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Angiogenesis Signaling Pathway


Angiogenesis plays a central role in tumor growth and progression, and its implications have been extensively investigated and described in the literature for various cancers. In the early 1970s, Folkman J was the first to develop the concept of angiogenesis-dependent tumor growth and postulated that the specific blocking of blood flow to the tumor should be a promising strategy for cancer treatment.

An Overview of Angiogenesis

Angiogenesis is defined as the process by which new blood vessels are formed from the pre-existing blood vessels in response to numerous mechanical, chemical, and inflammatory stimuli, enhancing tumor survival and progression. Tumor growth and metastasis depend on angiogenesis and lymph angiogenesis. Angiogenesis is an important factor in the progression of cancer, as tumor cells are dependent on neovascularization for oxygen and nutrients to sustain their growth. Angiogenesis is regulated through the balance of pro-angiogenic and anti-angiogenic factors, and these pro-angiogenic factors can be released by a variety of cells, including endothelial cells, monocytes, and tumor cells. During tumor growth, excessive release of angiogenic cytokines and growth factors induces an “angiogenic switch” which stimulates the quiescent, non-proliferating, nearby endothelial cells to grow and promote tumor progression.

The process of angiogenesis

Figure 1. The process of angiogenesis. (Rajabi, M; Mousa, S, A. 2017)

Angiogenesis is a complex developmental process involving basement membrane degradation, endothelial cell proliferation, migration, and tube formation. Angiogenesis plays a central role in normal development and wound healing and in the etiology of many diseases, such as psoriasis, diabetic retinopathy, and cancer. Since angiogenesis plays an essential role in tumor growth and invasion, anti-angiogenesis has been pursued for over 20 years as a route to novel cancer therapies. Many anti-angiogenic therapies have now described that inhibits not only tumor growth but also cancer cell dissemination.

The Process of Angiogenesis Signaling Pathways

The cross-talk between ROS and Ca2+ homeostasis might be important during angiogenesis. It has been shown that, in response to nitric oxide, ROS can induce the activation of Ca2+ channels by glutathionylation. The activation of Nox4 ROS production in response to VEGF seems to be required. Nox2 and eNOS would participate in such activation downstream of Nox4. Eventually, this determines the entry of Ca2+ into the endoplasmic reticulum through Ca2+ channels and into the cytoplasm through plasma membrane-associated channels.

ROS can influence VEGF signaling and angiogenesis through the regulation of transcription. It has long been known that exogenous H2O2 can stimulate the expression or the activity of transcription factors required for angiogenesis, such as Ets-1, NF-kB, and STAT-3. Moreover, there are a number of important genes required for angiogenesis whose expression is ROS-dependent, such as monocyte chemoattractant protein-1 (MCP-1), vascular cell adhesion molecule 1 (VCAM-1), and matrix metalloproteinases (MMPs).

The transcription factor HIF1α displays a prominent position in the regulation of hypoxia-induced angiogenesis. The stabilization of HIF1α under hypoxia drives the expression of VEGF, angiopoietin, erythropoietin, and SDF-1. All of these cytokines have angiogenic properties. There are two different phases of HIF1α hypoxic stabilization. In the early stage, HIF1α stabilization depends on mitochondrial ROS production, and on VEGF production; then, VEGF stimulates the production of ROS through NADPH oxidases, which reinforces HIF1α stabilization. Interestingly, HIF1α also controls Nox4 promoter activity.

VEGFR2 activation begins by receptor dimerization and transphosphorylation, and then several signaling cascades are activated downstream, such as Ras/p38 MAPK (mitogen-activated protein kinase), PI3K/AKT, PLCγ/DAG/PKC/MEK/ERK. PLCγ can mediate calcium release which is induced by IP3. Within those pathways, Rac is a key downstream target/effector of PI3K and can also regulate ADPH oxidase (Nox). It is important to note that VEGFR2 can be directly modified by ROS, through the formation of an inactivating intramolecular disulfide bridge. This could be a feed-forward negative regulation system important for signal termination.

The Therapy for Angiogenesis

For therapeutic angiogenesis, it is essential to understand molecular mechanisms of angiogenesis and arteriogenesis in relation to tissue hypoxia. While angiogenesis refers to the process of growing new blood vessels, arteriogenesis involves remodeling of existing arterial vessels. Under tissue ischemia, angiogenesis and arteriogenesis simultaneously take place and both processes are essential for the establishment of functional collateral networks. Regulation of angiogenesis and arteriogenesis may involve a distinct set of vascular modulators that jointly accomplish the complex processes of angiogenic and vascular remodeling.

References:

1. Prieto-Bermejo, R; Hernández-Hernández, A. The Importance of NADPH Oxidases and Redox Signaling in Angiogenesis. Antioxidants (Basel). 2017, 6(2).
2. Cao, Y, H. Therapeutic angiogenesis for ischemic disorders: what is missing for clinical benefits? Discov Med. 2010, 9(46):179-84.
3. Rajabi, M; Mousa, S, A. The Role of Angiogenesis in Cancer Treatment. Biomedicines. 2017, 5(2).

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