Cancer progression in COVID-19: integrating the roles of renin angiotensin aldosterone system, angiopoietin-2, heat shock protein-27 and epithelial mesenchymal transition

Abstract

The ongoing coronavirus disease 2019 (COVID-19) pandemic has affected millions worldwide and has been found to cause severe disease in patients with underlying comorbidities. In patients with known malignancies, in addition to constraints in routine healthcare, the risk of being susceptible to developing severe forms of the disease is of grave concern. While follow-up studies on survivors of the severe acute respiratory syndrome (SARS) 2003 outbreak revealed increased susceptibility to infections, tumours and cardiovascular abnormalities, recent studies implicating angiopoietin 2 in induction of inflammatory intussusceptive angiogenesis and diffuse alveolar damage in COVID-19 patients raises the possibility of progression of carcinogenetic processes in patients with known malignancies. Angiotensin converting enzyme-2 (ACE-2) mediated cellular entry of SARS-Cov2 leads to receptor shedding of ACE-2 and disrupts the renin angiotensin aldosterone axis (RAAS). This augments the pro-inflammatory and proliferative effects of RAAS, while attenuating the anti-inflammatory and anti-proliferative angiotensin 1-7 /Mas pathway. Angiopoietin-2, a molecule responsible for angiogenesis and cancer progression which corelates with tumour load in certain cancers, is upregulated by angiotensin 2-AT1 Receptor axis. Tumour microenvironment-comprising of various cells, blood vessels and extra cellular matrix which express the RAAS peptides-plays a key role in cancer initiation, progression and metastasis. Angiotensin 2 induces the formation of a desmoplastic environment, favouring cancer cell growth. ACE-2 downregulation causes bradykinin accumulation which may exert its proliferative action via mitogen activated protein kinase pathways which has established roles in cancers of breast and kidney. In addition to cytokine storm causing organ damage, acute inflammation in COVID-19 may also cause epithelial mesenchymal transition and heat shock protein 27 phosphorylation, both of which are key mediators in cancer signalling pathways. We hypothesise that SARS-Cov2, by impacting the RAAS and immune system, has the potential to cause tumour cell proliferation, apoptosis evasion and metastasis, thereby increasing the possibility of cancer progression in patients with known malignancies.

On the origin of metastases: Induction of pro-metastatic states after impending cell death via ER stress, reprogramming, and a cytokine storm

“…A more extensive overlap in enrichment analyses was observed between the UP genes in PAMEs and the transcriptome of cells displaying an unrelated cytokine storm driven by severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) infection (Figure S6E). Whereas these findings might have implications for cancer patients with COVID-19 (Liang et al, 2020;Miyashita et al, 2020;Arnaldez et al, 2020;Saha and Anirvan, 2020;Francescangeli et al, 2020, but see Lee et al, 2020;Kuderer et al, 2020), they reveal that PITS parallels different cytokine storms instead of being SASP.…”

Machine Learning Assisted Prediction of Prognostic Biomarkers Associated With COVID-19, Using Clinical and Proteomics Data

“…The dysregulation of APOM is also associated with hepatitis B virus (HBV) infected patients ( Gu et al, 2011 ). Another important protein associated with survival is angiopoietin (AGP), which is recently reported to cause inflammatory intussusceptive angiogenesis and diffuse alveolar damage in COVID-19, and the progression of carcinogenetic events in cancer patients ( Saha and Anirvan, 2020 ). Q96PL1_SG3A2 is highly expressed and shows antifibrotic activity in the lungs ( Cai et al, 2014 ).…”

ARID1A knockdown enhances carcinogenesis features and aggressiveness of Caco-2 colon cancer cells: An in vitro cellular mechanism study

“…The angiogenesis is initially driven by secretion of angiogenic factors such as VEGF, angiopoietin and fibroblast growth factor from the cancer cells to recruit the endothelial cells to the cancer locale. It has been reported that expression levels of angiogenic factors can reflect the aggressiveness of cancers [77][78][79]. In hepatocellular carcinoma, ARID1A deficiency promotes angiopoietin-2-induced angiogenesis that correlates with the cancer progression and aggressiveness [80].…”