BREAKING! New International Study Warns That SARS-CoV-2 Infections Will Lead To Cancers Especially Colorectal Cancers Due to Disruption In Autophagy!
: A new international study comprising of researchers from the University of Turin-Italy, Shiraz University of Medical Sciences-Iran, University of Manitoba-Canada, Silesian University of Technology-Poland, University of Michigan-USA, Katowice School of Technology-Poland, Italian Institute for Genomic Medicine-Italy and the Candiolo Cancer Institute-Italy has alarmingly found that cancer will become one of the increasing conditions in Long COVID due to the ability of SARS-CoV-2 infections to cause disruptions in the human host cellular autophagy.
The researchers warn that although SARS-CoV-2 is not considered an oncogenic virus, the possibility of increased risk of cancer among COVID-19 survivors is extremely high. In their study findings, the study team provided an overview of the possible mechanisms leading to cancer development, particularly obesity-related cancers (e.g., colorectal cancer), resulting from defects in autophagy and the blockade of the autophagic flux, and also immune escape in COVID-19 survivors.
The study findings were published in the peer reviewed journal: Cancers
It should be noted that Thailand Medical News has been sounding the alarms since 2020 that SARS-CoV-2 will lead to an increase of a variety of cancers among those that were infected but many of our efforts were blocked by various American and British agencies and also by the mainstream media from these two countries.
It has been found that COVID-19 infection survivors suffer from a constellation of symptoms referred to as post-acute COVID-19 syndrome. However, in the wake of recent evidence highlighting the long-term persistence of SARS-CoV-2 antigens in tissues and emerging information regarding the interaction between SARS-CoV-2 proteins and various components of the host cell macroautophagy/autophagy machinery, the unforeseen long-term con
sequences of this infection, such as increased risk of malignancies, should be explored.
study findings also highlighted the potential long-term implications of COVID-19 infection in the prognosis of patients with cancer and their response to different cancer treatments.
In the human host, autophagy plays a prominent role in maintaining cellular homeostasis through the removal of damaged organelles, abnormal proteins, and invading organisms. Defects in autophagy are associated with various pathological conditions, including cancer. https://pubmed.ncbi.nlm.nih.gov/30633901/
Defects in autophagy can lead to accumulation of damaged mitochondria and alter cellular metabolism, leading to a high oxidative state. Furthermore, impairments in autophagy flux can lead to ER stress and subsequent accumulation of chaperone proteins and an eventual rise in the unfolded protein burden. This chronic injury to various cellular organelles and proteins and the accumulation of the genetic damage in cells with defective autophagy can lead to the development of pathophysiologies, as evidenced by the detection of loss-of-function mutations in different autophagy genes in various malignancies such as colorectal cancer. https://onlinelibrary.wiley.com/doi/abs/10.1002/path.2509
Autophagy also plays a significant role in promoting metastasis in certain tumors, particularly in RAS-driven cancers. https://pubmed.ncbi.nlm.nih.gov/24513958/
Mechanisms Supporting the Role of SARS-CoV-2 in Oncogenesis
It has been found that several oncogenic viruses exert their carcinogenesis through altering autophagy. https://pubmed.ncbi.nlm.nih.gov/32181249/
Though the oncogenic potential of SARS-CoV-2 has not yet been investigated, two other positive-sense single-strand RNA viruses, namely, hepatitis C virus/HCV and human T-cell lymphotropic virus type 1/HTLV-1, exploit the cellular autophagy machinery in order to cause liver cancer and adult T-cell leukemia/lymphoma/ATLL, respectively.
