Close this search box.

Spike Proteins, ACE2 and Cancer

It has been said:

“Wisdom is not wisdom when it is derived from books alone.”

This quote from an unknown author highlights the vast, what seems like an infinite chasm that exists between knowledge and wisdom. Knowledge does not equal wisdom, and by no means does wisdom come through the accumulation of knowledge. Likewise, it has been said that time results in more knowledge, but time and accumulation do not translate to wisdom.

Knowledge is just the accumulation of data. The accumulation of data is analogous to snowflakes accumulating on the road. Without action, the snowflakes simply accumulate. Wisdom is the processing and application of knowledge into points of action. This processing or application can be an action of conclusion, change in behavior, change in thinking, or change in paradigm. In many ways, foundational and original principles, personal experiences, and history are the bridges that connect knowledge and wisdom. Wisdom is the processing of this data through foundational and original principles, experiences, and history to set into motion the action to move the data to wisdom to clear the road of accumulating snow.

A primary and direct connection of the SARS-CoV-2 and spike proteins to cancer is through the same ACE2 receptors that have received so much media attention over the last almost two years. It is interesting to note that individuals with cancer are said to be at higher risk from SARS-CoV-2 infection than those without cancer. Why? In part, it is because of the same ACE2 receptors [1] [2].  Angiotensin-converting enzyme-2 receptor expression is increased in many cancer types (see below). Cancer is listed as one of the many comorbidities, along with obesity, advanced age, diabetes, hypertension, and cardiovascular disease, in the SARS-CoV-2 increased infection risk profile. But, does listing cancer as a comorbidity mean that the spike protein, whatever the source (infection or an injection), is the right approach to help people with cancer? That is a big question that I will work to answer by connecting a few dots below.

Angiotensin-converting enzyme-2 (ACE2)

First, what the heck is ACE2? The ACE2 is an important membrane protein that converts the vasoconstrictor angiotensin II to angiotensin as a part of the renin-angiotensin-aldosterone system (RAAS). ACE2 as a part of the RAAS regulates blood volume and systemic vascular resistance and is implicated in high blood pressure, cardiovascular function, diabetes, and as a receptor for the severe acute respiratory syndrome coronavirus—see SARS-CoV-2.

Angiotensin-converting enzyme 2 (ACE2) is expressed across the spectrum of many different cancer types. Cancer types that express ACE2 are primarily the solid variety of tumors, including lung cancer, breast cancer, colorectal cancer, cervical cancer, esophageal cancer, liver cancer, renal cell cancer, and uterine cancer [3]. Here, cancer cells serve as a reservoir for viruses. Think of the solid ball of tumor cells as a high rise and each cell a reservoir, or room, for viruses. Specific to this virus and the spike protein, this is kind of a build it (tumor cells), and they will come (virus), and prosper (viral increase in number), and grow (increase infection and inflammation) concept [4] [5]. This changes the entire perspective on the relationship between cancer and the SARS-CoV-2 virus. It helps to clarify why the spike protein, whatever the source, is not good in patients with cancer.

Remember, the spike protein is, in fact, a toxin or a toxicant depending on its source of origin [6] [7]. And what is a toxin or a toxicant? A toxin is a substance created by a living organism, i.e. parasite, virus, or bacteria, which causes harm. The word toxin comes from the Latin word toxicus meaning poison. A toxicant is a synthetic substance created outside a living organism which too causes harm. The level of harm or dysfunction plays no role in whether a substance meets the criteria for labeling as a toxin or toxicant; just simply that it causes harm or dysfunction.

The debate of whether the spike protein is a toxin or toxicant is beyond its straight forward, pro-carcinogenic impact. Beyond the impact of the spike protein with the pro-carcinogenic plasminogen activator inhibitor-1 (PAI-1) [8] and natural killer (NK) cells [9], this blogpost will highlight the research supported mechanisms and impact for far worse. It is consistent with currently published science to state that cancer patients are at higher risk from complications with SARS-CoV-2 infection, and increased risk for complications from the spike protein. These statements are not mutually exclusive but inclusive. I don’t just want to make broad, general statements but provide the evidence for the exact currently known mechanisms of how the SARS-CoV-2 spike protein contributes to cancer morbidity and mortality—primarily through metastasis.

