Integrin αVβ3 receptors
Contrary to most thought, research, and publications, the ACE2 receptors are not the only doorway or focus point for complications with the SARS-CoV-2 virus. At least via current understanding, look at the ACE2 receptors as the front door entry into the cell. But, there are side doors, and I am sure there will be back doors discovered someday. That is just the way science works—time provides new discovery, that is, if science is allowed to follow the natural course of discovery.
What are Integrin αVβ3 receptors?
Integrin αVβ3 receptors, also known as vitronectin receptors, contain α and β transmembrane subunits. Integrins represent a type of cell adhesion molecule that connects the cytoskeleton of the cell with the extra-cellular matrix (ECM) outside the cell. This interconnectivity builds an intra-cellular and inter-cellular network that traverses the entire body. The extra-cellular matrix is a key component in cancer’s tumor microenvironment (TME). Beyond the integrins’ involvement in cancer and TME, it is part of normal cellular connectivity and cell signaling.
In cancer, our evolving perspective of the TME, including the tumor immunologic environment (TIME), is changing how we view and understand carcinogenesis, invasion, and metastasis. Cancer can no longer be seen as a solid ball of cells isolated without connectivity to the rest of the body. Instead, cancer is a collection of abnormal cells with:
- Abnormal metabolism
- Abnormal cell signaling
- Abnormal function
- Abnormal immunologic function
- Abnormal genetic expression
These actively interact with the body through the tumor microenvironment and the tumor immunologic environment through the existing inter-cellular networks.
Integrins integrate and connect the different intracellular and extra-cellular cellular components together to include the TME. Beyond simple interconnectivity, integrins play a role in cell signaling. This additional role in communication supports differentiation, migration, survival, and proliferation, all supportive in cancer.
If the ACE2 is the front door, integrin αVβ3 receptors are an alternative side door for the SARS-CoV-2 spike protein cell entry. If the ACE2 is the front door, integrin αVβ3 receptors are an alternative side door for the SARS-CoV-2 spike protein cell entry. Similar to ACE2, integrin αVβ3 receptors are expressed on platelets. In addition to the ACE2 receptors, the SARS-CoV-2 spike protein can use integrin αVβ3 receptors to increase platelet activation and all the adverse associated problems previously highlighted in the previous post Spike Proteins, ACE2, and Cancer.
Beyond the expression on platelets, integrin αVβ3, and the previously mentioned ACE2, receptors are highly expressed on both epithelial and endothelial cells. It is the co-expression of Integrin αVβ3 receptors on platelets and endothelial cells that integrate the platelets, the cancer cell-platelet aggregate, and the intended target, activated endothelium, for metastasis.
What is epithelium, and what is endothelium?
Epithelium is one of the four types of tissue that make up the body:
Epithelial tissue is made up of epithelial cells. The ultimate origin is the epithelium. Epithelial cells make up epithelial tissue that collectively encompasses the epithelium. Epithelium makes up tissue types that include secretory, absorptive, protection, transportation, and sensory function. So, any tissue type in the body that functions in these areas is classified as epithelial tissue.
Endothelial cells, like epithelial cells, are derived from the epithelium. Endothelial cells are a specialized sub-type of epithelial cell. Whereas epithelial cells line the inner and outer surfaces of organs and the body as a whole, endothelium only covers the inner surfaces of the blood vessels throughout the body [i]. This point is why the endothelium is central to the havoc caused by spike proteins and platelets, whether it be blood clots, tumor growth, and tumor metastasis. Activated endothelium highly expresses the integrin αVβ3 receptors, similar to the previously mentioned ACE2, and the activated endothelium is at the center of the convergence of spike proteins, platelets, and cancer cells. To be more exact, endothelium plays a crucial role in epithelial to mesenchymal transition (EMT) induction, which is key to cancer aggressiveness, growth, metastasis, and poor prognosis [ii] [iii] [iv]. Epithelial to mesenchymal transition is how an immobile cancer cell becomes mobile, essential to the spread of cancer.
Integrin αVβ3 receptors and thyroid hormones
Integrin αVβ3 receptors are an interesting non-genomic signaling doorway, in contrast to the “classic” genomic hormone signaling, some hormones employ. In fact, the non-genomic signaling pathway dominates in the rapidly dividing environment of cancer. One example is thyroid hormones, particularly T4 and reverse T3. In cancer, T4 and reverse T3 can promote cancer growth non-genomically via the Integrin αVβ3 receptors [v] [vi]. Yes, you did read that right. Begs the question of why T4 only therapy, levothyroxine, and Synthroid, is used in individuals with cancer? I guess there is a basic lack of understanding of the dynamics of thyroid physiology by physicians, the medical schools that teach them, and the continuing medical education that is supposed to continue to teach them. Hmmm. This, genomic versus non-genomic signaling is also found with estrogen, progesterone, testosterone, and cortisol. However, the integrin αVβ3 receptors are only involved with the non-genomic signaling pathway of the T4 and reverse T3 thyroid hormones. To learn more about this non-genomic signaling pathway, check out a past webinar I gave with ZRT labs on the topic of genomic versus non-genomic thyroid hormone signaling in cancer.
