[Signaling 101] Vascular Endothelial Growth Factor (VEGF) Signaling (Part III)

Let's look at how VEGF/ VEGFR signaling is manipulated by tumor/ cancer cells.

WHAT HAPPENS TO VEGF SIGNALING IN CANCER?

Tumor cells go through hyper-proliferation. As a result of uncontrollable growth, there is a lack of necessary factors such as nutrients and oxygen for growth. Therefore, these tumor cells need their own vasculature and must induce angiogenesis for further growth. 

Hypoxia (resulting from uncontrolled cancer cell proliferation) is one of the major inducing factors of angiogenesis by cancer cells. 

The important molecule to note is hypoxia inducible factor-1 (HIF-1a), which is a transcription factor of VEGF. In normoxia (normal oxygen-level), the activity of HIF-1a is regulated by its degradation by VHL protein activity. Oxygen in the blood attaches to the HIF-1a in radical form, which gets process of two -OH groups. -OH groups serves as a tag for VHL to recognized the HIF-1a. Then, VHL group induces ubiquitination of HIF-1a, inhibiting the transcription factor from expressing VEGF.  

In hypoxia, however, as a result of oxygen depletion, HIF-1a does not attach attach to any oxygen groups and the following molecules that lead to its degradation. Therefore, HIF-1a is continuously active as a transcription factor, overexpressing VEGF. In addition, HIF-1a is a transcription factor for its own expression. Therefore, hypoxic conditions lead to increased levels of both HIF-1a and VEGF.