Blood vessel growth in the brain relies on a protein found in tumour blood vessels.

Do blood vessels that feed tumours differ from other blood vessels? Fourteen years ago, experiments designed to answer that question led to the discovery of several genes that are more active in tumour-associated blood vessels than in normal blood vessels. New research from the Johns Hopkins University now reveals the normal function of one of those genes and suggests it could be a good target for anticancer drug therapy.  The research is published in the journal Developmental Cell.

The mystery of the gene, TEM5, began in 2000 with research conducted by the team. The researchers compared gene activity in normal blood vessels to those infiltrating colorectal tumours. Among other differences were nine genes that were highly active in the tumour-associated blood vessels, which the researchers dubbed tumour endothelial, marker (TEM) 1 through 9. Endothelial refers to the type of cell that makes up blood vessels.

Over the ensuing decade, further experiments revealed clues regarding the function of individual TEMs. By 2010, it was known that mice missing TEM5, also known as GPR124, have defective blood vessel growth in the brain and spinal cord. The mice also showed defective formation of the blood-brain barrier, the molecular ‘wall’ crucial to protecting the brain.

The TEM5 protein was known to be located in the outer membrane of cells, likely receiving signals from outside the cell and passing information on to a network of proteins inside the cell. But it wasn’t known what signal it responds to and which protein network it connects to.

The team’s first clue was that the blood vessel defects in mice missing TEM5 looked similar to the defects found in mice that were missing two members of the Wnt family of signalling proteins, a well-known group of 19 related proteins used for communication between cells. Using cells grown in the laboratory the team tested each of the 19 known Wnt proteins and found that only two of them can activate TEM5. Remarkably, they were the same two Wnt proteins previously found to play an essential role in blood vessel development in the brain and spinal cord.

To test whether TEM5 uses the Wnt signalling system in blood vessels, the researchers artificially activated this system specifically in blood vessel cells in mice lacking TEM5. The blood vessel defects disappeared, confirming the relationship between TEM5 and Wnt.

The researchers state that TEM5 might be a good target for cancer therapy because, although TEM5 is crucial for embryonic blood vessel development, mice do well if TEM5 is eliminated after birth. The current study also suggests that temporarily disabling Wnt signalling in blood vessels might be used to improve drug treatment of brain diseases. Some potentially effective drugs cannot be used for treating brain diseases because they cannot cross the blood-brain barrier. Temporarily disabling that barrier might allow these drugs to gain access to the brain.

Source:  The Johns Hopkins University

Canonical Wnt signaling in endothelial cells (ECs) is required for vascularization of the central nervous system (CNS) and for formation and maintenance of barrier properties unique to CNS vasculature. Gpr124 is an orphan member of the adhesion G protein-coupled receptor family that is expressed in ECs and is essential for CNS angiogenesis and barrier formation via an unknown mechanism. Using canonical Wnt signaling assays in cell culture and genetic loss- and gain-of-function experiments in mice, we show that Gpr124 functions as a coactivator of Wnt7a- and Wnt7b-stimulated canonical Wnt signaling via a Frizzled receptor and Lrp coreceptor and that Gpr124-stimulated signaling functions in concert with Norrin/Frizzled4 signaling to control CNS vascular development. These experiments identify Gpr124 as a ligand-specific coactivator of canonical Wnt signaling.  Gpr124 Controls CNS Angiogenesis and Blood-Brain Barrier Integrity by Promoting Ligand-Specific Canonical Wnt Signaling.  Nathans et al 2014.

Canonical Wnt signaling in endothelial cells (ECs) is required for vascularization of the central nervous system (CNS) and for formation and maintenance of barrier properties unique to CNS vasculature. Gpr124 is an orphan member of the adhesion G protein-coupled receptor family that is expressed in ECs and is essential for CNS angiogenesis and barrier formation via an unknown mechanism. Using canonical Wnt signaling assays in cell culture and genetic loss- and gain-of-function experiments in mice, we show that Gpr124 functions as a coactivator of Wnt7a- and Wnt7b-stimulated canonical Wnt signaling via a Frizzled receptor and Lrp coreceptor and that Gpr124-stimulated signaling functions in concert with Norrin/Frizzled4 signaling to control CNS vascular development. These experiments identify Gpr124 as a ligand-specific coactivator of canonical Wnt signaling. Gpr124 Controls CNS Angiogenesis and Blood-Brain Barrier Integrity by Promoting Ligand-Specific Canonical Wnt Signaling. Nathans et al 2014.

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