SARS-CoV-2 receptor, whereas the serine protease, TMPRSS2, primes the virus for cell entry through cleavage of the viral spike protein (S). The expression of TMPRSS2 is significantly high in normal prostate tissue and is regulated in large part by an androgen response element in the promoter region. Therefore, we decided to investigate the status of these two genes in various tumors from The Cancer Genome Atlas (TCGA) database using the cBioportal platform. We analyzed over 46,000 tumor samples from 176 studies and found that aggressive metastatic prostate cancer, including neuroendocrine prostate cancer (NEPC), has significantly higher amplification (copy number alteration) of the ACE2 and TMPRSS2 genes compared to other cancers. Next, we focused on drugs that could simultaneously target ACE2 or TMPRSS2 and oncogenic pathways and would be beneficial for prostate cancer patients infected with SARS-CoV-2. Although several inhibitors are validated in literature for both ACE2 and TMPRSS2, very limited studies were performed to see the effect on cancer cells. Therefore, we analyzed a cytotoxic effect database of over 130,000 drugs on NCI-60 cell lines with COMPARE algorithm and found two relevant compounds, NSC-148958 (FT-701) and NSC-280594 (triciribine phosphate), which target ACE2 and TMPRSS2, respectively. Computational data are currently validating different prostate cancer cell-lines and their response to these drugs. In summary, our findings provide the premise that men who are at risk for or diagnosed with prostate cancer may be more susceptible to severe infection and death in response to SARS-CoV-2 due to the high expression of ACE2 and TMPRSS2, and triciribine phosphate and FT-701 could be a therapeutic intervention to target co-occurrence of COVID-19 and prostate cancer. Citation Format: Alakesh Bera, Eric Russ, Digonto Chatterjee, John Karaian, Madhan Subramanian, Sreejato Chatterjee, Surya Radhakrishnan, Michael Eklund, Harvey Pollard, Meera Srivastava. A prediction of prostate cancer deaths spiking by SARS-CoV-2 infection [abstract]. In: Proceedings of the AACR Virtual Meeting: COVID-19 and Cancer; 2020 Jul 20-22. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(18_Suppl):Abstract nr S01-03.

Cardiovascular and cardiometabolic prevention: high-level priority in the era of COVID-19.

Cardiovascular and cardiometabolic prevention: high-level priority in the era of COVID-19.

High Expression of ACE2 on Keratinocytes Reveals Skin as a Potential Target for SARS-CoV-2

Since December 2019, a novel coronavirus, severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), has emerged in Wuhan, Hubei, China, as an etiological agent causing a new infectious respiratory disease, coronavirus disease 2019, which manifests as fever, severe respiratory illness, and pneumonia (Huang et al., 2020). With significant morbidity and mortality, coronavirus disease 2019 has now evolved into a global pandemic (Park, 2020). To date, more than 3 million cases of coronavirus disease 2019 have been reported worldwide, including 252,336 deaths, according to the World Health Organization.