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Resistance to Inhibitors of Angiogenesis

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Resistance to Anti-Cancer Therapeutics Targeting Receptor Tyrosine Kinases and Downstream Pathways

Part of the book series: Resistance to Targeted Anti-Cancer Therapeutics ((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.

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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

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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.

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The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Department of Cell Biology and Cancer Science, Rappaport Faculty of Medicine, Technion—Israel Institute of Technology, 1 Efron St. Bat Galim, Haifa, 31096, Israel

    Nili Dahan, Ksenia Magidey & Yuval Shaked

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  1. Nili Dahan
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  2. Ksenia Magidey
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  3. Yuval Shaked
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Correspondence to Yuval Shaked .

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  1. Department of Biological Regulation, Weizmann Institute of Science, Rehovot, Israel

    Yosef Yarden

  2. Department of Microbiology, Immunology and Genetics, Ben-Gurion University of the Negev, Beer-Sheeva, Israel

    Moshe Elkabets

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Dahan, N., Magidey, K., Shaked, Y. (2018). Resistance to Inhibitors of Angiogenesis. In: Yarden, Y., Elkabets, M. (eds) Resistance to Anti-Cancer Therapeutics Targeting Receptor Tyrosine Kinases and Downstream Pathways. Resistance to Targeted Anti-Cancer Therapeutics, vol 15. Springer, Cham. https://doi.org/10.1007/978-3-319-67932-7_9

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