[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.

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

Now that we have covered the different types of VEGF and their receptors, let us discuss the functional characteristics of these molecules. 

What are the functions of these receptors?

Different receptors have different functions: (1) VEGFR1 and VEGFR2 is involved in vasculogenic and angiogenic pathways while (2) VEGFR3 is involved in lymphanogenic pathway. In general, however, VEGFR receptor signaling works to increase permeability, proliferation, survival, migration, and mobilization vascular endothelial cells.

How does VEGF signaling mechanism look like?

Here's a figure that briefly shows the signaling mechanism of VEGF. 

<Kerbel RS. N Engl J Med 2008;358:2039-2049.>

After VEGF and receptor interaction, the tyrosine kinase domain gets auto-phosphorylated, meaninig phophosphate groups (PO4) get attached to the receptor's inner cell domain. Then, neighboring signaling molecules such as PLC gamma, PI3K, etc attaches to this kinase domain and get activated or inactivated through phosphorylation. The resulting effect of the signaling cascade is vascular permeability, proliferation, etc that were mentioned previously.

[Signaling 101] Vascular Endothelial Growth Factor (VEGF) Signaling (PART I)

When talking about cancer, we often come across acronyms like VEGF, VEGFR, EGFR, IGF, IGFR, etc... which after a few, sound and look the same. Our goal here is to pick one of them each month and go into the details about each of these cellular molecules that play important role in our body and can serve and potential targets for cancer therapy.

First, we are going to tackle Vascular Endothelial Growth Factors, also known as VEGF.

WHAT IS VEGF? 

VEGF (vascular endothelial growth factor), which was previous called VPF (vascular permeability factor) is a molecule that plays a major role in tumor growth by inducing angiogenesis. Angiogenesis is the process of new blood vessel formation from pre-existing vessels. This process plays a major role in:

1) stimulating proliferation and migration of endothelial cells for new vessels
2) contributing to the progress of a benign tumor (okay) to a malignant one (BAD!).

VEGF, thus, plays a role in turning a  normally co-existing tumor to a malignant cancer. As a result, there has been many research and drug discovery targetting VEGF to treat cancer.

HOW IS VEGF PRODUCTION INITIATED IN THE FIRST PLACE?

VEGF production is induced by cellular environmental factors such as hypoxia (insufficient oxygen), sex hormones such as androgen and estrogen, chemokines (chemical signaling molecules), as well as by genetic changes of oncogene (cancer inducing genes) or mutational inactivation of tumor suppressor gene. This molecule in a normally functioning body is produced to induce vasculogenesis for maintaining the overall homeostasis of oxygen, nutrients, and other essential factors that should be kept in balance throughout the body. However, cancer cells can manipulate this system that exists to benefit the host for their growth and mobilization in their host's body.

ARE THERE DIFFERENT KINDS OF VEGF? 

Yes, VEGF exists in six different forms: VEGF-A, VEGF-B, VEGF-C, VEGF-D, VEGF-E, and (ironically) PIGF (placental growth factor). They interact with three types of receptors: VEGFR (vascular endothelial factor receptor)-1, VEGFR-2, and VEGFR-3. Here's a little chart I made to makes things a little easier to see which factor binds to which receptor:

Receptors	Ligands
VEGFR-1	VEGF-A, VEGF-B, and PIGF
VEGFR-2	VEGF-A, VEGF-C, VEGF-D, and VEGF-E
VEGFR-3	VEGF-C, VEGF-D

I have made a mini-matching game to help you remember which factor binds to which receptor. :)

(will continue on part II...)