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Review
. 2019 Dec 12:9:1399.
doi: 10.3389/fonc.2019.01399. eCollection 2019.

Contribution of Angiogenesis to Inflammation and Cancer

Dolores Aguilar-Cazares  1 , Rodolfo Chavez-Dominguez  1   2 , Angeles Carlos-Reyes  1 , César Lopez-Camarillo  3 , Olga N Hernadez de la Cruz  3 , Jose S Lopez-Gonzalez  1
Affiliations
Review

Contribution of Angiogenesis to Inflammation and Cancer

Dolores Aguilar-Cazares et al. Front Oncol. .

Abstract

During carcinogenesis, advanced tumors are surrounded by both stromal and immune cells, which support tumor development. In addition, inflammation and angiogenesis are processes that play important roles in the development of cancer, from the initiation of carcinogenesis, tumor in situ and advanced stages of cancer. During acute inflammation, vascular hyperpermeability allows inflammatory mediators and immune response cells, including leukocytes and monocytes/macrophages, to infiltrate the site of damage. As a factor that regulates vascular permeability, vascular endothelial growth factor (VEGF) also plays a vital role as a multifunctional molecule and growth factor. Furthermore, stromal and immune cells secrete soluble factors that activate endothelial cells and favor their transmigration to eliminate the aggressive agent. In this review, we present a comprehensive view of both the relationship between chronic inflammation and angiogenesis during carcinogenesis and the participation of endothelial cells in the inflammatory process. In addition, the regulatory mechanisms that contribute to the endothelium returning to its basal permeability state after acute inflammation are discussed. Moreover, the manner in which immune cells participate in pathological angiogenesis release pro-angiogenic factors that contribute to early tumor vascularization, even before the angiogenic switch occurs, is also examined. Also, we discuss the role of hypoxia as a mechanism that drives the acquisition of tumor hallmarks that make certain cancers more aggressive. Finally, some combinations of therapies that inhibit the angiogenesis process and that may be a successful strategy for cancer patients are indicated.

Keywords: angiogenesis; cancer; carcinogenesis; inflammation; metastasis; vascular hyperpermeability; vasculogenic mimicry.

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Figures

Figure 1
Figure 1
Angiogenesis involvement in chronic inflammation and cancer. Some harmful agents induce stress in resident cells releasing danger-associated molecular patterns (DAMPs), activating endothelial cells. Activated endothelium express adhesion molecules enabling immune cells extravasation for harmful agent elimination, and lastly tissue reparation. Whether the harmful agent is maintained, a positive feedback loop persists mediated by cytokines secreted by immune and stromal cells, causing chronic inflammation. In this case, more healthy tissue cells are damaged by the harmful agent or by reactive oxygen and nitrogen species (RONS) released by the emerging influx of leukocytes through vascular hyperpermeability. Sustained cellular damage may lead to carcinogenesis initiation. According to cancer immunoediting theory, immune cells recruitment might eliminate transformed cells (Elimination phase). However, in this complex microenvironment, some cytokines act as growth factors for transformed cells or in the endothelium increase vascular hyperpermeability and leukocyte transmigration. These immune cells destroy susceptible tumor clones (Equilibrium phase). Tumor development induces metabolic alterations leading to the angiogenic switch; while, immune cell infiltration now promotes tumor growth (Escape phase). At advanced cancer stages, tumor mass viability is maintained by sustained angiogenesis and vasculogenic mimicry. This complex and dynamic environment promotes phenotypic changes into aggressive tumors, which take advantage of the tortuous vascular branches generating metastatic foci. It should be noted that inside the endothelium circle, the three phases of the immunoediting cancer theory are indicated. The intensity of the color represents the gradual activation of the endothelium. Created with Biorender.com.
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