**Author details**

Keiko Fujita<sup>1</sup> \* and Masumi Akita<sup>2</sup>

\*Address all correspondence to: kfujita@saitama‐med.ac.jp

1 Department of Anatomy, Faculty of Medicine, Saitama Medical University, Saitama, Japan

2 Division of Morphological Science, Faculty of Medicine, Biomedical Research Center, Saitama Medical University, Saitama, Japan

## **References**


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**5. Conclusions and perspectives**

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JP16K11353.

Keiko Fujita<sup>1</sup>

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**Author details**

\* and Masumi Akita<sup>2</sup>

Saitama Medical University, Saitama, Japan

\*Address all correspondence to: kfujita@saitama‐med.ac.jp

**Acknowledgements**

cular endothelial cells and might be able to form tumor vessels.

222 Physiologic and Pathologic Angiogenesis - Signaling Mechanisms and Targeted Therapy

Tumor angiogenesis has been widely mentioned as a process that new blood vessels are devel‐ oped from preexisting host blood vessels surrounding the tumors. However, we propose a paradigm change. Our results suggest that CD133‐positive CSCs differentiate into tumor vas‐

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This work was supported in part by JSPS KAKENHI Grant Numbers JP25462779 and

1 Department of Anatomy, Faculty of Medicine, Saitama Medical University, Saitama, Japan 2 Division of Morphological Science, Faculty of Medicine, Biomedical Research Center,

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## **VEGF-Mediated Signal Transduction in Tumor Angiogenesis VEGF-Mediated Signal Transduction in Tumor Angiogenesis**

Lucia Napione, Maria Alvaro and Federico Bussolino Bussolino

Additional information is available at the end of the chapter Additional information is available at the end of the chapter

Lucia Napione, Maria Alvaro and Federico

http://dx.doi.org/10.5772/66764

#### **Abstract**

The vascular endothelial growth factor-A (VEGF) plays a crucial role in tumor angiogenesis. Through its primary receptor VEGFR-2, VEGF exerts the activity of a multitasking cytokine, which is able to stimulate endothelial cell survival, invasion and migration into surrounding tissues, proliferation, as well as vascular permeability and inflammation. The core components of VEGF signaling delineate well-defined intracellular routes. However, the whole scenario is complicated by the fact that cascades of signals converge and branch at many points in VEGF signaling, thus depicting a complex signal transduction network that is also finely regulated by different mechanisms. In this chapter, we present a careful collection of the best-characterized VEGF-induced signal transduction pathways, attempting to offer an overview of the complexity of VEGF signaling in the context of tumor angiogenesis.

**Keywords:** VEGF, signaling, angiogenesis, endothelial cells

## **1. Introduction**

It has been over four decades that Judah Folkman hypothesized, demonstrated and emphasized the critical importance of angiogenesis in tumor growth [1]. His experimental studies showed that in the absence of vascularization a tumor would grow only to a finite size of few thousand cells, restricted by the inability of oxygen and nutrients to penetrate the tissue beyond the diffusion limits of approximately 1–2 mm. To overcome this passive diffusionlimited size, the tumor must perturb the physiological state of its environment inducing the

and reproduction in any medium, provided the original work is properly cited.

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons © 2017 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution,

so-called angiogenic switch that implicates the transition from quiescent to active endothelium leading to the vascularization of the growing cell mass. The angiogenic switch was initially hypothesized to be triggered by the production and release of a growth factor called TAF (tumor angiogenesis factor) by tumor cells [2]. Indeed, the explosive growth in tumor angiogenesis research identified and characterized a number of angiogenic inducers. Among them, vascular endothelial growth factor (VEGF) is recognized as the major tumor angiogenesis factor [3].

VEGF family consists of five secreted proteins (VEGF-A, VEGF-B, VEGF-C, VEGF-D and placental growth factor). In terms of endothelial biology and tumor angiogenesis, VEGF-A (hereafter referred as VEGF)—in particular VEGF-A165—is considered to be the most physiologically relevant form. VEGF angiogenic potential is strictly dependent on its multifunctional activity. Indeed, the coordinated arrangement of endothelial cells to form and maintain new vascular tubes requires the induction of vascular permeability, endothelial cell migration, proliferation and survival. These biological responses take place in the endothelium via a complex network of intracellular signal transduction pathways, mainly mediated by VEGFinduced VEGF receptor 2 (VEGFR-2) activation [4].

In this chapter, after a short historical synopsis of Judah Folkman's hypotheses and main discoveries in the field of tumor angiogenesis, we will present a careful collection of the best characterized VEGF-induced signal transduction mechanisms, attempting to offer an overview of the complexity of VEGF signaling. The most intriguing aspect is that cascades of kinases, activity of other enzymes and recruitment of adapter proteins converge and branch at many points in VEGF signaling, emphasizing how linear pathways can integrate to form a complex signal transduction network. If multitasking and integrated signaling go some way toward an understanding of the functional versatility of VEGF, it becomes quite complicated to elucidate how specific information is processed through these pathways and how signaling events are regulated in order to trigger a specific cellular behavior.