This is not the first time that research or that ground breaking discovery has identified a connection between a virus and cancer. According to research, approximately 20% of all cancers globally are caused by infectious agents, i.e., viruses, bacteria, and parasites [10]. Viruses are at the top of that list. Viruses can hijack cellular metabolism and reprogram cells for oncogenic metabolism, leading to oncogenic transformation. Other viruses shown to contribute to and cause cancer include the adenovirus, Herpes simplex type I and II (HSV1 and HSVII), Human cytomegalovirus (CMV), Human papillomavirus (HPV), HIV, Hepatitis C virus, and the Epstein-Barr virus [11].

The details of the role that ACE2 expression plays in cancer are essential to better understanding the connection between the SARS-CoV-2 associated spike protein, whatever the source (infection, injection, or booster), and cancer. As I previously mentioned, many solid cancer tumor types express ACE2. Why? A look at a few cancer types will help to provide more insight.

Angiotensin converting enzyme 2 has been shown in vitro and in vivo studies to reduce angiogenesis and provide a favorable prognosis in breast cancer [12]. In addition to neogenesis, Angiogenesis is the irregular, tortuous blood vessel supply that is critical to cancer survival. Angiogenesis and neogenesis create the roadmap to fuel the growing tumor’s massive metabolic demand and remove the associated waste that is a byproduct of the high metabolism of tumor growth. The opposite is true; low ACE2 expression is associated with a worse survival prognosis. The implication is that an increase in ACE2 expression provides protection against tumor growth in some breast cancer types and is associated with a favorable prognosis—improved survival 11.

Similarly, a decrease in breast cancer cell ACE2 expression correlates with an advancing stage in breast cancer [13]. This points to an indirect relationship of decreasing ACE2 and a progression of breast cancer from stage I to stage III and stage IV. In lung cancer, high ACE2 expression inhibits cancer cell growth [14]. In uterine and kidney cancer, ACE2 expression is associated with an increase in tumor microenvironment immune infiltration and improved prognosis [15]. Despite the favorable effect in cancer, ACE2 expression increases SARS-CoV-2 infection risk. Again, as previously mentioned, the two statements are not mutually exclusive but are inclusive. Not to make it more confusing, but instead, to show the complexity, high ACE2 expression is associated with a decrease in survival in HER-2+ breast cancer [16].

It is essential to understand that the endothelium is at the center of this wheel of the dysfunction cascade [17] [18]. Endothelium is critical to the cancer, platelet, cytokine storm, and metastasis process, discussed in the previous blog post, that triggers the long list of associated problems involving platelets to include metastasis [19] [20] [21] [22]. More, the endothelium is center stage of the convergence of the cytokine storm, LPS induced metabolic endotoxemia, SARS-CoV-2 spike protein, platelet—cancer cell aggregate, which leads to SARS-CoV-2 acute respiratory distress syndrome [23] [24], thromboembolism [25] [26], myocarditis [27], and cardiomyopathy [28]. Because of the published research presented here, I add that cancer proliferation and metastasis be added to this list. But how? It is readily apparent that the endothelial dysfunction occurs through the down regulation of the same angiotensin-converting enzyme 2 (ACE2) receptor expression and signaling [29] [30]. To be clear, this is the same down-regulation of ACE2 expression that also sits at the heart of its pro-cancer impact—discussed below.