In this post, instead of the non-genomic pro-cancer signaling with T4 and reverse T3 thyroid hormones, integrin αVβ3 serves as a binding site for the SARS-CoV-2 spike proteins. Both in vivo and in vitro studies have shown that the spike protein, whatever the source, damages vascular endothelial [vii]. And why is damage to vascular endothelial cells important to this discussion? Damaged vascular endothelium attracts platelets to the site of injury for repair and clotting. Damaged endothelium is activated endothelium; because of the spike proteins, the arriving platelets are hyper-activated. The stage is set for metastasis at the sites of spike protein-induced endothelial damage. That is beyond its contribution to angiogenesis and epithelial to mesenchymal transition. More specific details on that in a later blog post, maybe.
Beyond the SARS-CoV-2 spike protein and ACE2 receptor interaction, the spike protein’s interaction with integrin αVβ3 receptors can increase the risk of cancer metastasis. Similar to the increased expression of ACE2 receptors in cancer, integrin αVβ3 receptor expression is increased in cancer cells and plays a role in aggressiveness, progression, and ultimately prognosis. For example, in breast cancer, integrin αVβ3 receptors promote cancer invasion and bone metastasis . How many women with breast cancer are on T4 only therapy and never have reverse T3 levels checked? Hmmm. The integrin αVβ3 receptors promote angiogenesis [viii], induce epithelial to mesenchymal transition to increase the mobility of cancer cells, help to promote the platelet—cancer cell aggregates that protect circulating cancer cells, increase the survival of the circulating cancer cells, increase the ability of cancer cells to attach to distant, damaged, vascular endothelial cells to invade, and promote micrometastasis that eventually results in macrometastasis. Together, the SARS-CoV-2 spike proteins and the damaged endothelium aid the endothelium invasion and resultant metastasis through the hyper-activated platelets and the integrin αVβ3 receptors.
An excellent analogy to explain the impact between spike proteins, integrin αVβ3, and endothelium in cancer is one of instrument flight rules (IFR) versus visual flight rules (VFR) in flight, particularly in the navigation of landing. Visual flight rules require visibility and line of sight to see the runway to fly and land. In contrast, instrument flight rules do not require a line of sight, which allows planes flying via IFR to land at night and in conditions of poor visibility, i.e., fog, rain, and snow. Instrument flight rules ensure the plane always reaches its target safely. For IFR navigation to work, the airport must turn on a beacon and assign it to a specific aircraft. In this analogy, the airplane seeks the beacon, and the airport provides the beacon. This combination provides navigation in all aspects of flight, and it makes sure the plane always reaches its intended target. In cancer, think of the cancer cell-platelet aggregate as the plane carrying the passengers (cancer cells) seeking the beacon through IFR and the endothelium damage as the airport runway beacon. In cancer, the circulating cancer cells are flying IFR via the hyper-activated platelets in the cancer cell—platelet aggregate, and the damaged endothelium beacon ensures that the circulating cancer cells will navigate their landing safely. We would best avoid this safe landing because this safe travel and landing leads to metastasis.
The spike proteins, through the integrin αVβ3 receptors, damage the endothelium and activate the platelets simultaneously, but it all begins with the endothelium. Beyond the increase in clotting risk (thromboembolism) associated with integrin αVβ3, there is an increase in:
- pro-inflammatory signaling
- cell growth
- cell survival
- immune escape
- physical escape
- epithelial to mesenchymal transition
- circulating tumor cell survival
- endothelial adhesion
All of which increase cancer growth and metastasis . The result is an increase in:
- oncogenic metabolic shift
- oncogenic transformation
- oncogenic signaling
- oncogenic immune dysfunction
- physical escape
- immune escape
As serious and life-threatening of an issue as the increase in systemic blood clotting risk is with integrin αVβ3 receptors, the increased risk of metastasis is an equal if not more significant concern. It is important to remember that metastasis leads to 90% of cancer-related morbidity and mortality. And according to the Prospective Urban and Rural Epidemiology (PURE) study, conducted between January 2005 and December 2016, cancer is the #1 cause of death, ahead of CVD, in high-income Countries [ix]. More, cancer is responsible for twice as many deaths as cardiovascular disease (CVD) in high-income countries. Of course, the U.S. would classify itself as a “high-income” country. And according to the CDC in 2010, cancer was the leading cause of death, ahead of CVD, in twenty-one states. Alaska was the first state to cross that threshold in 1993.
