What is Metastasis?

Metastasis refers to the spread of cancer from its primary location to new locations to form secondary tumours. It’s one of the main causes of cancer-related death.

The process of metastasis

Some cells from the primary tumour break off and enter the bloodstream by intravasation. These cells are known as circulating tumour cells (CTCs). In the bloodstream, CTCs are subject to mechanical pressure from compression of blood vessels, ultimately leading to their arrest at a secondary site. Here, they extravasate and colonise the new site, forming a secondary tumour.¹

What is Angiogenesis?

In order to grow past 2mm in diameter, cancer cells require a blood supply to receive oxygen. Cancer cells can grow their vascular tissue (blood vessels) in angiogenesis. This process is considered essential to establish metastases (secondary tumours). Many proteins, known as angiogenic factors, are released by tumours to bring about angiogenesis.²

Angiogenic factors

VEGF

Vascular endothelial growth factor (VEGF) is a signal protein overexpressed in cancer cells, stimulating the growth of vascular (blood vessel) cells. It binds to VEGF receptors (VEGFRs), causing pre-existing blood vessels to grow branches which supply blood to the cancer cells.³

HIF and the Angiogenic cycle

Hypoxia-inducible factor (HIF) regulates a cell’s response in the case of hypoxia (low oxygen). A high expression of HIF is associated with poor prognosis for cancer patients. The blood vessels that supply tumours are often abnormal; they are tortuous and may have dead ends. Furthermore, due to excess VEGF secreted by tumour cells, the blood vessels may be more permeable (leaky). As a result, blood supply to the tumour cells is poor, creating a hypoxic environment. This leads to the expression of HIF, which induces the expression of VEGF and other angiogenic factors. This results in a growth cycle of more abnormal blood vessels, therefore, more hypoxia and more release of HIF.⁴

Anti-Angiogenic therapies

Angiogenesis appears to be a good target for cancer therapies since it is such a key component of metastasis, the main cause of cancer deaths. 

VEGF inhibitors

VEGF inhibitors are often combined with chemotherapy in the treatment of cancers such as colorectal and breast cancers. They inhibit VEGF, stopping it from binding and activating VEGFRs. However, they can have side effects such as: 

• Hypertension (high blood pressure)⁵
• Tachycardia (high heart rate)⁵
• Arterial blood clots (which can lead to stroke)⁵
• Proteinuria (excess proteins in urine)⁵

Summary

Metastasis (spread of cancer from its primary location to a secondary site) is a key cause of most cancer-related deaths. To survive and grow, metastases (secondary tumours) need a blood supply, which they get through a process called angiogenesis, the growth of new blood vessels. Angiogenesis occurs due to signal proteins such as vascular endothelial growth factor (VEGF) and hypoxia-inducible factor (HIF). Most antiangiogenic treatments are VEGF inhibitors, which often result in side effects such as hypertension, tachycardia, blood clots and proteinuria.