Resistance to Inhibitors of Angiogenesis

Chapter
Part of the Resistance to Targeted Anti-Cancer Therapeutics book series (RTACT, volume 15)

Abstract

Angiogenesis, a process that is predominantly driven by the vascular endothelial growth factor (VEGF) signaling pathway, plays an essential role in tumor progression and metastasis. Accordingly, a range of anti-angiogenic agents, most of which block VEGF or its receptor, have been approved for the treatment of various malignant diseases. However, the clinical benefits of anti-angiogenic therapy are relatively modest for several reasons, some of which are related to the development of therapy resistance. Since anti-angiogenic agents target the tumor-supporting vascular system rather than the tumor cells themselves, resistance is dependent on the interplay between the host- and tumor-mediated pathways. In general, the activation of various evasive mechanisms allows for sustained tumor vascularization and growth despite the therapeutic blockade of the drug target. These mechanisms include the upregulation of bypass angiogenic pathways, pro-angiogenic activity of infiltrating stromal cells and alternative vascularization processes. In addition, off-target effects of anti-angiogenic drugs have implications for tumor aggressiveness. In this chapter, we discuss the molecular and cellular mechanisms contributing to therapy resistance as well as possible strategies to improve the clinical outcome.

Keywords

Chemokines Chemokine receptors Tumor microenvironment Angiogenesis Bone marrow-derived cells 

Abbreviations

BMDC

Bone marrow-derived cell

CAF

Cancer-associated fibroblast

CRC

Colorectal cancer

ECM

Extracellular matrix

EGF

Epidermal growth factor

EMT

Epithelial-mesenchymal transition

FDA

Food and Drug Administration

FGF

Fibroblast growth factor

GBM

Glioblastoma multiforme

G-CSF

Granulocyte colony stimulating factor

GIST

Gastrointestinal stromal tumor

HCC

Hepatocellular carcinoma

HGF

Hepatocyte growth factor

HIF-1

Hypoxia inducible factor-1

MDSC

Myeloid-derived suppressor cell

NSCLC

Non-small-cell lung cancer

OS

Overall survival

PDGF

Platelet-derived growth factor

PFS

Progression-free survival

PlGF

Placental growth factor

PNET

Pancreatic neuroendocrine tumor

RCC

Renal cell carcinoma

SCF

Stem cell factor

SDF-1α

Stromal derived factor-1α

TAM

Tumor-associated macrophage

TEM

Tie2-expressing monocyte

TH17

T helper type 17

TKI

Tyrosine kinase inhibitor

VEGF

Vascular endothelial growth factor

VEGFR

Vascular endothelial growth factor receptor

Notes

Acknowledgments

This book chapter is primarily supported by the European Research Council (#260633) and Rappaport Institute funds given to YS. KM is supported by a student fellowship from the Lyon Sachs University of Toronto— Technion Collaboration Fund.

Conflict of Interest

The authors declare that they have no conflict of interest.

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© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Cell Biology and Cancer Science, Rappaport Faculty of MedicineTechnion—Israel Institute of TechnologyHaifaIsrael

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