One of the most fascinating, and at the same time unsettling, features of cancer is its ability to hijack the body’s normal biological processes for its own benefit. Tumor cells do not simply grow uncontrollably; they are also capable of reshaping the biological environment around them to ensure their survival. One of the most important mechanisms involved in this adaptation is angiogenesis, the process through which new blood vessels are formed. Angiogenesis is essential for life. Without it, the human body would not be able to grow, repair damaged tissues, or respond effectively to various physiological conditions. However, in the context of cancer, this same process becomes a powerful tool that allows tumors to expand, invade nearby tissues, and eventually spread to other parts of the body.
Understanding how tumors exploit angiogenesis has profoundly changed the way scientists and physicians approach cancer treatment. Today, it is widely recognized that blocking the formation of new blood vessels can be an effective strategy to limit tumor growth and improve therapeutic outcomes.
All cells in the human body require oxygen and nutrients to survive. These vital resources are delivered through the circulatory system, which functions as a vast distribution network connecting every cell to the blood supply. When a tumor first begins to develop, it can initially survive using the existing blood vessels within the surrounding tissue. However, this supply is limited. As the tumor grows, a point is reached where the available oxygen and nutrients are no longer sufficient to sustain its expansion.
Research has shown that tumors cannot grow beyond approximately one to two millimeters in diameter without developing their own vascular system. At this stage, tumor cells begin to release chemical signals that stimulate nearby blood vessels to grow toward the tumor. This process enables the tumor to obtain the resources necessary for continued growth. Moreover, the newly formed blood vessels also make it easier for cancer cells to enter the bloodstream and travel to other organs, leading to what is known as metastasis.
Angiogenesis itself is a highly organized biological process involving multiple cellular and molecular stages. Under normal conditions, it is carefully regulated by a balance between factors that stimulate blood vessel formation and those that inhibit it. When this balance is disrupted—as occurs in cancer—the body enters a state of active angiogenesis.
The process begins when tumor cells release signaling molecules that activate endothelial cells, the cells that line the interior of blood vessels. These cells respond to the signal by initiating a cascade of events that ultimately leads to the formation of new capillaries. First, enzymes are released that degrade the extracellular matrix, the structural tissue surrounding blood vessels. This allows endothelial cells to detach and move away from the original vessel.
Next, these cells migrate toward the angiogenic signal, begin to proliferate, and organize themselves into tubular structures that eventually develop into functional blood vessels. Finally, these newly formed vessels stabilize through the recruitment of supporting cells that help maintain their structure.
Angiogenesis can occur through different mechanisms. Researchers have identified two main ways in which new blood vessels are generated. The first is known as sprouting angiogenesis. In this process, new capillaries grow outward from existing blood vessels. Endothelial cells proliferate and migrate, forming tubular structures that eventually connect with other vessels and become part of a new vascular network.
The second mechanism is called intussusceptive angiogenesis, a less widely known but equally important process. Instead of forming entirely new vessels, existing vessels divide internally to create additional vascular structures. This second mechanism is particularly efficient because it requires less cellular proliferation and can occur more rapidly.
The formation of new blood vessels is regulated by a complex network of proteins and growth factors that act as biochemical signals. Among the most important of these molecules is vascular endothelial growth factor (VEGF), considered the primary regulator of angiogenesis. VEGF directly stimulates endothelial cell proliferation and migration, promoting the development of new blood vessels.
In many tumors, the production of VEGF is significantly increased, allowing the tumor to rapidly activate the formation of its own vascular network. Another important group of molecules includes fibroblast growth factors (FGF), which also stimulate cell proliferation and contribute to blood vessel development.
Angiopoietins, meanwhile, play a key role in regulating the stability and maturation of blood vessels. These proteins help determine whether newly formed vessels will stabilize and persist or instead regress. Additional molecules such as TGF-β, PDGF, and enzymes known as matrix metalloproteinases (MMPs) also play critical roles in tissue remodeling and vascular formation. The interaction among these factors creates a highly coordinated signaling network that regulates angiogenesis under both normal and pathological conditions.
One of the most powerful triggers of angiogenesis is hypoxia, a condition in which tissues receive insufficient oxygen. As tumors grow rapidly, cells located in the inner regions of the tumor mass begin to experience oxygen deprivation. This lack of oxygen activates specialized proteins known as hypoxia-inducible factors (HIFs).
These proteins function as molecular oxygen sensors. When oxygen levels drop, they activate genes responsible for producing angiogenic factors such as VEGF. As a result, the tumor sends signals that stimulate the formation of new blood vessels in order to restore oxygen and nutrient supply. This mechanism makes hypoxia one of the main drivers of tumor growth.
