[Frontiers in Bioscience S3, 216-225, January 1, 2011]
Angiogenic and lymphangiogenic cascades in the tumor microenvironment

Mitsuho Onimaru1, Yoshikazu Yonemitsu2

1Division of Pathophysiological and Experimental Pathology, Department of Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan, 2R and D Laboratory for Innovative Biotherapeutics Graduate School of Pharmaceutical Sciences, Kyushu University

TABLE OF CONTENTS

1. Abstract
2. Introduction
3. Molecular systems in tumor cells for promoting blood/lymph-angiogenesis
3.1. An expression profile of blood/lymph-angiogenesis-related factors in tumor cells
3.2. Activation systems of tumor cell-associated receptors in a paracrine manner
3.3. Activation systems of tumor cell-associated receptors in an autocrine manner
3.3.1. The VEGF-A/VEGFR-2 autocrine system
3.3.2. The PDGF-AA/PDGFR-alfa autocrine system
3.3.3. The VEGF-C/VEGFR-3 autocrine system
4. Molecular systems among stromal cells for inducing "functional" angiogenesis
4.1. Differential therapeutic effects between VEGF-A and FGF-2 in cytokine therapy
4.2. The essential role of endogenous blood/lymph.angiogenesis-related factors in cytokine therapy mediated by FGF-2
4.3. Spatiotemporal coordination of blood/lymph angiogenesis-related systems in cytokine therapy mediated by FGF-2
4.3.1. Temporal coordination
4.3.2. Spatial coordination 5. The features of angiogenic response in the tumor microenvironment
5.1. Pro-blood/lymph-angiogenic factors rich microenvironment in tumor
5.2. The essential role of spatiotemporal coordination among host stromal cells during tumor associated angiogenesis 6. Perspective
7. Acknowledgement
8. Reference

1. ABSTRACT

Blood and lymphatic vessels in tumor tissue are major components of the tumor microenvironment. These vessels are newly formed from pre-existing host vessels stimulated by pro-blood-angiogenic and pro-lymph-angiogenic (pro-blood/lymph-angiogenic) factors expressed in tumor cells. Tumor cells establish a specific stromal microenvironment fostering tumor growth, in which blood/lymph-angiogenesis are involved. The tumor-associated blood/lymph-angiogenesis is continually induced by complicated cytokine networks, namely pro-blood/lymph-angiogenic factor-mediated paracrine and autocrine interactions among tumor cells and stromal cells including endothelial cells (ECs) and non-endothelial mesenchymal cells (neMCs). In this review, we provide an overview of the features of tumor-associated blood/lymph-angiogenesis based on recent and updated information obtained mainly from our studies. With regard to the constituent cell-dependent molecular mechanisms that regulate tumor blood/lymph-angiogenesis, we focus on: 1) the role of blood/lymph-angiogenesis-related factors/receptors expressed in tumor cells; and 2) the role of blood/lymph-angiogenesis-related factors/receptors expressed in stromal cells (ECs and neMCs). Finally, we discuss the features of tumor-associated blood/lymph-anigogenesis, especially a vessel abnormality through the viewpoint of blood/lymph-angiogenic cascades in tumor microenvironment for better understanding of the tumor vascular biology.