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Review
. 2018 Jul 2:8:248.
doi: 10.3389/fonc.2018.00248. eCollection 2018.

Unraveling the Role of Angiogenesis in Cancer Ecosystems

Iratxe Zuazo-Gaztelu  1 , Oriol Casanovas  1
Affiliations
Review

Unraveling the Role of Angiogenesis in Cancer Ecosystems

Iratxe Zuazo-Gaztelu et al. Front Oncol. .

Abstract

Activation of the tumor and stromal cell-driven angiogenic program is one of the first requirements in the tumor ecosystem for growth and dissemination. The understanding of the dynamic angiogenic tumor ecosystem has rapidly evolved over the last decades. Beginning with the canonical sprouting angiogenesis, followed by vasculogenesis and intussusception, and finishing with vasculogenic mimicry, the need for different neovascularization mechanisms is further explored. In addition, an overview of the orchestration of angiogenesis within the tumor ecosystem cellular and molecular components is provided. Clinical evidence has demonstrated the effectiveness of traditional vessel-directed antiangiogenics, stressing on the important role of angiogenesis in tumor establishment, dissemination, and growth. Particular focus is placed on the interaction between tumor cells and their surrounding ecosystem, which is now regarded as a promising target for the development of new antiangiogenics.

Keywords: angiogenesis; angiogenic tumor ecosystem; antiangiogenics; intussusception; sprouting angiogenesis; vasculogenesis; vasculogenic mimicry.

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Figures

Figure 1
Figure 1
Cellular and molecular components of the tumor ecosystem that shape the tumor angiogenic landscape. The cellular components primarily consist of tumor and normal cells, together with the vascular endothelial and pericyte cells and the stromal fibroblasts [cancer-associated fibroblasts (CAFs)]. The immune cell compartment comprises mainly tumor-infiltrating macrophages, dendritic cells (DCs), and lymphocytes. Figure was created using Servier Medical Art according to a Creative Commons Attribution 3.0 Unported License guidelines 3.0 (https://creativecommons.org/licenses/by/3.0/). Simplification and color changes were made to the original cartoons.
Figure 2
Figure 2
Mechanisms implicated in blood vessel formation. In the tumor ecosystem, blood vessels grow by sprouting angiogenesis (A). In addition, less frequent neovascularization mechanisms include recruitment of bone marrow-derived endothelial progenitor cells (EPCs) (B), intussusceptive microvascular growth (C), and vasculogenic mimicry (D). Figure was created using Servier Medical Art according to a Creative Commons Attribution 3.0 Unported License guidelines 3.0 (https://creativecommons.org/licenses/by/3.0/). Simplification and color changes were made to the original cartoons.
Figure 3
Figure 3
Tumor angiogenesis inhibition strategies. Due to the complexity of tumor angiogenesis, it can be inhibited at different levels. Direct vessel signaling inhibition approaches include VEGF ligand inhibitors, VEGFR receptor inhibitors, and other growth factors inhibitors released by stromal or tumor cells. Other examples are tyrosine kinase (TK) inhibitors, that block endothelial and pericyte cell activation, thus blocking their proliferation, migration, and survival. Novel antiangiogenic strategies are directed toward endothelial progenitor cell (EPC) recruitment inhibition, via stromal-derived factor 1 (SDF-1)/C-X-C chemokine receptor type 4 (CXCR4) signaling blockade, and extracellular matrix (ECM) remodeling inhibition. Figure was created using Servier Medical Art according to a Creative Commons Attribution 3.0 Unported License guidelines 3.0 (https://creativecommons.org/licenses/by/3.0/). Simplification and color changes were made to the original cartoons.
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