Although tumors generate new blood vessels, these structures are usually very different from normal blood vessels. Tumor vessels tend to be disorganized, structurally unstable, highly permeable, and irregularly distributed throughout the tumor mass.
These abnormalities create a complex tumor microenvironment that can interfere with drug delivery and contribute to treatment resistance.
The recognition of angiogenesis as a key factor in tumor growth led researchers to develop an innovative therapeutic strategy: blocking the formation of blood vessels to halt tumor progression. This approach is known as anti-angiogenic therapy.
Figure 1. Tumor angiogenesis is triggered by hypoxia within the tumor microenvironment, activating signals that promote the growth of new blood vessels from existing vasculature. These vessels supply oxygen and nutrients but often develop with abnormal structure and function, influencing tumor progression and therapeutic response.
Rather than directly attacking cancer cells, these treatments focus on blocking the signals that allow tumors to build their vascular networks. Several strategies can be used to achieve this goal. Some therapies inhibit the production of angiogenic factors, while others block their receptors on endothelial cells or enhance the activity of molecules that naturally suppress angiogenesis.
Today, several drugs that target angiogenesis are approved for clinical use in different types of cancer. One of the best known is bevacizumab, a monoclonal antibody that binds to VEGF and prevents it from activating its receptors. Other drugs include sunitinib, sorafenib, pazopanib, axitinib, and regorafenib. These medications are used in the treatment of various cancers, including kidney, lung, colorectal, liver, and certain gastrointestinal tumors.
However, while anti-angiogenic therapies can slow tumor growth, they rarely eliminate tumors completely when used alone. For this reason, they are often combined with other treatments such as chemotherapy, immunotherapy, or targeted therapies. Clinical studies have shown that these combinations can improve patient survival and increase treatment effectiveness. By attacking the tumor from multiple angles, combined therapies make it more difficult for cancer cells to adapt and survive.
Despite the progress made in recent decades, significant challenges remain in the development of anti-angiogenic therapies. Some tumors are capable of developing resistance to these treatments or activating alternative pathways that allow them to continue growing. Additionally, certain drugs may cause side effects related to alterations in the vascular system. This alone is the reason that a lower, more frequent dose of chemotherapy is suggested, called low-dose metronomic chemotherapy, which targets angiogenesis at the lower dose but remains cytotoxic without anti-angiogenesis at the traditional doses.
To overcome these limitations, researchers are exploring new strategies, including the use of nanotechnology to improve drug delivery directly to tumors. Nanoparticles made from materials such as gold, silver, or engineered biological compounds can act as carriers that transport anti-angiogenic drugs with greater precision, increasing their effectiveness while reducing side effects.
The study of angiogenesis has fundamentally transformed our understanding of cancer. Instead of viewing tumors simply as clusters of malignant cells, scientists now recognize them as complex biological systems that interact constantly with their surrounding environment.
By blocking the formation of blood vessels, researchers aim to weaken the support system that allows tumors to grow and spread. Although many questions remain, ongoing research into angiogenesis continues to open new possibilities for developing treatments that are both more effective and less aggressive. Ultimately, understanding how tumors manipulate the body’s normal biological processes not only deepens our knowledge of the disease but also helps us design smarter strategies to fight it.
Main reference:
Al-Ostoot, F. H., Salah, S., Khamees, H. A., & Khanum, S. A. (2021). Tumor angiogenesis: Current challenges and therapeutic opportunities. Cancer treatment and research communications, 28, 100422. https://doi.org/10.1016/j.ctarc.2021.100422
Other references:
Park, S. Y., Matte, A., Jung, Y., Ryu, J., Anand, W. B., Han, E. Y., Liu, M., Carbone, C., Melisi, D., Nagasawa, T., Locascio, J. J., Lin, C. P., Silberstein, L. E., & De Franceschi, L. (2020). Pathologic angiogenesis in the bone marrow of humanized sickle cell mice is reversed by blood transfusion. Blood, 135(23), 2071–2084. https://doi.org/10.1182/blood.2019002227
Yanagisawa, H., Sugimoto, M., & Miyashita, T. (2021). Mathematical simulation of tumour angiogenesis: angiopoietin balance is a key factor in vessel growth and regression. Scientific reports, 11(1), 419. https://doi.org/10.1038/s41598-020-79824-8
Faraji, A., Oghabi Bakhshaiesh, T., Hasanvand, Z., Motahari, R., Nazeri, E., Boshagh, M. A., Firoozpour, L., Mehrabi, H., Khalaj, A., Esmaeili, R., & Foroumadi, A. (2021). Design, synthesis and evaluation of novel thienopyrimidine-based agents bearing diaryl urea functionality as potential inhibitors of angiogenesis. European journal of medicinal chemistry, 209, 112942. https://doi.org/10.1016/j.ejmech.2020.112942