You likely have heard a lot about these ACE2 receptors in the discussion of COVID-19 over the last almost two years. According to current research, they are the primary means by which the SARS-CoV-2 virus gains access to cells. The SARS-CoV-2 virus gains access to the ACE2 receptors via the infamous spike proteins expressed on the virus’s surface. Think of the spike protein as the key to opening the door, the ACE2, to gain entry into the cell’s internal machinery. In addition to the spike protein, there is a membrane protein, nucleocapsid protein, and envelope protein expressed by the SARS-CoV-2 virus. There are numerous tissue types (brain, eyes, nasal cavity, oral cavity, cardiovascular system, lungs, liver, kidneys, reproductive organs) throughout the body that express the ACE2 receptors. But the lung is the tissue type that is most heavily concentrated with ACE2 receptors [31]. It should then come as no surprise that one of the primary organs affected by this virus is the pulmonary system—particularly the lungs. The result is pneumonia and, worse, Acute Respiratory Distress Syndrome (ARDS).

Beyond the SARS-CoV-2 spike protein ACE2 receptor activation, spike proteins alone increase platelet aggregation and P-selection expression through the same ACE2 receptor activation [32]. Yes, it appears that platelets too express ACE2 [33]. The end result is platelet hyperactivation. According to the authors of the article, SARS-CoV-2 binds ACE2 to enhance thrombosis in COVID-19,

“…both complete SARS-CoV-2 virus as well as the SARS-CoV-2 spike protein are able to induce platelet activation.”

In the case of cancer, platelet hyperactivity, including an increase in platelet aggregation, will increase the cancer cell-platelet aggregate, discussed previously, and its associated increase in cancer metastasis implications highlighted previously. In addition, an increase in the adhesion molecule, P-selectin, on platelets will increase angiogenesis and metastasis [34] [35] [36]. It is readily apparent that spike protein ACE2 receptor activated platelets and P-selectin expression will aid metastasis.

“Circulating tumor cells attach to the microvasculature of target organs, penetrate the vessel wall, and survive and proliferate within their new tissue microenvironments.” [37]

The spike protein to cancer is like giving candy to a classroom of sleep-deprived elementary school kids—watch out for the mayhem as they bounce off the walls.

 Consider this thought for a moment. Based on the information presented, what would be the impact of platelet hyperactivation in individuals with cancer, or even individuals at high risk of cancer, that also have co-existing endothelium damage? It is safe to say that any adult older than 40 or with any chronic disease of aging has some degree of endothelium dysfunction or damage. The obvious impact would be a significant increase in morbidity and mortality. Remember, metastasis is the cause of 90% of morbidity and mortality in cancer. It just so happens that the spike protein accomplishes both. Hmmm.

 What is the connection between the SARS-CoV-2 spike protein and ACE2, and what is the corresponding relevance to cancer? Just as in endothelium described previously, the spike protein down-regulates ACE2 expression on cancer cells [38] [39] [40]. Yes, you did read that correctly. The implications in cancer are significant, profound, and relatively straightforward. As mentioned previously in the study “SARS-CoV-2 cell receptor gene ACE2-mediated immunomodulation in breast cancer subtypes[41], decreasing ACE2 expression correlates with advancing breast cancer stage, i.e., stage II, stage III, stage IV. The implication here is an advancing stage of cancer is associated with increased morbidity and mortality. There is a decrease in prognosis and survival in the cancer types that highly express ACE2. This connection helps explain why the angiotensin-converting enzyme inhibitor (ACE inhibitor) and angiotensin receptor blocker (ARB) class of hypertension medications are linked to an increase in cancer risk in some studies because of their decrease in ACE2 expression 40 [42]. As mentioned previously, this connection is not universal across cancer types because the opposite holds in HER-2 + breast cancer. This lack of uniformity highlights another issue in cancer treatment today; a one-size-fits-all approach will never work in cancer treatment.

