**Author details**

Endothelial cell invasion into the surrounding tissue is made possible by means of the release of MMPs, which degrade the basal membrane and the extracellular matrix and allow the migration of endothelial cells to form capillary sprouts. Endothelial cells express different MMPs, and it has been reported that their expression is induced by VEGF and regulated by Ets transcription factors [112, 113]. Signaling pathways, such as MAP kinase cascade, PI3K/ AKT axis, and Ca2+-specific signals, converge on the Ets transcription factors, controlling their

VEGF-induced endothelial cell migration and proliferation are tightly regulated and coordinated spatio-temporal behaviors, which—in parallel with sustained cell survival—enable angiogenic sprouting and capillary lumen formation, necessary to create the new vessels devoted to support tumor growth and metastasis spread. VEGF-induced endothelial survival and proliferation are stimulated primarily via PI3K/AKT and PLCγ/ERK pathways, respectively, involving—as above described—several signaling intermediates. VEGF-induced endothelial cell migration appears to be regulated by a larger number of pathways, including the

In this chapter, we attempted in particular to describe the best characterized signal transduction events downstream to VEGF/VEGFR-2 axis involved in tumor angiogenesis. Multiple VEGF-induced signaling pathways take part in the promotion of different biological responses in endothelial cells. Although it is possible to recognize distinct patterns along VEGF-induced signaling, they are intricate, characterized by the involvement of a number of enzymes and adaptor/scaffold proteins—whose activity converges and branches at many point—and by the presence of VEGFR-2 molecular partners influencing endothelial cell sensitivity to VEGF and receptor signal output. This depicts a complex signal network induced by VEGF, where the apparent redundancy in operating signaling pathways is likely to reflect a need for a fine-tuning and a differential control of the biological effects in response to VEGF [25]. Although past decade has seen an important advancement in our understanding of VEGF signaling, there is still a lack of insight in many aspects of VEGF/VEGFR-2 signal transduction, in particular for what concerns its fine regulation. A further elucidation of the multifaced VEGF signaling network in the context of endothelial biology is crucial for developing new potential anti-angiogenic therapies. In parallel with current therapies that directly target VEGF and VEGFR-2, agents able to influence key molecular player—proximal, median or distal to VEGFR-2—could

Publication costs have been supported by "Associazione Italiana per la Ricerca sul Cancro"

involvement of PLCγ, PI3K, RHO GTPases, SRC and FAK activities.

240 Physiologic and Pathologic Angiogenesis - Signaling Mechanisms and Targeted Therapy

activity.

**5. Conclusions**

be of clinical interest.

**Acknowledgement**

(AIRC), project code 12182.

Lucia Napione1,2, \*, Maria Alvaro1,2 and Federico Bussolino1,2

\*Address all correspondence to: lucia.napione@ircc.it


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**Provisional chapter**
