Unraveling the relationship between the renin–angiotensin system and endometrial cancer: a comprehensive review

Figures

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  Figure 1. Representation of the renin–angiotensin system. The secretion of estrogen and pro-renin from the ovary, placenta, and decidua through a series of events results in artery constriction and vasodilation. Renin, the major candidate responsible for converting inactive angiotensinogen to active Angiotensin, is produced by the liver. Furthermore, the combined effect of angiotensin and receptor for angiotensin (AT2R) convert AngI to AngII via ACE. ACE II comes into play and catalyzes the final conversion of AngII to Ang (1–7), ending in a variety of responses along with the production of aldosterone.

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  Figure 2. TNFα signaling pathway. The components of the renin–angiotensin system pathway involved in the conversion of angiotensin I to angiotensin II via ACE activate the TNFα receptor for the progression of the cascade of the signaling pathway for cancer development. In the TNF signaling pathway, TNFR1 transmits inflammatory signals by recruiting RIP1 and TRAF2 and apoptotic signals by recruiting FADD and caspase 8. To transmit signals related to inflammation, TNFR2 binds TRAF1 and TRAF2. Pro-caspase 8, the long isoform of FLICE-like inhibitory protein, and non-ubiquitylated receptor-interacting serine/threonine-protein kinase 1 (RIPK1) are additional apoptosis signaling pathways by which TNF can cause cell death (FLIPL).

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  Figure 3. TGF-β signaling. The renin–angiotensin system primary component ANG II activates TGF-β and Smad3. TGF-ligand and TGF-receptor bind to form a complex. The receptor-induced phosphorylation of R-Smads leads to an interaction with cytoplasmic Smad2/3. Phosphorylated Smads combine with Smad4, which facilitates the transport to the nucleus where it connects with multiple transcription factors for transcriptional activities. Smad complexes start a negative loop, which makes Smad7 stop R-Smads from getting any more phosphorylation. TGF-receptors also phosphorylate TAK1 and CREB, which are involved in neuronal differentiation, axonal growth, cell cycle progression, and antidepressant effects.

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  Figure 4. Proposed model for the actions of TGF-β1 on PTEN, PI3K–AKT signaling, and cell migration in type II endometrial cancer cells.

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  Figure 5. Tissue renin–angiotensin system in endometrial cancer. The physiologically active AngII may be produced with greater ACE1 abundance. The upregulation of the pro-angiogenic and pro-proliferative factors works together to boost the activation of the (P)RR and AGTR1-mediated intracellular signaling cascades, which would then drive the synthesis of TGFB1 and PI3KR1 and aid in the development of tumors. Through vascularization, the presence of MAS1 and increased ACE2 may promote tumor formation (24).

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  Figure 6. The renin–angiotensin system induces signal transduction pathways that are linked to cell division, migration, invasion, apoptosis suppression, and angiogenesis. Angiotensinogen type 1 receptor activation leads to a cascade of signaling pathways involving JAK, p38MPK, PKC, and JNK, causing the migration and invasion of tumor cells. PRR activates the vascular endothelial growth factor receptor (VEGFR) and epidermal growth factor receptor to activate the PI3K/AKT/mTOR and Ras/Raf/ERK pathways, respectively, for cell proliferation. Moreover, the inhibition of caspase 3 via the AKT pathway leads to inhibition of apoptosis, whereas VEGFR and MAS receptors are involved in angiogenesis (24).

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  Figure 7. Renin–angiotensin system cascade. Activation of pro-renin by PRR forms angiotensin from angiotensinogen. ACE then converts AngI to the biologically active AngII. Angiotensin binds to either the angiotensin II type 1 receptor (AT1R) or the angiotensin II type 2 receptor (AT2R). The downstream pathway run, by binding to AT1R, stimulates angiogenesis, fibrosis, migration, and invasion, whereas binding to AT2R acts antagonistically, blocking proliferation, angiogenesis, migration, and invasion.

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  Figure 8. ACE2 mRNA expression was found to increase in tumor tissue as compared to the adjacent non-cancerous tissue.

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  Figure 9. Illustration of the authorized P(RR) signaling with major key components which include pro-renin, ANG-1, ANG-2 AT1R, and TGF-BETA. Abnormally active pro-renin binds to its receptor P(RR), causing the formation of angiotensin-1 from angiotensinogen. Upon interaction of ANG-1 with ACE, it forms ANG-2, which binds to its respective receptor, i.e., AT1R causing TGF-beta formation. This erratic signaling stimulates proliferation, angiogenesis migration, and invasion.

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  Figure 10. Schematic signaling shows the involvement of the renin–angiotensin system. Activation of the Akt signaling pathway in a variety of ways. This pathway performs numerous cellular tasks.

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  Figure 11. Frequent mutations in endometrial carcinoma. EC, endometrial cancer.

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  Figure 12. Representative inhibitors of the PI3k/Akt/mTOR pathway.