The role of redox system in metastasis formation

The metastatic cancer disease represents the real and urgent clinical need in oncology. Therefore, an understanding of the complex molecular mechanisms sustaining the metastatic cascade is critical to advance cancer therapies. Recent studies highlight how redox signaling influences the behavior of metastatic cancer cells, contributes to their travel in bloodstream from the primary tumor to the distant organs and conditions the progression of the micrometastases or their dormant state. Radical oxygen species not only regulate intracellular processes but participate to paracrine circuits by diffusion to nearby cells, thus assuming unpredicted roles in the communication between metastatic cancer cells, blood circulating cells, and stroma cells at site of colonization. Here, we review recent insights in the role of radical oxygen species in the metastasis formation with a special focus on extravasation at metastatic sites. Supplementary Information The online version contains supplementary material available at 10.1007/s10456-021-09779-5.


Reducing pathway Topic Possible role in metastatic process
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Thioredoxins
Trx-interacting protein This protein is required for VEGFR2 catalytic activity via the inhibitory Sglutationylation of low molecular weigh tyrosine phosphatase associated with VEGFR2 Metastatic niche [1] Trx-interacting protein The association between this protein with NLRP3 inflammasome induced by ROS promote endothelial inflammatory response MCC extravasation [2] Trx-interacting protein This protein is involved in endothelialleukocyte adhesion MCC extravasation [3,4] Trx reductase The mitochondrial isoform is required to maintain anti-inflammatory properties of ECs and their angiogenic potential MCC extravasation; Metastatic niche [3] Peroxideroxins

Prx1
It promotes VEGF production in ECs and trigger an autocrine loop [5] Prx1 It prevents inflammatory response in early atherosclerosis [6] Prx2 It prevents inflammatory response in atherosclerosis [7] Prx2 It maintains in reduced state VEGFR2 enabling its activity [8] Prx6 It maintains EC barrier function and its deletion increase vasopermeability [9,10] GSH & PPP NADPH It is required for NOS3 activity and indeed the control of vasopermeability and vascular tone [11] Glucose-6-phosphate dehydrogenase (G6PDH) It is the limiting step of PPP and its genetic manipulation alters angiogenic response of ECs G6PDH GSPDH deficiency favours leukocyte adhesion [13] GSH GSH regulates eNOS production induced by the adhesion molecule ICAM-1 [14,15] GSH S-glutathionylation of regulation of the low molecular weight protein tyrosine phosphatase and focal adhesion kinase, which are key mediators of VEGF-mediated cell migration [16] GSH The ratio of GSH:GSSG decrease enhances protein S-glutathionylation, increased ROS, and enhanced VEGFR2 activation [17] GSH The redox-sensitive Ca2+ store maintenance via S-glutathione adducts on the key SERCA 2 Cys-674 thiol is required for normal angiogenic EC function [18] GSH By up-regulating Nrf2, GSH maintains EC barrier function and prevents inflammatory response [19,20] GSH S-glutathionylation of NOSIII induces NO uncoupling in ECs [21] Glutaredoxin-1 Glutaredoxin-1 is an enzyme that removes GSH from S-glutathionylated proteins. It regulates VEGF pathway. [22] GSH peroxidase The deletion of this enzyme promotes NOS uncoupling and enhances ROS production [23,24] Supplemental Tyr phosphorylation of VE-cadherin destabilizes adherens junction and favors leukocyte extravasation.
[ [35][36][37] The tyrosine phosphorylation status of VE-cadherin is regulated by the phosphatases SHP2 and VE-PTP and the kinases Src and proline rich tyrosine kinase 2, which are respectively inhibited and activated by ROS. [38,39] Leukocyte extravasation depends on phosphatidylinositol kinase [40] ROS levels are associated with an increase in the signaling of phosphoinositide-3,4,5-trisphosphate via oxidation of PTEN and subsequent activation of phosphatidylinositol kinase [41,42] During leukocyte diapdesis endothelial CD99 activates protein kinase A and forms a complex with the A-kinase anchoring protein ezrin, and the soluble adenylyl cyclase. Protein kinase A stimulates membrane trafficking from the lateral border recycling compartment to sites of transmigration.
[43] ROS may activate protein kinase A and change the subcellular localization of ezrin. [44,45] Transient receptor potential canonical 6 (TRPC6) calcium channel controls lateral border recycling compartment trafficking and thus control leukocyte extravasation.
[46] ROS activate TRPC6 and promotes TRPC6 trafficking to the plasma membrane. On the other hands they inhibit TRPC6 expression. [47,48] During inflammation Pannexin 1 channels release ATP, which in autocrine manner stimulates purinergic receptors and VCAM1 expression, thus favoring leukocyte extravasation.