Angiogenic Signaling Pathways and Anti-angiogenic Therapies in Human Cancer

  • Aejaz Nasir


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.


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 



Breast carcinoma


Chromosomal instability


Colorectal carcinoma


Draining vein


Eastern Cooperative Oncology Group


Epidermal growth factor receptor


Feeder artery


Food and Drug Administration


Fibroblast growth factor receptor


Fluorescent in situ hybridization


Fetal liver kinase 1


Folinic acid, 5-fluorouracil, and irinotecan


Gastroesophageal junction


Gastrointestinal stromal tumor


Glomeruloid microvascular proliferation


Hepatocellular carcinoma


Human epidermal growth factor receptor 2


Hepatocyte growth factor


Immunoglobulin G




Irinotecan, bolus fluorouracil, and leucovorin


α Interferon-α


Mast cell


Myeloid-derived suppressor cells


Mesenchymal epithelial transition factor


Medullary thyroid carcinoma


Microvascular density


Next-generation sequencing


Neuropilin 1


Neuropilin 2


Non-small cell lung carcinoma


Ovarian cancer


Overall survival


Pancreatic cancer


Platelet-derived growth factor


Platelet-derived growth factor receptor-beta


Progression-free survival


Placental growth factor


Renal cell carcinoma


Ribonucleic acid


Tumor associated macrophage


Tumor-associated macrophages


The Cancer Genome Atlas


Transforming growth factor-beta


Tyrosine kinase inhibitors


Regulatory T cells


Vascular endothelial growth factor


Vascular endothelial growth factor receptor


Vascular permeability factor



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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