VEGF, Angiogenesis and Colorectal Cancer

There are many complicated aspects of colorectal cancer. For one, colorectal tumors can result from alterations in many different biological pathways that lead to uncontrolled cell growth. What we do know is that tumors, like other body tissue, require a steady supply of oxygen and nutrients to grow. Facilitating this supply are blood vessels, which form through a process known as angiogenesis.

Angiogenesis is a normal body process, but certain cancer treatments are designed to halt this process and prevent further tumor growth. It might worry you that the cancer treatment may cause you more harm than good, but we hope that a better understanding of angiogenesis in the context of colorectal cancer can help alleviate your concerns.

For a start, let’s take a deep dive into angiogenesis, specifically focusing on the VEGF family of proteins.

Vascular endothelial growth factor, or VEGF for short, are small molecules that bind to receptors found on the surface of cells. Specifically, VEGF binds to receptors VEGF receptor-1 and VEGF receptor-2 — both of which are displayed on the surface of endothelial cells. These are the cells that make up the inner lining of blood vessels.

VEGF is directly associated with the growth and formation of new blood vessels from existing vascular networks — the process referred to as angiogenesis. Cells that are lacking in oxygen secrete VEGF, which attracts and stimulates endothelial cells. These cells multiply and contort their cell structures to construct the cylindrical walls of capillaries. These capillaries are able to penetrate through existing tissue layers, gravitating towards where VEGF is concentrated.

Other proteins are required to recruit different cell types such as pericytes and smooth muscle cells that are essential to form the outer portion of healthy blood capillaries and other blood vessels.

Now that we know how VEGF and angiogenesis occurs in healthy tissue, let’s explore how this applies to tumors and cancerous growth.

While cancer cells may not resemble healthy somatic cells in many ways, like most normal cells, they require nutrients and oxygen to grow. Cells in tumors are constantly multiplying, but due to their unstable genetic structures, many of these cells also undergo programmed cell death.

Earlier research showed that tumor cells cease to grow if they are located more than 0.2 mm away from blood vessels, while tumor cells found further away die.

From this, we have two key takeaways:

1. Tumor size can stagnate when cell growth and death is at an equilibrium, and
2. Tumors need to be within 0.2 mm of blood vessels to grow.

The 0.2 mm distance is significant — it is the distance at which oxygen can effectively diffuse from blood vessels into living tissue. Oxygen is key for cellular growth, and the lack of it results in hypoxia. Cancer cells that enter a hypoxic state then secrete angiogenic signals such as VEGF to attract a blood supply to the tumor. This is particularly important when tumors attempt to grow larger than 1–2 mm in diameter.

Cells in larger tumors are unable to receive sufficient oxygen through diffusion. The resultant hypoxic tissue environment triggers an angiogenic switch, which provokes an increase in hypoxia inducible factor-1ɑ (HIF-1ɑ) and 1β transcription factors, both of which are gene regulatory proteins. It is these factors that activate the transcription and production of angiogenic factors such as VEGF. The increased levels of VEGF then draw endothelial cells to the tumor tissue and result in the growth of new blood vessels.

We now know how cancer cells utilize VEGF to provoke angiogenesis to accelerate growth in tumor size. How does this come into play in colorectal cancer?

The source of fecal occult blood

As earlier mentioned, VEGF is only responsible for the initial recruitment of endothelial cells to form the inner lining of capillaries. Other proteins such as angiopoietin-1 and angiopoietin-2 are necessary for endothelial cells to recruit pericytes and smooth muscle cells, which are crucial for newly formed capillaries to mature into well-constructed vessels.

However, this is not the case in tumor-induced angiogenesis. Unlike healthy vessels, capillaries formed around tumors are tortuous, leaky, have inconsistent diameters and have many branches with dead ends. These abnormalities likely result from an imbalance of signaling molecules (such as the overexpression of VEGF).

On one hand, the poorly formed blood vessels in colorectal tumors manifest as one of the more easily detected symptoms of colorectal cancer: fecal occult blood.

On the other hand, the uneven distribution of blood vessels results in irregular blood flow to the tumor, which then creates hypoxic regions in the tissue. Cancer cells that carry certain mutations are able to survive in that hypoxic environment — these cancer cells are usually more malignant and result in more rapid and aggressive tumor growth.

The route for metastasis

The process of angiogenesis has importance beyond just providing tumors with the oxygen and nutrients to grow. The newly formed blood vessels are linked to the existing vascular network, including to vessels in healthy parts of the body. This provides the cancer cells an ‘escape route’ to spread to other distant organs. In the case of colorectal cancer, the organs cancer is most likely to metastasize are the liver and lungs.

In many human tumor types, the density of capillaries per microscope field increases in lockstep with increasing degrees of malignancy, suggesting that tumor invasiveness and intense angiogenesis are tightly coupled processes.

However, the relationship is not necessarily causal. It is not yet fully understood if intense formation of blood vessels enables cancer cells to grow more aggressively, or if it is just an indicator or marker for an underlying aggressive phenotype.

While we still do not know everything about the relationship between angiogenesis and colorectal cancer, what we do know is enough basis to target the process as a way to treat cancer. These treatments usually attempt to block the receptors that VEGF binds to, thus preventing endothelial cells from being recruited to form new blood vessels. This in turn prevents the tumor from growing and spreading.

At the moment, drugs developed to target angiogenesis are still in the testing phase, and have not yet begun clinical trials on humans. However, such targeted therapy can potentially improve the effectiveness of chemotherapy.

We hope that in helping you better understand one of the underlying causes of cancer, you might find the treatment options presented to you less intimidating. Your team of doctors or a second opinion can help clarify the best available treatment for your condition and circumstances.