Hypoxia And Cancer

  • Maia ChristodoulouPost graduate - MSc Cancer Immunology and biotechnology, University of Nottingham
  • Nuria TolosanaBachelor of Applied Science - BASc, Biomedical Sciences, General Edinburgh Napier University
  • Toiba Mujtaba Khan MSc Precision Medicine, University of Leeds

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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 hypoxia1,

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

By Maia Christodoulou: Created with BioRender.com

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: 

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 

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. 

References

  1. Muz B, Puente P de la, Azab F, Azab AK. The role of hypoxia in cancer progression, angiogenesis, metastasis, and resistance to therapy. Hypoxia (Auckl) [Internet]. 2015 [cited 2024 Apr 18]; 3:83–92. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5045092/.
  2. Chen Z, Han F, Du Y, Shi H, Zhou W. Hypoxic microenvironment in cancer: molecular mechanisms and therapeutic interventions. Sig Transduct Target Ther [Internet]. 2023 [cited 2024 Apr 18]; 8(1):1–23. Available from: https://www.nature.com/articles/s41392-023-01332-8.
  3. Li Y, Zhao L, Li X-F. Hypoxia and the Tumor Microenvironment. Technol Cancer Res Treat [Internet]. 2021 [cited 2024 Apr 18]; 20:15330338211036304. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8358492/.
  4. Challapalli A, Carroll L, Aboagye EO. Molecular mechanisms of hypoxia in cancer. Clin Transl Imaging [Internet]. 2017 [cited 2024 Apr 18]; 5(3):225–53. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5437135/.
  5. Vaupel P, Harrison L. Tumor hypoxia: causative factors, compensatory mechanisms, and cellular response. Oncologist [Internet]. 2004 [cited 2024 Apr 18]; 9 Suppl 5:4–9. Available from: https://pubmed.ncbi.nlm.nih.gov/15591417/.
  6. Krock BL, Skuli N, Simon MC. Hypoxia-Induced Angiogenesis. Genes Cancer [Internet]. 2011 [cited 2024 Apr 19]; 2(12):1117–33. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3411127/.
  7. Rankin EB, Giaccia AJ. Hypoxic control of metastasis. Science [Internet]. 2016 [cited 2024 Apr 19]; 352(6282):175–80. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4898055/.
  8. Rankin EB, Giaccia AJ. The role of hypoxia-inducible factors in tumorigenesis. Cell Death Differ [Internet]. 2008 [cited 2024 Apr 19]; 15(4):678–85. Available from: https://www.nature.com/articles/cdd200821.
  9. Jing X, Yang F, Shao C, Wei K, Xie M, Shen H, et al. Role of hypoxia in cancer therapy by regulating the tumor microenvironment. Mol Cancer [Internet]. 2019 [cited 2024 Apr 19]; 18:157. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6844052/.
  10. Kopecka J, Salaroglio IC, Perez-Ruiz E, Sarmento-Ribeiro AB, Saponara S, De Las Rivas J, et al. Hypoxia as a driver of resistance to immunotherapy. Drug Resistance Updates [Internet]. 2021 [cited 2024 Apr 19]; 59:100787. Available from: https://www.sciencedirect.com/science/article/pii/S1368764621000455.
  11. Zhuang Y, Liu K, He Q, Gu X, Jiang C, Wu J. Hypoxia signaling in cancer: Implications for therapeutic interventions. MedComm (2020) [Internet]. 2023 [cited 2024 Apr 19]; 4(1):e203. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9870816/.
  12. Hompland T, Fjeldbo CS, Lyng H. Tumor Hypoxia as a Barrier in Cancer Therapy: Why Levels Matter. Cancers (Basel) [Internet]. 2021 [cited 2024 Apr 19]; 13(3):499. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7866096/.

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This content is purely informational and isn’t medical guidance. It shouldn’t replace professional medical counsel. Always consult your physician regarding treatment risks and benefits. See our editorial standards for more details.

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Maia Christodoulou

Post graduate - MSc Cancer Immunology and biotechnology, University of Nottingham

Maia is a Masters of Science graduate from the University of Nottingham, and has a Bachelors of Science in Biological sciences from Durham University. She is experienced in conducting scientific research and has strong knowledge of clinical research and development. She also has strong business acumen having worked in the life science events field, liaising with big pharmaceutical and biotechnological company executives. She has years of writing experience in the forms of reports, literature reviews, presentations and articles.

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