Hypoxia & Cancer, And How Hyperbaric Oxygen Therapy (HBOT) helps in treating Hypoxia
Cancer is the leading cause of death in the United States. It is responsible for one out of every four deaths in the country. The number of new cancer cases being diagnosed each year is increasing. More people live longer, and risk factors like smoking, not being active, and being overweight are becoming more common.
Hypoxia & Cancer
Hypoxia, a low oxygen level, is present in most cancers. Still, its amount varies depending on the tumor type. A growing tumor needs oxygen greater than the amount available. Also, the distance between cells and the blood vessels already there grows. This makes it harder for oxygen to spread throughout the environment and makes the air even less oxygenated. On average, the amount of oxygen in hypoxic tumor tissue is between 1% and 2% O2 or less. That is why hypoxic tumor tissues need more oxygen to grow.
The oxygen level of the tumor can be affected by several things, such as how oxygenated the tissue was when it was first formed, the tumor size and stage, the method used to measure oxygen, and the part of the heterogenic tumor tissue where the measurement was taken.
Tissue normoxia, also called physoxia, is the state where healthy tissues have the right amount of oxygen in their surroundings. Because each organ has its own network of blood vessels and level of metabolic activity that’s why healthy tissues ability to get oxygen from one organ to the next can be very different. The amount of oxygen in a person’s brain can be as low as 4.6% and as high as 9.5% in the renal cortex of kidney. On average, 9.5% of the oxygen in the body is found in the kidneys. These oxygen levels are very different from what was found in the tests done in a lab. This means cell culture is done in hyperoxic conditions instead of the physoxic levels seen in similar organs since the oxygen concentration usually used in a lab is 20.9% O2.
Cancer cells may respond to low oxygen by dying or surviving. Hypoxia exposure period affects cancer cell response. In most cases, acute hypoxia is induced by the temporary closure of blood vessels for a few minutes.
Reversing causes cycle hypoxia or oxygen fluctuations. In vitro studies of acute hypoxia frequently involve continuous hypoxia for up to 72 hours. Hypoxia helps cells to survive by initiating autophagy, an apoptotic and metabolic response. Autophagy requires lower oxidative metabolism. Other researchers found that cyclic hypoxia increases reactive oxygen species (ROS), which promotes tumor cell survival and proliferation.
Changing blood flow and persistent hypoxia cause increased cellular alterations. Larger tumors show more alterations, which lead to hypoxia. Hypoxia affects DNA repair processes such as homologous recombination and mismatch repair, causing genetic instability and mutagenesis. Hypoxia also causes DNA breakage and replication errors. Acute hypoxia delays DNA damage and apoptosis, causing genetic instability.
Cycling hypoxia indicates tumor oxygenation. Intermittent reoxygenation happens in cancer because the blood vessels in the tumor aren’t working right and the blood supply isn’t uniform. Chronic or acute hypoxic areas can influence clinical responses to therapy by affecting tumor growth, dissemination, and cell death.
Hypoxia causes resistance to radiation and chemotherapeutic in cancer patients
Blood vessel formation
Endothelial cells form the blood vessel walls, creating a seal between blood and tissue and interacting with the extracellular matrix (ECM). As the tumor grows, abnormal angiogenesis can happen in cancer cells with a blood supply that grows too quickly.
Metastasis is linked to increased angiogenesis. A permeable and heterogeneous vasculature allows tumor cells to circulate and move to new, unaffected areas, away from unfavorable hypoxic conditions. Overexpression of HIF- subunits in tumors and metastases is linked to aggressive malignancies and a low survival rate.
Hypoxic cells are more likely to metastasize and be more aggressive and invasive. For example, multiple myeloma cancer cells grown in the lab under low oxygen (Hypoxia) conditions and then injected into mice moved to the new bone marrow faster than cells grown in normal conditions.
Radiation and drug resistance
Despite treatments that induce apoptosis in cancer cells, they remain resistant to this process. A vast number of cancer patients relapse and suffer from recurring tumors as a result of the micro-residual disease. A subpopulation of tumor cells can adapt to hypoxic conditions and become resistant to chemo- and radiotherapy.
One of the most critical hurdles to cancer treatment is cancer cells’ failure to undergo apoptosis in response to treatment. The resistant subpopulation of cancer cells, known as micro-residual disease, is the cause of recurrence and frequent malignancies in cancer patients. This condition can also cause metastasis or cancer spreading to other body regions.
Hypoxia in a tumor arises from uncontrolled cell proliferation, changed metabolic processes, and abnormal tumor blood arteries, all of which decrease oxygen and nutrition supply.