The implications between the spike protein, whatever the source, and ACE2 in cancer are concrete, but we need to connect a few dots (highlighted above) to make the connection more clear. Angiotensin-converting enzyme 2 is highly expressed in cancer cells. For the most part, ACE2 expression is associated with a decrease in cancer invasion, advancing stage, and metastasis. Additional research has shown that a decrease in ACE2 expression is associated with advancing cancer stage. And finally, the spike protein down-regulates ACE2 expression. To summarize, the connection of these dots point directly to the spike protein down-regulation of ACE2 expression as a significant contributor to cancer invasion, advancing stage, and metastasis, which worsens cancer prognosis and survival. Currently, there are two sources of the spike protein— SARS-CoV-2 infection and injection. 

Does infection or injection produce more spike proteins than the other? The scientific jury is still out on that question. But, research published in the New England Journal of Medicine has shown that the injection produces a higher spike protein antibody response than natural infection 32. The implication is that the injection produces more spike proteins because it produces more spike protein-directed antibodies. However, the direct data to support that relationship remains outstanding. In my literature review, it doesn’t appear that the questions have been asked or investigated. My guess is we may never see that data. It does not take a quantum leap of logic to conclude that repetitive boosters will increase spike proteins.

 It is important to understand that science is not just about waiting on double-blinded, randomized placebo-controlled trials; worse, waiting for some “expert panel” or waiting on a single expert to tell all collective physicians what to do and think and what algorithm recipe to use. Science is also about the foundation of observation and connecting the dots found through observation, literature search, with scientific investigation. This is highlighted in a recent New England Journal of Medicine opening:

 “…the path between the laboratory and the bedside runs both ways: clinical observations often pose new questions for laboratory investigations that then lead back to the clinic.” [43]

 As the spike protein down regulates ACE2 expression, the specific cancer implications of a decrease in ACE2 include: 

  • Proliferation/Growth [44] [45] [46]
  • Angiogenesis 11 45
  • Epithelial to mesenchymal transition (EMT) [47] [48] [49]
  • Metastasis [50] [51]
  • Pro-carcinogenic alterations in the tumor microenvironment (TME) [52] [53]
  • Pro-carcinogenic Immunomodulation [54] [55] [56] [57]
  • Increase in tumor cell stemness [58]

 The effects of the SARS-CoV-2 virus, specifically the spike protein and ACE2 expression, extend far beyond broad cancer supporting effects listed. The specific genetic alteration effects, i.e., VEGF, C-MYC, EGF, FGF, PDGF, TGF-beta, and IGF are also known. In addition, there are profound negative implications of its effects on cancer treatment. But, this post is too long already to discuss the individual genetic alterations—maybe in another post.

 In review, whatever the source of the spike protein, research points to an increase in endothelium damage and dysfunction, angiogenesis potential, platelet hyperactivity, platelet—cancer cell aggregation, immune evasion, circulating tumor cell survival, natural killer cell suppression, cancer cell intravasation and micrometastasis, which all point to an increase in metastasis. The result will be an increase in cancer incidence, recurrence, morbidity, and mortality. This is a completely unforced error for those with cancer or those at high risk for cancer. Observation and the connection of the dots in the research suggest that cancer may be our next greatest concern.

[1] Zhang H, Quek K, Chen R, Chen J, Chen B. Expression of the SARS-CoV-2 receptor ACE2 reveals the susceptibility of COVID-19 in non-small cell lung cancer. J Cancer 2020; 11(18):5289-5292. doi:10.7150/jca.49462.

[2] Liang W, Guan W, Chen R, et al. Cancer patients in SARS‐CoV‐2 infection: a nationwide analysis in China. Lancet Oncol. 2020;21(3):335–337.

[3] Li Y, Xu Q, Ma L, et al. Systematic profiling of ACE2 expression in diverse physiological and pathological conditions for COVID-19/SARS-CoV-2. J Cell Mol Med. 2020;24(16):9478-9482. doi:10.1111/jcmm.15607

[4] Huang, S. H. et al. Have cells harboring the HIV reservoir been immunoedited? Front Immunol. 2019;10,2.

[5] Huang, S. H. et al. Latent HIV reservoirs exhibit inherent resistance to elimination by CD8+ t cells. J Clin Investig. 2018;128:876–889.