Both ACE2 (the major SARS-CoV-2 receptor) and TMPRSS2 (a transmembrane serine protease necessary for viral cell entry) display a very high level of expression in the human gastrointestinal tract. This virus can infect and actively replicate in human enterocytes. https://pubmed.ncbi.nlm.nih.gov/32404436/
Shockingly, recent study on the gastrointestinal biopsies of 14 individuals performed four months after their COVID-19 diagnosis reported persistence of the viral nucleic acids and antigens in 50% of the cases. https://pubmed.ncbi.nlm.nih.gov/33461210/
Persistent shedding of SARS-CoV-2 viral particles for months after the resolution of the symptoms has also been reported in the nasopharyngeal specimens obtained from individuals with previous infection. This continued presence of the viral antigens in different tissues could have serious long-term consequences for survivors of COVID-19 infection. https://www.tandfonline.com/doi/full/10.1080/10408363.2021.1884640
It has been found that various SARS-CoV-2 proteins interact with different components of the cellular autophagy pathway. For example, viral ORF3a protein interacts with VPS39, a part of the homotypic fusion and protein sorting/HOPS complex, leading to the inhibition of the fusion of autophagosomes with lysosomes. https://pubmed.ncbi.nlm.nih.gov/33947832/
Also, SARS-CoV-2 Nsp15 blocks the induction of autophagy, whereas the viral ORF7a protein decreases the acidity of lysosomes, which can interfere with autophagosome–lysosome fusion as well as cargo degradation. https://pubmed.ncbi.nlm.nih.gov/33974846/
Furthermore, accumulation of SQSTM1 and an increase in the processed LC3B (LC3B-II) levels have been observed upon SARS-CoV-2 envelope (E) protein overexpression. https://pubmed.ncbi.nlm.nih.gov/33974846/
All these past study findings indicate that various SARS-CoV-2 antigens block autophagic flux in the infected cells.
Conversely, a recent study showed that the protein encoded by viral ORF8 leads to major histocompatibility complex I (MHC-I) degradation in the affected cells by targeting these molecules for lysosomal degradation through the BECN1-dependent autophagy pathway. https://www.pnas.org/content/118/23/e2024202118.short
Importantly the persistence of the SARS-CoV-2 antigens in the enterocytes could lead to long-term defects in the cellular autophagy machinery, as evidenced by recent studies. The blockage in the autophagic flux in these cells would lead to the accumulation of SQSTM1/p62 (an autophagic receptor protein), reactive oxygen species, organelle damage, and genetic alterations in response to different stresses, eventually leading to tumorigenesis
An approximate 1.5-fold increase in SQSTM1 levels in the presence of SARS-CoV-2 ORF3a, ORF7a, or E proteins has been observed. https://pubmed.ncbi.nlm.nih.gov/33974846/
SQSTM1 plays a significant role in tumor transformation due to its important function as a signaling molecule interacting with many oncogenic pathways, including those involving NFE2L2/NRF2 and NFKB/NF-κB. https://pubmed.ncbi.nlm.nih.gov/22424619/
Numerous studies also reported evidence of mitochondrial dysfunction, excessive production of reactive oxygen species, ER stress, and unfolded protein responses in the cells infected with SARS-CoV-2. As mentioned, these pathological events could be, in part, a result of disturbed autophagy flux in the cells.
Furthermore, disrupted cell cycle regulation due to autophagy defects would lead to the uncontrolled proliferation of cells carrying defective genetic materials, paving the way for the development of cancer. https://internal-journal.frontiersin.org/articles/10.3389/fonc.2017.00051/full
Also, activation of compensatory mechanisms in colorectal cancer cells in specific contexts secondary to the inhibition of autophagy lead to tumor growth. https://pubmed.ncbi.nlm.nih.gov/31383875/
Alarmingly this could in turn lead to a higher risk of cancer development and more rapid proliferation of tumor cells among COVID-19 survivors.
Downregulation of MHC-I is one of the major mechanisms of the immune evasion by tumor cells through escaping detection by CD8+ T-cells and their cytotoxicity. This adaptive immune escape mechanism is observed in many malignancies, including colorectal cancer, and is associated with a poor prognosis. MHC-I degradation through the BECN1-dependent autophagy pathway induced by viral ORF8 could, therefore, provide a fertile soil for carcinogenesis by blunting the ability of the immune system to detect the cancer cells because their neo-antigens are no longer presented on the MHC-I molecules.
It should be noted that SARS-CoV-2 antigens have also been detected in various other human organs, such as the lungs, heart, kidneys, hepatobiliary system, and the lymphatic system. Although most of these findings have been reported in post-mortem studies and the persistence of the viral antigens in these organs among COVID-19 survivors has not so far been assessed due to technical and ethical considerations, it is likely that viral particles could linger in these tissues, continuing to interact with the host cell autophagy machinery and therefore inducing carcinogenesis in various organ systems.
