Hypoxia And Cancer

Overview

Hypoxia is a well-known factor linked with cancer. Cancer is a disease that causes uncontrollable cell growth in the body. Hypoxia is the lack of oxygen that is dissolved in our blood plasma. In most of the cells of our body, this is bad as we need oxygen to live.

Moreover, hypoxic conditions in cancer tumours can cause the tumour to thrive and grow.¹ This is also known as tumour hypoxia and is a common characteristic in a wide variety of solid tumours.² Tumours with hypoxia can be hard to treat and lead to a worse disease prognosis.³

What is hypoxia?

Our blood has red blood cells, which carry oxygen molecules to our tissues except for tumours, which are starved of oxygen. We measure hypoxia by quantifying the activity of oxygen molecules dissolved in blood plasma using pressure units called millimetres of mercury (mmHg). Tissue is hypoxic if the oxygen tension falls lower than 10 mmHg, whereas in normal tissue oxygen tension is 40 to 60 mmHg.²

Causes of tumour hypoxia 

Hypoxia in tumours occurs when its vascular supply, which is made up of your blood vessels, is interrupted, or when the tumour grows too fast and large for its vascular supply.^2,4

Hypoxia in tumours can either be acute or chronic 

Acute hypoxia 

• Perfusion-related, which is where blood actively flows through blood vessels to tissue
• Short-term exposure to hypoxia, which is usually reversible and happens when tumour vessels open and close transiently¹
• Abnormal structure and function of vessels that supply the tumour with oxygen leading to on-and-off oxygen fluctuations, called cycling hypoxia^1,5 

Chronic hypoxia

• Diffusion-related, which is where oxygen moves passively from a high concentration to a low concentration
• It is long-term exposure to hypoxia and can be irreversible 
• Tumour cells multiply and grow too fast which creates a large distance that oxygen cannot diffuse across
• This happens when the tumour is too far away from normal working blood vessels creating long diffusion distances between blood vessels and tumour cells⁵
• Usually present in larger tumours and causes long-term cellular changes¹

Besides acute and chronic hypoxia, there is also anaemic hypoxia. Anaemic hypoxia is caused by a reduction in the amount of oxygen the blood can carry to the tumour.⁵ This can either be because of the presence of the tumour or can be brought about by treatment.⁵

For cancer cells to survive and thrive, hypoxia activates signalling pathways within them, which causes them to change themselves to promote survival.⁴ We can think of the cancer cells as evolving in response to hypoxia to give the tumour a better chance of survival against your immune system which is trying to kill the tumour.

Effects of hypoxia on tumours

The effect of low oxygen levels on cancer cells can either lead to death or survival of the tumour, this partly depends on what time the cells are exposed to hypoxia.¹ Both chronic and acute hypoxia cause genetic instability in the cancer cells by creating mutations.¹ Hypoxic tumours are associated with lower survival because these cancers are known to be aggressive and are also resistant to cancer therapies.⁴

Hypoxia triggers the activation of specific factors in the genes of cancer cells. These factors are called hypoxia-inducible factors (HIF).⁷ These factors affect the genes that promote the growth and survival of cancer. HIF are shown to be increased in a variety of human tumours, and their presence is related to poor patient outcomes.⁸

Tumorigenesis

Tumorigenesis is the process where normal cells become cancer cells. The genetic instability caused by hypoxia is thought to transform cells into cancerous cells.¹ Tumorigenesis encompasses tumour formation, progression and responsiveness to therapy. 

Hypoxia promotes tumorigenesis through:⁸

• Increasing angiogenesis - forming new blood vessels
• Controls cancer cell metabolism - changes metabolism pathway to get nutrients to grow
• Increasing cell proliferation - rapid cancer cell growth
• Stimulating metastasis - spreading of cancer to other areas of the body
• Preventing differentiation- cancer cells stay in uncontrolled growth and do not become mature
• Hides from the body’s immune system - so immune cells cannot find and kill the cancer²

Angiogenesis 

Angiogenesis is the process of forming new blood vessels. Abnormal angiogenesis happens in cancers, which cause the cancer to grow and progress. Initially in cancer, what happens is that the tumour cells grow so fast that they outgrow the blood vessel supply, and so uptake less oxygen, causing hypoxia.

This then triggers new blood vessel growth to supply the tumour with nutrients by promoting genes that increase blood vessel growth and consequently promote rapid and chaotic blood vessel formation.^1,6

Metastasis

Metastasis is the spreading of cancer from the initial site to other parts of the body. It is the cause of 90% of all cancer-related deaths.⁷ Hypoxia can cause cancer to metastasise by increasing genetic instability in those cells, which can cause the cancer to be triggered to spread.⁴ This happens when hypoxia switches on genes that allow the tumour cells to move, enabling them to move around the body and settle at a different site.¹ 

Resistance to therapy

Hypoxia is known to reduce the effectiveness of current cancer therapies by activating genes that increase drug resistance or reduce the potency of the drugs.²

Hypoxic tumours are resistant to: 

• Radiotherapy - which causes cell damage leading to cancer cell death² 
• Chemotherapy drugs - which use anti-cancer drugs to cause cancer cell death⁹
• Tumour removal - if the cancer has already spread 
• Targeted therapy - where drugs attack genetic pathways in cancer cells⁹
• Types of immunotherapy - where the immune system is used to target cancer¹⁰
  • Chimeric Antigen Receptor (CAR) T-cell therapy 
  • Immune checkpoint inhibitors (ICI)

Around 80–90% of deaths of patients with cancer are attributed to drug resistance.² However, studies show that combinations of immunotherapy treatments can help overcome drug resistance.¹⁰

Treatments for tumour hypoxia 

Combination therapy of improving oxygen in the tumour has been shown to improve hypoxia and response to other treatments.¹¹ 

The method through which hypoxia is relieved is as follows: 

• Hypoxia-targeted drugs - drugs that target HIF, genes and hypoxic cells¹¹
• Combination therapy - chemotherapy or radiotherapy with hypoxia-targeting drugs¹²
• Improving tumour oxygenation via various methods:¹¹
  • Supplemental hyperoxia therapy - which improves tissue oxygenation and reduces tumour hypoxia
  • Hyperbaric oxygen treatment (HBOT) - where you breathe pure oxygen in a special hyperbaric chamber
• Nanoparticle carriers - small particles that deliver oxygen to the tumour 

Combining oxygenation therapy, like HBOT, can be used to improve current conventional therapies. Oxygen therapy can also improve new treatments for aggressive tumours, such as photodynamic therapy.¹¹ Reducing the amount of hypoxia in the tumour’s environment can also improve current immunotherapies, like ICI.² 

Risk factors that can cause hypoxia in cancer 

If blood vessel cells are exposed to harmful substances, hypoxic cancer can form. Some of these risk factors include:² 

• Drugs that can change DNA directly or indirectly
• Carcinogens - like cigarette smoke 
• Presence of pathogenic microorganisms - like bacteria, fungi, viruses
• An acidic tumour microenvironment (TME) - can damage the shape of your blood vessel cells and cause hypoxia

Summary

Tumour hypoxia closely affects cancer progression, metastasis and responsiveness to cancer drugs. Due to this, hypoxia seems like a determining factor in the outcome of cancer and more research surrounding this area will positively impact the future of cancer treatment. If you have been diagnosed with hypoxic cancer, your health practitioner will discuss the current treatment therapies available and clinical trials.