Selective blockade of tumor angiogenesis

Abstract

Blocking tumor angiogenesis is an important goal of cancer therapy, but clinically approved anti-angiogenic agents suffer from limited efficacy and adverse side effects, fueling the need to identify alternative angiogenesis regulators. Tumor endothelial marker 8 (TEM8) is a highly conserved cell surface receptor overexpressed on human tumor vasculature. Genetic disruption of Tem8 in mice revealed that TEM8 is important for promoting tumor angiogenesis and tumor growth but dispensable for normal development and wound healing. The induction of TEM8 in cultured endothelial cells by nutrient or growth factor deprivation suggests that TEM8 may be part of a survival response pathway that is activated by tumor microenvironmental stress. In preclinical studies, antibodies targeted against the extracellular domain of TEM8 inhibited tumor angiogenesis and blocked the growth of multiple human tumor xenografts. Anti-TEM8 antibodies augmented the activity of other anti-angiogenic agents, vascular targeting agents and conventional chemotherapeutic agents and displayed no detectable toxicity. Thus, anti-TEM8 antibodies provide a promising new tool for selective blockade of neovascularization associated with cancer and possibly other angiogenesis-dependent diseases.

Biomarkers Discovery for Colorectal Cancer: A Review on Tumor Endothelial Markers as Perspective Candidates

“…All of these data support the hypothesis that anti-TEM8 antibodies display potent antitumor activity. These antibodies are functionally involved in selective inhibition of angiogenesis and by that means indirectly block the tumor development [102]. …”

Studies in Mice Reveal a Role for Anthrax Toxin Receptors in Matrix Metalloproteinase Function and Extracellular Matrix Homeostasis

“…As Antxr1 KO mice develop normally and thrive but fail to support strong tumor growth, it has been hypothesized that a key function of ANXTR1 may be to serve in stress-mediated responses [21]. This concept fits with the observation that TEM8 is highly expressed in endothelial cells in the stressful environment of a growing tumor.…”

“…Thus, the mechanism by which Antxr1 contributes to tumor growth in this particular study was not delineated but clearly involved a stromal component of the tumor microenvironment. A recent follow-up study using these Antxr1 KO mice bred to an immunodeficient background revealed slower growth of multiple human tumor xenografts that was due in part to reduced tumor vasculature [20,21]. Since the ANTXRs are highly expressed on tumor vasculature, it is logical to hypothesize that targeting the receptors might serve as a potential new strategy for developing anti-angiogenic therapies to treat cancer.…”

“…Since the ANTXRs are highly expressed on tumor vasculature, it is logical to hypothesize that targeting the receptors might serve as a potential new strategy for developing anti-angiogenic therapies to treat cancer. Numerous studies addressing this hypothesis have been published and will not be elaborated upon in this review, as this topic is amply covered in the literature [9,21]. …”

“…This concept fits with the observation that TEM8 is highly expressed in endothelial cells in the stressful environment of a growing tumor. In fact, Chaudhary and St. Croix found that TEM8 is induced in cultured endothelial cells upon growth factor deprivation [20] or amino acid starvation [21], two conditions that tumor endothelial cells may be exposed to.…”