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Review
. 2021 Feb 4:10:612802.
doi: 10.3389/fonc.2020.612802. eCollection 2020.

Endothelial YAP/TAZ Signaling in Angiogenesis and Tumor Vasculature

Affiliations
Review

Endothelial YAP/TAZ Signaling in Angiogenesis and Tumor Vasculature

Aukie Hooglugt et al. Front Oncol. .

Abstract

Solid tumors are dependent on vascularization for their growth. The hypoxic, stiff, and pro-angiogenic tumor microenvironment induces angiogenesis, giving rise to an immature, proliferative, and permeable vasculature. The tumor vessels promote tumor metastasis and complicate delivery of anti-cancer therapies. In many types of tumors, YAP/TAZ activation is correlated with increased levels of angiogenesis. In addition, endothelial YAP/TAZ activation is important for the formation of new blood and lymphatic vessels during development. Oncogenic activation of YAP/TAZ in tumor cell growth and invasion has been studied in great detail, however the role of YAP/TAZ within the tumor endothelium remains insufficiently understood, which complicates therapeutic strategies aimed at targeting YAP/TAZ in cancer. Here, we overview the upstream signals from the tumor microenvironment that control endothelial YAP/TAZ activation and explore the role of their downstream targets in driving tumor angiogenesis. We further discuss the potential for anti-cancer treatments and vascular normalization strategies to improve tumor therapies.

Keywords: Angiogenic therapy; TAZ; cancer; endothelium; mechanotransduction; tumor angiogenesis; tumor vasculature; yes-associated protein (YAP).

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Schematic overview of tumor microenvironment factors that promote endothelial YAP/TAZ activity. (A) During physiological angiogenesis, pro-angiogenic cytokines and growth factors activate YAP/TAZ signaling in endothelial cells (ECs) through GPCRs and RTKs, such as VEGFR2 or Tie2. (B) Hypoxia induces secretion of pro-angiogenic factors to promote tumor angiogenesis and consequently YAP/TAZ activity in the tumor microenvironment (TME). Elevated levels of pro-angiogenic factors promote the formation of a dense and disorganized tumor vasculature, resulting in disturbed blood flow patterns (C) and increased interstitial fluid pressure (D) that mechanically activate YAP/TAZ. The integrity of the tumor endothelium is weakened due to decreased cell-cell interactions between the ECs and/or pericytes. YAP/TAZ are further mechanically activated in the TME by ECM stiffening (E), which is promoted by the cancer-associated fibroblasts (CAFs).
Figure 2
Figure 2
The tumor microenvironment (TME) and downstream transcriptional targets of YAP/TAZ engage in a positive feedback program that sustains YAP/TAZ activity in the endothelium. In quiescent endothelial cells YAP/TAZ are kept inactive and sequestered in the cytoplasm via interaction with 14-3-3 proteins, Angiomotin (AMOT) proteins or the VE-cadherin complex. Alternatively, inactive YAP/TAZ can be targeted for ubiquitin-mediated degradation. External cues from the tumor microenvironment (TME), including pro-angiogenic growth factors, inflammatory cytokines, stiff extracellular matrix (ECM), hypoxia, and disturbed blood flow activate YAP/TAZ leading to their translocation to the nucleus ( Figure 1 ). In parallel, multiple TME factors activate the transcription factors STAT3 and AP-1. Within the nucleus, YAP/TAZ interacts with several transcription factors, most notably the TEA domain family members (TEADs), but also with STAT3 and β-catenin to induce transcription of downstream target genes. Activated YAP/TAZ induce the expression of angiogenic and inflammatory cytokines, Rho GAPs and GEFs and extracellular matrix (ECM) remodeling proteins that engage in a positive feedback system that sustains YAP/TAZ activity. (1) angiogenic and inflammatory cytokines maintain the pro-angiogenic and inflammatory TME. Moreover, the angiogenic effectors of YAP/TAZ (such as Ang2 and VEGF) destabilize VE-cadherin-based adherens junctions (AJs), further promoting the activity of YAP/TAZ. (2) Rho GAPs and GEFs control the level of Rho-GTPase activities, crucial switches that organize the actomyosin cytoskeleton, AJs and integrin-based focal adhesions (FA). In turn, the FAs and actomyosin cytoskeleton transduce forces from stiff ECM and maintain the nuclear translocation of YAP/TAZ. (3) ECM remodeling proteins are secreted and remodel the TME in favor of YAP/TAZ activity.

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