[6] Singh RD, Barry MA, Croatt AJ, et al. The spike protein of SARS-CoV-2 virus induces heme oxygenase-1: Pathophysiologic implications [published online ahead of print, 2021 Dec 14]. Biochim Biophys Acta Mol Basis Dis. 2021;166322. doi:10.1016/j.bbadis.2021.166322

[7] Kim ES, Jeon MT, Kim KS, Lee S, Kim S, Kim DG. Spike Proteins of SARS-CoV-2 Induce Pathological Changes in Molecular Delivery and Metabolic Function in the Brain Endothelial Cells. Viruses. 2021 Oct 8;13(10):2021. doi: 10.3390/v13102021.

[8] Han M, Pandey D. ZMPSTE24 Regulates SARS-CoV-2 Spike Protein-enhanced Expression of Endothelial PAI-1. Am J Respir Cell Mol Biol. 2021;65(3):300-308. doi:10.1165/rcmb.2020-0544OC

[9] Bortolotti D, Gentili V, Rizzo S, Rotola A, Rizzo R. SARS-CoV-2 Spike 1 Protein Controls Natural Killer Cell Activation via the HLA-E/NKG2A Pathway. Cells. 2020;9(9):1975. doi:10.3390/cells9091975

[10] Ahmadi Ghezeldasht S, Hassannia T, Rafatpanah H, Hekmat R, Valizadeh N, Ghayour Mobarhan M, Rezaee SA. Oncogenic Virus Infections in the General Population and End-stage Renal Disease Patients With Special Emphasis on Kaposi’s Sarcoma Associated Herpes Virus (KSHV) in Northeast of Iran. Jundishapur J Microbiol. 2015 Mar 21;8(3):e14920. doi: 10.5812/jjm.14920.

[11] Blackadar CB. Historical review of the causes of cancer. World J Clin Oncol. 2016;7(1):54-86. doi:10.5306/wjco.v7.i1.54

[12] Zhang Q, Lu S, Li T, et al. ACE2 inhibits breast cancer angiogenesis via suppressing the VEGFa/VEGFR2/ERK pathway. J Exp Clin Cancer Res. 2019;38(1):173.

[13] Bhari VK, Kumar D, Kumar S, Mishra R. SARS-CoV-2 cell receptor gene ACE2 -mediated immunomodulation in breast cancer subtypes. Biochemistry and Biophysics Reports. Dec 2020; 24.100844.

[14] Cheng Q, Zhou L, Zhou J, Wan H, Li Q, Feng Y. ACE2 overexpression inhibits acquired platinum resistance-induced tumor angiogenesis in NSCLC. Oncol Rep. 2016 Sep;36(3):1403-10. doi: 10.3892/or.2016.4967.

[15] Yang J, Li H, Hu S, Zhou Y. ACE2 correlated with immune infiltration serves as a prognostic biomarker in endometrial carcinoma and renal papillary cell carcinoma: implication for COVID-19. Aging (Albany NY). 2020;12(8):6518-6535. doi:10.18632/aging.103100

[16] Nair MG, Prabhu JS, Ts S. High expression of ACE2 in HER2 subtype of breast cancer is a marker of poor prognosis. Cancer Treat Res Commun. 2021;27:100321. doi: 10.1016/j.ctarc.2021.100321.

[17] Libby P, Luscher T. COVID-19 is, in the end, an endothelial disease. Eur Heart J. 2020, 41, 3038–3044.

[18] Lowenstein CJ, Solomon SD. Severe COVID-19 Is a Microvascular Disease. Circulation. 2020;142:1609–1611.

[19] Sims JT, Krishnan V, Chang CY, Engle SM, Casalini G, Rodgers GH, Bivi N, Nickoloff BJ, Konrad RJ, de Bono S, Higgs RE, Benschop RJ, Ottaviani S, Cardoso A, Nirula A, Corbellino M, Stebbing J. Characterization of the cytokine storm reflects hyperinflammatory endothelial dysfunction in COVID-19. J Allergy Clin Immunol. 2021 Jan;147(1):107-111. doi: 10.1016/j.jaci.2020.08.031.

