Angiogenesis inhibitors are a fairly new idea in fighting cancer and several other pathological diseases.

Angiogenesis is a term describing how new blood vessels are formed in the body.

Angiogenesis takes place when "an endothelial cell forming the wall of an existing small blood vessel is activated, makes matrix metalloproteinase (MMP) enzymes that break down the ECM (extracellular matrix), invades the matrix, and then begins to proliferate." 

Eventually, strings of new endothelial cells organize into hollow tubes, creating new networks of blood vessels that supply a given tissue with nutrients to promote growth and repair.  (Antiangiogenic Strategies and Agents in Clinical Trials)

To understand how angiogenesis promotes tumor growth, you need to first understand how a tumor occurs in the body. All tumors start from one endothelial cell and grow into a tumor a few millimeters in size.

This process occurs with all tumors including cancerous ones. The tumor needs to set up a network of blood vessels to continue its growth.

This study goes into the detachment of the tumor in a little more detail. ¡†

Tumor angiogenesis suggests that tumors initially co-op existing blood vessels within an organ for their nutrient blood supply. Shortly thereafter, the existing vasculature destabilizes, most likely through the release of Ang-2 by endothelial cells.

This loss of vascular integrity leads to relative hypoxia within the tumor, which in turn leads to up-regulation of VEGF (vascular endothelial growth factor) in the tumor cells.

These events then lead to a robust angiogenic response. (Endothelial Survival Factors as Targets for Antineoplastic Therapy)

What researchers are trying to find is a way to stop this angiogenic response and stop tumor growth.

Angiogenic and antiangiogenic factors are usually well balanced in the body; unless a pathological condition exists (Endothelial Survival Factors as Targets for Antineoplastic Therapy).

The tumor has many way of activating cells to produce angiogenesis. The tumor may use other cells to produce angiogenic factors such as proteins, and genes. Also the tumor is able to adapt to its environment. The tumor adapts so well due to the fact that it is made up of several different kinds of cells. Therefore angiogenesis plays a key role in tumor growth, and that's why there is so much research being done. There are several factors involved in angiogenesis that are being looked at right now.

One is VEGF,

a second is blocking integrins, and

a third is blocking the endothelial survival factors.

VEGF is a well-known angiogenesis factor. The "physiologic action of this protein includes regulation of endothelial cell permeability and proliferation.¡" (Angiogenesis inhibition in solid tumors)

Being able to inhibit this protein will allow researchers a chance to control some aspects of the endothelial cell, which is the problem to begin with. Right now doctors are using the amount of VEGF found in a patient's body as an indicator of how serious the cancer is.

There have been several clinical tests, each showing positive effects, but also having problems. One uses a monoclonal antibody, which will block the VEGF to prevent its activation of the VEGFR-2 the receptor for VEGF. What this means is that it will inhibit the soft tissue tumors from forming. In laboratory mice that were injected with colon cancer liver metastases in their spleen showed a forty percent improvement with the monoclonal antibody.

This test also seemed tolerable for the patients but didn't show tremendously great results overall. This idea may need to be combined with another inhibitor or added to the normal treatment of cancer to produce better results. Blocking of integrins is a second pathway to preventing tumor growth. 

Integrins are a widely distributed family of cell surface x/b (alpha/beta3) proteins that bind cells to components of the extracellular matrix and mediate cell-cell interactions.  (Integrins as Targets of Angiogenesis Inhibition)

Integrins are important to angiogenesis because they provide support to the smaller blood vessels that feed the tumors. Integrins became important in cancer originally to determine relapse-free survival.

Researchers very quickly picked up on the fact that this test not only gave a patient's outcome. But blocking of integrins could also be used to fight cancer.

The intergin seems to act on a molecular level and can encode the DNA and allow angiogenesis to occur in that manner. What they used in the test to block the integrin was a cyclic peptide intravenously. The results showed "regression of human tumors transplanted onto chick cloriallantoic membrane." 

The article doesn't go into detail of how long the regression lasted, if there was a relapse and if studies of this inhibitation were to take place in humans. This study still seems to be on the early stages of development.

But seems to be a step in the right direction.

Blocking integrins may also play a role in the endothelial survival factors, another area of research on angiogenesis inhibition.

A third class of antiangiogenesis inhibitors, are the endothelial survival factors.

This research targets the old blood vessels, and the new ones that directly support the tumors growth and survival. This combines both the VEGF and the integrin system to target the already made vessels.

Using both systems the researchers hope not to just stop new growth. But, to destroy any blood supply, that is already maintaining the tumors. This form of treatment may possibly have some success in humans. Although, research hasn't been done yet.

They did run into a few problems throughout the study. The study showed that when the patients¡Ù p53 gene was deactivated the treatment had less of an effect.

"The loss of the p53 gene apparently renders tumor cells better able to survive in the low-oxygen conditions present in tumors deprived of an ample blood supply."(Obstacle for Promising Cancer Therapy)

The p53 gene also allows the VEGF to over produce itself and that again causes the new blood vessels to be produced. Therefore, the tumor is able to mutate in a way that it can maneuver around the latest treatment. Researchers are doing studies to understand in more detail what happens to the cell when the p53 gene is deactivated.

So far they have found that some cells in the tumor are more susceptible to hypoxia, when the gene is turned on. This discovery isn't really a step backwards, but more of a step sideways. Due to the fact that we may be able to manipulate the area, cells, and structure around the tumor in another way.

Also another positive note is that we haven't found any tumor cell that can exist without oxygen.

As long as tumor cells continue to need oxygen to survive, we have a chance to knock cancerous tumors out.

Throughout the research that I have done on this topic, there are a few key factors that remained the focus in every article on angiogenesis.

One is that tumors need a network of blood vessels to survive and grow larger.

They are also able to mutate against most treatments that have been tried.

Another aspect of these articles that was very interesting was that no one seems to be looking for a silver bullet to cure all cancer.

Keshet, Eli. And Ben-Sasson, Shmuel. Anticancer Drug Targets Approaching Angiogenesis. The Journal of Clinical Investigation Dec, 99. Vol 104 #11.

Marx, Jean. Obstacle for Promising Cancer Therapy. Science, 2/25/2002, Vol295, Issue 5559, p.1444.

Neils Reinmuth, MD. Oliver Stoeltzing, MD. Weinbiao Liu, MD. Syed A Ahmad MD. Young D Jung, MD. PhD, Fan Fan. BS. Alexander Parikh, MD. Lee M Ellis, MD. Houston Texas. Endothelial Survival Factors as Target for Antineoplastic Therapy. The Cancer Journal, Vol 7, Supplement 3 Nov/Dec 2001.

Rosen, Lee. Angiogenesis Inhibition in Solid Tumors. Cancer Journal, Vol 7, Supplement 3 Nov/Dec 2001.