In review, whatever the source of the spike protein, whether active SARS-CoV-2 infection, injection, or repetitive injection, there is an increase in:
- endothelium damage
- platelet hyperactivity
- cancer cell—platelet aggregation
- immune evasion
- epithelial to mesenchymal transition
- increase in circulating tumor cell survival
The result will be an increase in cancer incidence, recurrence, metastasis, morbidity, and mortality—an utterly unforced error and the next pandemic. And that doesn’t include the up to 50% drop in cancer diagnosis [x] during the heart of the COVID-19 pandemic as the CDC, hospitals, and medical organizations recommended that cancer screening and other health prevention services be postponed, and patients avoided screening. Unfortunately, this drop in the diagnosis of the top six cancers (breast, colorectal, lung, pancreatic, gastric and esophageal) disproportionally affected women (75%). What about the ability to chew gum and walk at the same time? Everybody is focused on the immediate impact of SARS-CoV-2 infection and prevention, and appropriately so. But not despite other responsibilities. In medicine, viral pandemics are not the only responsibility. This hyper-focus is incredibly short-sighted, and a more long-term perspective is required. Observation and the connection of the dots in the data suggest that cancer is the coming next pandemic. The numbers of this imminent cancer pandemic will far exceed the numbers of the COVID-19 pandemic, and the impact will be significantly higher than what caused it— the COVID-19 pandemic from the SARS-CoV-2 spike proteins. But I wonder, will anybody talk about it? Will anybody notice?
[i] Panawala, Lakna. (2017). Difference Between Epithelial and Endothelial Cells.
[ii] Sigurdsson V, Hilmarsdottir B, Sigmundsdottir H, et al. Endothelial induced EMT in breast epithelial cells with stem cell properties. PLoS One. 2011;6(9):e23833. doi:10.1371/journal.pone.0023833
[iii] De Wever O, Pauwels P, De Craene B, Sabbah M, Emami S, et al. Molecular and pathological signatures of epithelial-mesenchymal transitions at the cancer invasion front. Histochem Cell Biol. 2008;130:481–494.
[iv] Hugo H, Ackland ML, Blick T, Lawrence MG, Clements JA, et al. Epithelial – mesenchymal and mesenchymal – epithelial transitions in carcinoma progression. J Cell Physiol. 2007;213:374–383.
[v] Frédéric Flamant, Sheue-Yann Cheng, Anthony N. Hollenberg, Lars C. Moeller, Jacques Samarut, Fredric E. Wondisford, Paul M. Yen, Samuel Refetoff, Thyroid Hormone Signaling Pathways: Time for a More Precise Nomenclature. Endocrinology. Jul 2017;158(7): 2052–2057. https://doi.org/10.1210/en.2017-00250
[vi] Kalyanaraman H, Schwappacher R, Joshua J, et al. Nongenomic thyroid hormone signaling occurs through a plasma membrane-localized receptor. Sci Signal. 2014;7(326):ra48. doi:10.1126/scisignal.2004911
[vii] Lei Y, Zhang J, Schiavon CR, et al. SARS-CoV-2 Spike Protein Impairs Endothelial Function via Downregulation of ACE2. Preprint. bioRxiv. 2020;2020.12.04.409144. Published 2020 Dec 4. doi:10.1101/2020.12.04.409144
[viii] Liu Z, Wang F, Chen X. Integrin alpha(v)beta(3)-Targeted Cancer Therapy. Drug Dev Res. 2008;69(6):329-339. doi:10.1002/ddr.20265
[ix] Teo K, Chow CK, Vaz M, Rangarajan S, Yusuf S; PURE Investigators-Writing Group. The Prospective Urban Rural Epidemiology (PURE) study: examining the impact of societal influences on chronic noncommunicable diseases in low-, middle-, and high-income countries. Am Heart J. 2009 Jul;158(1):1-7.e1. doi: 10.1016/j.ahj.2009.04.019.
[x] Kaufman HW, Chen Z, Niles J, Fesko Y. Changes in the Number of US Patients With Newly Identified Cancer Before and During the Coronavirus Disease 2019 (COVID-19) Pandemic. JAMA Netw Open. 2020 Aug 3;3(8):e2017267. doi: 10.1001/jamanetworkopen.2020.17267.
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