[20] Fajgenbaum DC, June CH. Cytokine Storm. N Engl J Med. Dec 2020;383:2255-2273. doi: 10.1056/NEJMra2026131

[21] Fodor A, Tiperciuc B, Login C, Orasan OH, Lazar AL, Buchman C, Hanghicel P, Sitar-Taut A, Suharoschi R, Vulturar R, Cozma A. Endothelial Dysfunction, Inflammation, and Oxidative Stress in COVID-19—Mechanisms and Therapeutic Targets. Oxidative Medicine and Cellular Longevity. 2021.

[22] Coperchini F, Chiovato L, Croce L, Magri F, Rotondi M. The cytokine storm in COVID-19: An overview of the involvement of the chemokine/chemokine-receptor system. Cytokine Growth Factor Rev. 2020 Jun;53:25-32. doi: 10.1016/j.cytogfr.2020.05.003.

[23] Iwasaki M, Saito J, Zhao H. et al. Inflammation Triggered by SARS-CoV-2 and ACE2 Augment Drives Multiple Organ Failure of Severe COVID-19: Molecular Mechanisms and Implications. Inflammation. 2021;44:13–34.

[24] Petruk G, Puthia M, Petrlova J, Samsudin F, Strömdahl AC, Cerps S, Uller L, Kjellström S, Bond PJ, Schmidtchen AA. SARS-CoV-2 spike protein binds to bacterial lipopolysaccharide and boosts proinflammatory activity. J Mol Cell Biol. 2020 Oct 12;12(12):916-932. doi: 10.1093/jmcb/mjaa067.

[25] Perico L, Benigni A, Casiraghi F, Ng LFP, Renia L, Remuzzi G. Immunity, endothelial injury and complement-induced coagulopathy in COVID-19. Nat. Rev. Nephrol. 2021;17:46–64.

[26] Sardu C, Gambardella J, Morelli MB, Wang X, Marfella R, Santulli G. Hypertension, Thrombosis, Kidney Failure, and Diabetes: Is COVID-19 an Endothelial Disease? A Comprehensive Evaluation of Clinical and Basic Evidence. J Clin Med. 2020;9:1417.

[27] Kumar N, Zuo Y, Yalavarthi S, Hunker KL, Knight JS, Kanthi Y, Obi AT, Ganesh SK. SARS-CoV-2 Spike Protein S1-Mediated Endothelial Injury and Pro-Inflammatory State Is Amplified by Dihydrotestosterone and Prevented by Mineralocorticoid Antagonism. Viruses. 2021 Nov 3;13(11):2209. doi: 10.3390/v13112209.

[28] Gundry SR. Abstract 10712: Mrna COVID Vaccines Dramatically Increase Endothelial Inflammatory Markers and ACS Risk as Measured by the PULS Cardiac Test: a Warning. Circulation. 2021;144:A10712

[29] Lei Y, Zhang J, Schiavon CR, et al. SARS-CoV-2 Spike Protein Impairs Endothelial Function via Downregulation of ACE 2. Circ Res. 2021;128(9):1323-1326. doi:10.1161/CIRCRESAHA.121.318902

[30] Zhao Y, Kuang M, Li J, et al. SARS-CoV-2 spike protein interacts with and activates TLR41. Cell Res 2021;31:818-820.

[31] Salamanna F, Maglio M, Landini MP, Fini M. Body Localization of ACE-2: On the Trail of the Keyhole of SARS-CoV-2. Front Med (Lausanne). 2020 Dec 3;7:594495. doi: 10.3389/fmed.2020.594495.

