Cancer begins with the uncontrolled division of cells, forming a mass called a tumor. Like all growing tissues, this mass requires a constant supply of oxygen and nutrients, which are delivered exclusively by the body’s circulatory system.
A tumor can only grow to about one to two millimeters by relying on diffusion from nearby blood vessels. To become larger and potentially spread, the tumor must actively secure its own dedicated network of blood vessels. This requirement sets a fundamental limit on how large a malignant growth can become without co-opting the body’s vascular infrastructure.
The Natural Process of Blood Vessel Formation
The growth of new blood vessels from a pre-existing vascular network is known as angiogenesis. In a healthy adult, this process is tightly regulated and generally inactive, only activating briefly when needed. Angiogenesis is a normal part of female reproductive cycles and the body’s response to physical injury, being fundamental to healing wounds and regenerating damaged tissue.
The process is initiated when cells in an oxygen-deprived area release signaling molecules. These molecules bind to receptors on the endothelial cells lining nearby mature vessels, activating them. Activated endothelial cells release specialized enzymes that break down the basement membrane, allowing the cells to proliferate and migrate outward. They form delicate new sprouts toward the source of the chemical signal.
These sprouting endothelial cells form tiny tubes that eventually connect to establish a new, functional loop for blood flow. The final step involves recruiting supporting cells, called pericytes, which wrap around the new vessel walls to provide stability and structure. Once the tissue’s oxygen and nutrient needs are met, the activating signals diminish, and the process shuts down, returning the vasculature to a dormant state.
The Tumor’s Molecular Switch
Malignant tumors exploit this natural pathway by forcing the balance to favor vessel growth, a shift called the “angiogenic switch.” This switch is triggered when rapid tumor cell proliferation outpaces the available oxygen supply, creating regions of low oxygen, or hypoxia, within the mass. These hypoxic conditions stabilize a key regulatory protein known as the Hypoxia-Inducible Factor (HIF).
Stabilized HIF moves to the cell nucleus and initiates the transcription of genes responsible for creating pro-angiogenic proteins, most notably Vascular Endothelial Growth Factor (VEGF). The tumor and its surrounding cells secrete copious amounts of VEGF, which acts as a powerful recruiter for endothelial cells. This constant signaling causes nearby vessels to sprout relentlessly and chaotically toward the tumor.
The vessels formed under the tumor’s command are structurally abnormal compared to healthy capillaries. They are tortuous, dilated, and poorly organized, often lacking the stabilizing layer of pericytes. This structure makes them leaky and inefficient at delivering blood, which paradoxically perpetuates the tumor’s hypoxic state and further drives VEGF production.
Therapeutic Strategies to Block Vessel Growth
The understanding that a tumor requires a dedicated blood supply led to the development of anti-angiogenic therapies. The rationale is to “starve” the tumor by cutting off its lifeline of oxygen and nutrients, thereby halting its expansion. These treatments specifically target the endothelial cells of the tumor vasculature rather than the cancer cells themselves.
The primary focus of these therapies is the VEGF signaling pathway, given its role as the dominant signal in the angiogenic switch. There are three main therapeutic approaches:
Monoclonal Antibodies
One major class of drugs includes monoclonal antibodies, such as bevacizumab, which bind directly to and neutralize the circulating VEGF protein in the bloodstream. By sequestering the growth factor, the antibody prevents it from reaching and activating its receptors on the endothelial cells.
Fusion Proteins and TKIs
Specialized fusion proteins, sometimes called “VEGF traps,” act as decoy receptors with a high affinity for VEGF, effectively pulling the growth factor out of circulation. Small-molecule tyrosine kinase inhibitors (TKIs) represent a third approach; these drugs penetrate the cell and block the internal signaling machinery of the VEGF receptor (VEGFR). These anti-angiogenic agents are frequently administered in combination with traditional treatments like chemotherapy or radiation, leveraging the fact that a partially normalized tumor vasculature may temporarily improve the delivery of other anti-cancer drugs.
Overcoming Treatment Resistance
Anti-angiogenic therapies are effective in several cancer types, but their long-term impact is often limited by the tumor’s ability to develop resistance. This resistance can be intrinsic, meaning the tumor is naturally unresponsive, or acquired, developing after an initial period of successful treatment. Tumors employ various mechanisms to circumvent the blocked VEGF pathway.
One common strategy is switching the molecular signal by upregulating alternative pro-angiogenic factors, such as Fibroblast Growth Factor (FGF) or Platelet-Derived Growth Factor (PDGF). This allows the tumor to continue stimulating vessel growth through a different biological route. Tumors also enhance the recruitment of supportive cells, like pericytes, to stabilize the remaining vessels, or they recruit bone marrow-derived cells that contribute to new blood vessel formation.
The resulting increase in tumor hypoxia due to initial vessel pruning can also select for more aggressive cancer cells with a greater capacity for invasion. To address these bypass mechanisms, new research focuses on combination strategies that simultaneously target multiple growth factor pathways. Other approaches aim to “normalize” the existing tumor vasculature, making it less leaky and better perfused, which may improve the delivery and efficacy of other cancer treatments.