Abstract
ELTD1 is upregulated in tumor-associated vascular cells and promotes endothelial cell sprouting.
Major finding: ELTD1 is upregulated in tumor-associated vascular cells and promotes endothelial cell sprouting.
Approach: A core angiogenesis gene signature was identified in multiple types of human tumors.
Impact: ELTD1 inhibition reduces angiogenesis and tumor growth and is well tolerated in mice.
The efficacy of existing antiangiogenic therapies such as the anti-VEGF antibody bevacizumab is limited by intrinsic and acquired resistance. To identify additional targets that control tumor angiogenesis, Masiero and colleagues derived cancer type–specific angiogenesis gene signatures based on analysis of expression profiling and correlation with known vascular and endothelial cell (EC) genes in various primary human cancers. Although distinct metasignatures were observed in each tumor type, a 43-gene signature consisting of genes overexpressed in tumors was common to all cancers, including both known regulators of tumor angiogenesis and genes of unknown function. Expression of this core signature was reduced in tumor-associated stromal cells in response to treatment with antiangiogenic therapies and was regulated by the NOTCH ligand delta-like 4 (DLL). The top-ranked gene was EGF, latrophilin and seven transmembrane domain containing 1 (ELTD1), which encodes an orphan G-protein–coupled receptor of unknown function and was upregulated in tumor-associated ECs and vascular smooth muscle cells compared with normal ECs and tumor cells. Elevated ELTD1 expression in tumor-associated ECs was associated with increased microvascular density in multiple tumor types, including head and neck, renal, and ovarian cancer, was induced by the proangiogenic factors VEGF and basic fibroblast growth factor, and was repressed by DLL4, supporting a role for ELTD1 in tumor angiogenesis. Consistent with this idea, ELTD1 depletion decreased EC adhesion and sprouting and inhibited tip cell specification both in vitro and during zebrafish embryonic vascular development, leading to impaired vessel formation. Furthermore, knockdown of ELTD1 was well tolerated and resulted in suppression of tumor growth and metastasis and improved survival in mice. These results define a critical role for ELTD1 in promoting vessel formation and tumor angiogenesis and suggest ELTD1 as a potential therapeutic target.
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