[32] Zhang S, Liu Y, Wang X, Yang L, Li H, Wang Y, Liu M, Zhao X, Xie Y, Yang Y, et al. SARS-CoV-2 binds platelet ACE2 to enhance thrombosis in COVID-19. J. Hematol. Oncol. 2020;13:120. doi: 10.1186/s13045-020-00954-7.

[33] Zhang S, Liu Y, Wang X, et al. SARS-CoV-2 binds platelet ACE2 to enhance thrombosis in COVID-19. J Hematol Oncol. 2020;13:120.

[34] Qi CL, Wei B, Ye J, Yang Y, Li B, Zhang QQ, Li JC, He XD, Lan T, Wang LJ. P-selectin-mediated platelet adhesion promotes the metastasis of murine melanoma cells. PLoS One. 2014 Mar 14;9(3):e91320. doi: 10.1371/journal.pone.0091320.

[35] Schlesinger M. Role of platelets and platelet receptors in cancer metastasis. J Hematol Oncol. 2018;11(125).

[36] Lucotti S, Muschel RJ. Platelets and Metastasis: New Implications of an Old Interplay. Front Oncol. Sep 2020.

[37] Weber MR, Zuka M, Lorger M, et al. Activated tumor cell integrin αvβ3 cooperates with platelets to promote extravasation and metastasis from the blood stream. Thromb Res. 2016;140 Suppl 1(Suppl 1):S27-S36. doi:10.1016/S0049-3848(16)30095-0

[38] Gross S, Jahn C, Cushman S, Bar C, Thum T. SARS-CoV-2 Receptor ACE2-Dependent Implications on the Cardiovascular System: From Basic Science to Clinical Implications. J Mol Cell Cardiol. 2020;144:47–53. doi: 10.1016/j.yjmcc.2020.04.031

[39] Glowacka I, Bertram S, Herzog P, Pfefferle S, Steffen I, Muench MO, Simmons G, Hofmann H, Kuri T, Weber F, Eichler J, Drosten C, Pöhlmann S. Differential downregulation of ACE2 by the spike proteins of severe acute respiratory syndrome coronavirus and human coronavirus NL63. J Virol. 2010 Jan;84(2):1198-205. doi: 10.1128/JVI.01248-09.

[40] Haga S, Yamamoto N, Nakai-Murakami C, Osawa Y, Tokunaga K, Sata T, Yamamoto N, Sasazuki T, Ishizaka Y. Modulation of TNF-alpha-converting enzyme by the spike protein of SARS-CoV and ACE2 induces TNF-alpha production and facilitates viral entry. Proc Natl Acad Sci U S A. 2008 Jun 3;105(22):7809-14. doi: 10.1073/pnas.0711241105.

[41] Bhari VK, Kumar D, Kumar S, Mishra R. SARS-CoV-2 cell receptor gene ACE2 -mediated immunomodulation in breast cancer subtypes. Biochemistry and Biophysics Reports. Dec 2020; 24.100844.

[42] Hicks B M, Filion K B, Yin H, Sakr L, Udell J A, Azoulay L et al. Angiotensin converting enzyme inhibitors and risk of lung cancer: population based cohort study BMJ. 2018;363:k4209 doi:10.1136/bmj.k4209

[43] Murphy WJ, Longo DL. A Possible Role for Anti-idiotype Antibodies in SARS-CoV-2 Infection and Vaccination. N Engl J Med. 2021 Nov 24. doi: 10.1056/NEJMcibr2113694.

[44] Xu J, et al. The ACE2/Angiotensin-(1–7)/Mas receptor axis: pleiotropic roles in cancer. Front Physiol. 2017;8:276. doi: 10.3389/fphys.2017.00276.

[45] Zhou L, et al. Decreased expression of angiotensin-converting enzyme 2 in pancreatic ductal adenocarcinoma is associated with tumor progression. Tohoku J. Exp. Med. 2009;217(2):123–131. doi: 10.1620/tjem.217.123.

