Figure 3.

Role of RAAS in the tumor microenvironment. Immune cells can infiltrate tumors and differentiate into tumor-associated macrophages (TAM) derived mainly from circulating monocytes and are attracted to the tumor by chemokines. TAMs can stimulate tumor cell proliferation, angiogenesis, invasion and metastasis. Additionally, tumor microenvironment (TME) can influence the phenotype of circulating monocytes such as the Ly6C^high monocyte subset, giving them an immunosuppressive activity and a decreased responsiveness to inflammatory stimuli before their infiltration intoTME. Angiotensin-II (AngII) plays a relevant role in macrophage-mediated chronic inflammation, increasing macrophage progenitors and supplying of TAMs. Additionally, endothelial cells (EC) can promote pro-inflammatory signaling, favoring spontaneous metastasis in adjacent tumors through an aberrant expression of pro-inflammatory cytokines, extracellular matrix, alterations in the leukocyte adhesion process, increasing vascular cell adhesion molecule-1 (VCAM-1) and abnormal responses to oxidative stress. In ECs, AngII/AT1R signaling generates a pro-angiogenic response mediated by vascular endothelial growth factor (VEGF). AngII signaling activates TNF-α and NF-κB and upregulates pro-inflammatory endothelial chemokines. AngII has been reported to be able to promote VCAM-1 expression and enhance adhesion, growth, angiogenesis, and the inflammatory microenvironment through AT1R in hepatocellular carcinoma. It has been reported that angiogenesis promotes tumor cell metastasis. Image created with BioRender.com, Toronto, ON, Canada.