[Frontiers in Bioscience 16, 1024-1035, January 1, 2011]

The c-Fes protein tyrosine kinase as a potential anti-angiogenic target in cancer

Shigeru Kanda1,3, Yasuyoshi Miyata2

1Department of Molecular Microbiology and Immunology, Division of Endothelial Cell Biology, 2Department of Nephro-urology, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki 852-8501, 3Department of Experimental and Clinical Laboratory Medicine, National Hospital Organization, Nagasaki Hospital, 41-6 Sakuragi-machi, Nagasaki 851-0251, Japan

TABLE OF CONTENTS

1. Abstract
2. Introduction
2. Introduction
2.1. Angiogenic cellular processes by endothelial cells
2.2. VEGF-A as a central player in angiogenesis
2.3. Resistance to therapy targeting VEGF-mediated signaling
3. Roles of c-Fes in angiogenic processes induced by a variety of proangiogenic factors
3.1. FGF
3.2. Angiopoietins
3.3. SDF-1alpha
3.4. IL-8
3.5. VEGF
4. Future directions for therapeutic applications
5. Acknowledgments
6. References

1. ABSTRACT

Angiogenesis is implicated in many pathological conditions, including cancer progression. Novel approaches have enabled an understanding of how endothelial cellular processes are regulated in vivo during angiogenesis. Key players in angiogenesis are vascular endothelial growth factors (VEGFs) and Notch ligands. However, mechanisms of angiogenic responses by other proangiogenic factors in vivo are largely unknown. Research using cultured endothelial cells has shown that c-Fes is involved in the activation of phosphoinositide 3-kinase (PI3-kinase) downstream of a variety of cytokine receptors. The PI3-kinase/c-Akt pathway regulates cell survival, migration, and morphological differentiation of endothelial cells during angiogenesis, and c-Fes thus may be a potential target of anti-cancer therapy, especially for patients with anti-VEGF refractory cancer. In addition, a number of experiments have shown that a bone marrow-derived monocytic lineage regulates angiogenesis, and c-Fes is also expressed in these cells. Roles for c-Fes during angiogenesis will be the focus of extensive research in the future.