It should be noted that a recent study has reported that SARS-CoV-2 RNA can integrate into the genome of cultured human cells through reverse transcription. The authors also claimed that they were able to detect viral-host chimeric transcripts in the patient-derived tissues, suggesting that these transcripts are a result of integration of DNA copies of viral sequences in the human genome. https://pubmed.ncbi.nlm.nih.gov/33958444/
Such integrations can also lead to cancer.
Interestingly, a nation-wide population-based study conducted in Denmark investigating mortality rates among patients admitted to the hospitals for non-COVID-19 diseases during the pandemic from March 2019 to January 2021, and found a consistently higher mortality rate among patients with cancer compared with baseline pre-pandemic mortality rates among these patients. https://pubmed.ncbi.nlm.nih.gov/34035000/
Though this observation is likely due to a multitude of factors, it is possible that defects in autophagy and increased tumor immune evasion among patients with certain malignancies who had previously contracted this infection could have led to more a rapid progression of their cancer due to the processes described above. In addition, a 6.9-fold increase in tumor burden has been reported in patients who had been diagnosed with metastatic colorectal cancer after the first lockdown compared with those diagnosed prior to the lockdown. https://jamanetwork.com/journals/jamanetworkopen/article-abstract/2784019
Considering the paramount role of autophagy in maintaining tissue homeostasis, dysregulation in this process has been linked to cancer development and progression in a context-specific manner. https://www.sciencedirect.com/science/article/pii/S1550413117302097
The potential inhibition of the autophagy flux by SARS-CoV-2 antigens can deprive tumor cells of the building blocks essential for unconstrained tumor proliferation and could, therefore, limit tumor growth. However, the accumulation of dysfunctional organelles, particularly dysfunctional mitochondria, as a result of impaired autophagy can pave the way for the development of cancer. https://pubmed.ncbi.nlm.nih.gov/30154567/
Obesity is correlated with elevated systemic oxidative stress. The excessive nutrients supply, overwhelming the cellular Krebs cycle and mitochondrial respiratory chain, leads to mitochondrial dysfunction and increases the formation of reactive oxygen species (ROS). Elevation of intracellular ROS is known to lead to the upregulation of the cellular autophagic response, which subsequently removes defective mitochondria and therefore limits the generation of ROS.
The potential inhibition of autophagic flux as a result of the persistence of SARS-CoV-2 antigens in different tissues could blunt this protective mechanism and could particularly be more important in the pathogenesis of obesity-related cancers. ROS levels are higher in colorectal cancer cells compared with normal non-cancerous tissues. https://pubmed.ncbi.nlm.nih.gov/25584043/
ROS play a critical role in mediating tumorigenesis and colorectal cancer initiation driven by RAC1. The effects of ROS extend beyond the initiation of obesity-related cancers; they are anti-apoptotic factors promoting the survival of pancreatic cancer cells.
The study team stresses that the potential long-term oncogenic effects of SARS-CoV-2 antigens that inhibit the autophagic flux (e.g., NSP15, ORF3a, etc.) could be investigated through in vitro studies assessing changes in tumor formation following the long-term presence of these antigens in various human cell lines, such as human KRAS knockout cells.
The study team concluded, “Despite the short amount of time since SARS-CoV-2 was first reported in 2019, scientists around the globe have managed to unravel various aspects of this infectious disease. However, we are still far from a solid understanding of this emerging infection and many important questions, particularly those regarding the long-term complications of this disease, remain unanswered. In this work, building on the previous investigations demonstrating long-term persistence of the SARS-CoV-2 nucleic acids and antigens in human tissues and also other research studies showing the interaction of the viral particles with the host autophagy machinery, we hypothesize that SARS-CoV-2 could potentially be an oncogenic virus by blocking the autophagic flux, and also leading to immune escape by downregulation of MHC-I. We also propose that the resultant dysregulation in cellular autophagy could affect the response to treatment in cancer cells. Further laboratory-based, clinical, and population-based studies are required to explore this matter.”
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