Blocking Proangiogenesis Gene Could Stop Tumor Growth

A recent paper described the function of the proangiogenesis gene sphingosine 1-phosphate receptor-1 (S1P1) and suggested that drugs to block activity of this gene could help control tumor growth.

The protein encoded by the S1P1 gene is structurally similar to G protein-coupled receptors and is highly expressed in endothelial cells. It binds the ligand sphingosine-1-phosphate with high affinity and high specificity, and is thought to be involved in the processes that regulate the differentiation of endothelial cells. Activation of this receptor induces cell-cell adhesion.

Investigators at Weill Cornell Medical College (New York, NY, USA) have been working to define the molecular mechanisms of the angiogenic process, in which endothelial cells from preexisting blood vessels sprout, move, and then change to form new vascular channels. In the September 11, 2012, issue of the journal Developmental Cell they described a mechanism by which the G protein-coupled S1P receptor-1 (S1P1) stabilized the primary vascular network. A gradient of S1P1 expression from the mature regions of the vascular network to the growing vascular front was observed. In the absence of endothelial S1P1, adherens junctions were destabilized, barrier function was breached, and flow was perturbed, resulting in abnormal vascular hypersprouting.

Interestingly, S1P1 responded to S1P as well as laminar shear stress to transduce flow-mediated signaling in endothelial cells both in vitro and in vivo. These data demonstrated that blood flow and circulating S1P activated endothelial S1P1 to stabilize blood vessels in development and homeostasis.

"The body needs to make new blood vessels that transport oxygen and blood. We now know that VEGF (vascular endothelial growth factor) starts the process of sprouting new blood vessels from existing vessels, and S1P1 finishes it," said senior author Dr. Timothy Hla, professor of pathology and laboratory medicine at Weill Cornell Medical College. "Angiogenesis is abnormal in many diseases; by targeting both S1P1 and VEGF, it may be more effective to strike out disease than using just VEGF inhibitors alone."

"The S1P1 molecule acts like an antenna to sense blood flow. If blood flow is reduced, then normal S1P1 signaling is interrupted, destabilizing blood vessel formation, causing the endothelium to undergo an inflammatory process," said Dr. Hla. "This happens in many diseases with abnormal vessels, including rheumatoid arthritis, psoriasis, and even cancer. This research defines one of the fundamental mechanisms of blood vessel growth that is vital to normal health and that also fuels many diseases. This research could ultimately lead to our ability to better modulate blood vessel health and growth, especially in diseases that depend on extra blood to sustain them."

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