TEM8/ANTXR1 blockade inhibits pathological angiogenesis and potentiates tumoricidal responses against multiple cancer types

Amit Chaudhary; Mary Beth Hilton; Steven Seaman; Diana C Haines; Susan Stevenson; Peter K Lemotte; William R Tschantz; Xiaoyan M Zhang; Saurabh Saha; Tony Fleming; Brad St Croix

doi:10.1016/j.ccr.2012.01.004

TEM8/ANTXR1 blockade inhibits pathological angiogenesis and potentiates tumoricidal responses against multiple cancer types

Cancer Cell. 2012 Feb 14;21(2):212-26. doi: 10.1016/j.ccr.2012.01.004.

Authors

Amit Chaudhary¹, Mary Beth Hilton, Steven Seaman, Diana C Haines, Susan Stevenson, Peter K Lemotte, William R Tschantz, Xiaoyan M Zhang, Saurabh Saha, Tony Fleming, Brad St Croix

Affiliation

¹ Tumor Angiogenesis Section, Mouse Cancer Genetics Program, National Cancer Institute (NCI), National Institutes of Health (NIH), Frederick, MD 21702, USA.

Abstract

Current antiangiogenic agents used to treat cancer only partially inhibit neovascularization and cause normal tissue toxicities, fueling the need to identify therapeutic agents that are more selective for pathological angiogenesis. Tumor endothelial marker 8 (TEM8), also known as anthrax toxin receptor 1 (ANTXR1), is a highly conserved cell-surface protein overexpressed on tumor-infiltrating vasculature. Here we show that genetic disruption of Tem8 results in impaired growth of human tumor xenografts of diverse origin including melanoma, breast, colon, and lung cancer. Furthermore, antibodies developed against the TEM8 extracellular domain blocked anthrax intoxication, inhibited tumor-induced angiogenesis, displayed broad antitumor activity, and augmented the activity of clinically approved anticancer agents without added toxicity. Thus, TEM8 targeting may allow selective inhibition of pathological angiogenesis.

Publication types

Research Support, N.I.H., Intramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.

MeSH terms

Animals
Breast Neoplasms / genetics
Breast Neoplasms / pathology
Cell Line, Tumor
Colonic Neoplasms / genetics
Colonic Neoplasms / pathology
Female
Gene Expression Regulation, Neoplastic
Humans
Immunoglobulin G / pharmacology
Immunoglobulin G / toxicity
Lung Neoplasms / genetics
Lung Neoplasms / pathology
Melanoma / genetics
Melanoma / pathology
Mice
Mice, Knockout
Microfilament Proteins
Neoplasm Proteins / antagonists & inhibitors
Neoplasm Proteins / immunology
Neoplasm Proteins / physiology*
Neoplasms / blood supply*
Neovascularization, Pathologic* / genetics
Receptors, Cell Surface / antagonists & inhibitors
Receptors, Cell Surface / immunology
Receptors, Cell Surface / physiology*
Transplantation, Heterologous
Wound Healing / genetics

Substances

ANTXR1 protein, human
Immunoglobulin G
Microfilament Proteins
Neoplasm Proteins
Receptors, Cell Surface

Abstract

Publication types

MeSH terms

Substances

Grants and funding