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Angiogenic Signaling Pathways and Anti-angiogenic Therapies in Human Cancer

  • Aejaz Nasir
Chapter

Abstract

Vascular endothelial growth factor (VEGF) is the principal regulator of tumor angiogenesis and is overexpressed in the majority of solid tumors. Therapeutic inhibition of VEGF and its main receptor (VEGFR2) has shown significant clinical efficacy in several human cancers. However, in unselected patient populations, often these agents have not offered sustainable clinical benefit. Some of the challenges with the clinical efficacy of anti-VEGF/VEGFR therapies may be explained by the heterogeneity of human tumor vessels and variation in their sensitivity to VEGF/VEGFR inhibition. However, the process of tumor angiogenesis is far more complex with frequent cross talk between VEGF/VEGFR and other signaling pathways. In addition to anti-angiogenic effects, anti-VEGF/VEGFR agents also cause “normalization” of tumor vessels and “pruning” of normal vessels. In order to achieve significant improvement in clinical efficacy of anti-VEGF/VEGFR therapies in the near future, it will be important to (1) better understand the complex biology of VEGF/VEGFR and non-VEGF/VEGFR signaling pathways in the context of pathologic (aberrant) angiogenesis in human cancer tissues, (2) translate such biologic concepts into a more comprehensive molecular profiling and pathologic disease state characterization, and (3) advance the much needed predictive biomarker science to drive rational patient-tailoring and combinatorial therapeutic strategies in next-generation clinical trials of anti-angiogenic therapies. It will also be critical to identify and address other clinical and scientific challenges, including various primary and acquired mechanisms of resistance to anti-angiogenic therapies.

Keywords

Ramucirumab Bevacizumab Aflibercept Tyrosine kinase inhibitor Vascular endothelial growth factor (VEGF) Lung cancer Breast cancer Colon cancer Gastric cancer Vascular endothelial growth factor receptor (VEGFR) Tumor angiogenesis Anti-angiogenic therapy Tumor endothelial cells Pericytes Vascular normalization Microvascular density Hypoxia Angiogenesis PlGF NRP1 NRP2 Biomarker Molecular profiling Drug resistance 

Abbreviations

BRC

Breast carcinoma

CIN

Chromosomal instability

CRC

Colorectal carcinoma

DV

Draining vein

ECOG

Eastern Cooperative Oncology Group

EGFR

Epidermal growth factor receptor

FA

Feeder artery

FDA

Food and Drug Administration

FGFR

Fibroblast growth factor receptor

FISH

Fluorescent in situ hybridization

FLK1

Fetal liver kinase 1

FOLFIRI

Folinic acid, 5-fluorouracil, and irinotecan

GEJ

Gastroesophageal junction

GIST

Gastrointestinal stromal tumor

GMP

Glomeruloid microvascular proliferation

HCC

Hepatocellular carcinoma

HER2

Human epidermal growth factor receptor 2

HGF

Hepatocyte growth factor

IgG

Immunoglobulin G

IHC

Immunohistochemistry

ILF

Irinotecan, bolus fluorouracil, and leucovorin

INF

α Interferon-α

MC

Mast cell

MDSCs

Myeloid-derived suppressor cells

MET

Mesenchymal epithelial transition factor

MTC

Medullary thyroid carcinoma

MVD

Microvascular density

NGS

Next-generation sequencing

NRP1

Neuropilin 1

NRP2

Neuropilin 2

NSCLC

Non-small cell lung carcinoma

OC

Ovarian cancer

OS

Overall survival

PACA

Pancreatic cancer

PDGFR

Platelet-derived growth factor

PDGF-Rb

Platelet-derived growth factor receptor-beta

PFS

Progression-free survival

PlGF

Placental growth factor

RCC

Renal cell carcinoma

RNA

Ribonucleic acid

TAM

Tumor associated macrophage

TAMs

Tumor-associated macrophages

TCGA

The Cancer Genome Atlas

TGF-b

Transforming growth factor-beta

TKIs

Tyrosine kinase inhibitors

Treg

Regulatory T cells

VEGF

Vascular endothelial growth factor

VEGFR

Vascular endothelial growth factor receptor

VPF

Vascular permeability factor

Notes

Acknowledgments

The author would like to acknowledge the dedication and hard work of Timothy Holzer, Angie Fulford, Beverly Falcon, Drew Nedderman, Leslie O’Neal Reising, James Alston, and Mia Chen in the lab in developing and optimizing technically robust immunohistochemical and bright-field in situ hybridization technologies for VEGFR2, VEGFR3, and VEGFR1 for archival human tissues. Thanks to Jeff Hanson for supporting pathologic angiogenesis and oncologic disease state characterization analyses. Thanks also to Andrew Schade, Kelly Credille, Aafia Chaudhry, Katherine Marie Bell-McGuinn, Mayukh Das, Richard Walgren, Laura Benjamin, Bronislaw Pytowsky, Mark Uhlik, and Jeremy Graff for great scientific and clinical collaboration on tumor angiogenesis and anti-angiogenesis projects over the years.

DisclaimerExpert scientific and clinical views expressed in this chapter are those of the author.

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Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Aejaz Nasir
    • 1
    • 2
  1. 1.Diagnostic & Experimental Pathology, Tailored TherapeuticsEli Lilly & Co.IndianapolisUSA
  2. 2.BJ’s Diagnostic & Precision OncologyTampaUSA

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