However, a subset of tumor cells can adapt to Hypoxia and acquire resistance to chemotherapy and radiation even though Hypoxia is known to be lethal to the vast majority of cells. It has been at least 60 years since it was discovered that Hypoxia has a role in the phenomenon known as treatment resistance.
As a result of Hypoxia, cancer cells become more resistant to treatment. Underlying reasons are i) stopping cell division (quiescence), a condition of limited cell development that protects cells against external stresses; ii) inhibiting cell death processes such as apoptosis and senescence; and iii) controlling autophagy, p53, and mitochondrial function.
Altered drug transport
Additionally, reduced oxygenation alters drug transport in tumor tissue, which leads to chemoresistance, by reducing oxygen, which is essential to many chemotherapeutics’ cytotoxicity.
Without contact, crosstalk, and support from the tumor microenvironment, including stromal cells, immune cells, ECs, ECM, cytokines, and other mediators, the tumor would not thrive. In hypoxic tumor tissue, hypoxia-inducible alterations influence cancer cells and the tumor microenvironment.
Hypoxia increases pro-angiogenic chemicals, blood vessel development, and oxygen and nutrition for tumor cells. Hypoxia stimulates platelet, leukocyte, and smooth muscle cell activity by regulating inflammatory cells and growth factors. Increased EC adhesion to neutrophils facilitates NK cell migration and local inflammation.
Hypoxia regulates NO synthase expression, contributing to vasoconstriction. Targeting ECs will prevent or reverse tumor development since they nourish blood vessels.
Hyperbaric oxygen therapy to treat hypoxia
Whenever Hypoxia causes disease, the initial thought is to give the extra patient oxygen. How much oxygen enters hypoxic tissues is essential. Using Dalton’s and Henry’s principles, we can observe that HBOT modifies plasma oxygen levels and helps hemoglobin achieve maximum oxygen-carrying capability.
Because low oxygen pressure does not change hemoglobin’s oxygen-carrying capacity, it remains at 20 mL O2/dL of blood. Only the plasma’s oxygen content changes. 100% oxygen increases tracheal oxygen partial pressure to 713 mmHg. 100% oxygen gives blood 21.71 mL O2/dL. This is a 7.26 percent net increase in O2/dL.
This application can only distribute oxygen to places with enough blood. As with ischemia, 100% oxygen cannot treat the underlying disease. HBOT employs 100% oxygen at 1–3 atm local pressure.
HBOT has primary and secondary effects. Direct effects include enhancing oxygen supply and tension, antimicrobial activity, and reducing HIF-mediated effects. HBOT reduces ROS and boosts bodily repair, vasoconstriction, angiogenesis, and inflammation.
HBOT pressures are 1.5 to 3.0 atm. Lower partial pressures lessen barotrauma to the lungs, eardrums, sinuses, and teeth. Seizures from oxygen toxicity are rare with HBOT, but they have been reported. Standardized HBOT pressures and duration require additional investigation.
Hyperbaric therapy has applications for treating illnesses when a lack of oxygen harms tissues. HBOT uses oxygen under pressure as a medication to treat pathological conditions. Hyperbaric oxygen alters the transcription of DNA, cell organelles, tissue structure, and organ function. 25–35 sessions can make improvements permanent.
Due to increased oxygen partial pressure with 3 atm HBOT, more oxygen dissolves in plasma. Hemoglobin stores oxygen and the dissolved concentration in plasma delivers it. HBOT enhances the volume and flow of the oxygen river, enhancing tissue delivery. Theoretically, HBOT can increase oxygen supply .
Hypoxia affects cancer development by affecting cancer cells and TME(tumor microenvironment). It controls the formation of new tumor blood vessels, metabolism, cell maintenance, and cell death. It also causes cancer cell transfer and building cancer stem cell-like characteristics. These characteristics lead to drug resistance development. The hypoxia-activating transcriptional programs control each stage of cancer development. Increased tumor development and severity affect the patient’s life quality and survival rate. HBOT counters oxygen shortages, promote healing and angiogenesis, fights infection, and controls inflammation.
Inflammation is the physical way to all stresses; sometimes, it loses control. This can cause or contribute to chronic illness. HBOT’s anti-inflammatory benefits are rising. HBOT might be a new medication class, but dose and disease indications need additional investigation.
- Muz, B., De la Puente, P., Azab, F., & Azab, A. K. (2015). The role of hypoxia in cancer progression, angiogenesis, metastasis, and resistance to therapy. Hypoxia, 83. https://doi.org/10.2147/hp.s93413
- Choudhury, R. (2018). Hypoxia and hyperbaric oxygen therapy: A review. International Journal of General Medicine, 11, 431-442. https://doi.org/10.2147/ijgm.s172460