[46] Feng Y, Wan H, Liu J, Zhang R, Ma Q, Han B, Xiang Y, Che J, Cao H, Fei X, Qiu W. The angiotensin-converting enzyme 2 in tumor growth and tumor-associated angiogenesis in non-small cell lung cancer. Oncol Rep. 2010 Apr;23(4):941-8. doi: 10.3892/or_00000718.

[47] Stewart CA, Gay CM, Ramkumar K, et al. Lung cancer models reveal SARS-CoV-2-induced EMT contributes to COVID-19 pathophysiology. Preprint. bioRxiv. 2021;2020.05.28.122291.

[48] Lai YJ, Chao CH, Liao CC, et al. Epithelial-mesenchymal transition induced by SARS-CoV-2 required transcriptional upregulation of Snail. Am J Cancer Res. 2021;11(5):2278-2290.

[49] Stewart CA, et al. Lung cancer models reveal SARS-CoV-2-induced EMT contributes to COVID-19 pathophysiology. bioRxiv 2020.05.28.122291; doi:

[50] Yu C, Tang W, Wang Y, Shen Q, Wang B, Cai C, Meng X, Zou F. Downregulation of ACE2/Ang-(1-7)/Mas axis promotes breast cancer metastasis by enhancing store-operated calcium entry. Cancer Lett. 2016 Jul 1;376(2):268-77. doi: 10.1016/j.canlet.2016.04.006.

[51] Zhou L, et al. Decreased expression of angiotensin-converting enzyme 2 in pancreatic ductal adenocarcinoma is associated with tumor progression. Tohoku J. Exp. Med. 2009;217(2):123–131. doi: 10.1620/tjem.217.123.

[52] Elliott A, Saul M, Zeng J, Marshall JL, Kim ES, Nagasaka M, Lenz HJ, Schwartzberg L, Spetzler D, Abraham J, Xiu J, Stafford P, Michael Korn W. Pan-cancer analysis of RNA expression of ANGIOTENSIN-I-CONVERTING ENZYME 2 reveals high variability and possible impact on COVID-19 clinical outcomes. Sci Rep. 2021 Mar 11;11(1):5639. doi: 10.1038/s41598-021-84731-7.

[53] Malkani N, Rashid MU. SARS-COV-2 infection and lung tumor microenvironment. Mol Biol Rep. 2021;48:1925–1934.

[54] Niu X, Zhu Z, Shao E, Bao J. ACE2 Is a Prognostic Biomarker and Associated with Immune Infiltration in Kidney Renal Clear Cell Carcinoma: Implication for COVID-19. J Oncol. 2021 Jan 28;2021:8847307. doi: 10.1155/2021/8847307.

[55] Pasin F, Mascalchi Calveri M, Calabrese A, Pizzarelli G, Bongiovanni I, Andreoli M, Cattaneo C, Rignanese G. Oncolytic effect of SARS-CoV2 in a patient with NK lymphoma. Acta Biomed. 2020 Jul 13;91(3):ahead of print. doi: 10.23750/abm.v91i3.10141.

[56] Elliott A, Saul M, Zeng J, Marshall JL, Kim ES, Nagasaka M, Lenz HJ, Schwartzberg L, Spetzler D, Abraham J, Xiu J, Stafford P, Michael Korn W. Pan-cancer analysis of RNA expression of ANGIOTENSIN-I-CONVERTING ENZYME 2 reveals high variability and possible impact on COVID-19 clinical outcomes. Sci Rep. 2021 Mar 11;11(1):5639. doi: 10.1038/s41598-021-84731-7.

[57] Kalyanaraman B. Reactive oxygen species, proinflammatory and immunosuppressive mediators induced in COVID-19: overlapping biology with cancer. RSC Chem Biol. 2021;2(5):1402-1414.

[58] Lai YJ, Chao CH, Liao CC, et al. Epithelial-mesenchymal transition induced by SARS-CoV-2 required transcriptional upregulation of Snail. Am J Cancer Res. 2021;11(5):2278-2290