There were an estimated 1.7 million new cancer diagnoses in the United States in 2019, according to the American Cancer Association. It is the 2nd leading cause of death within the country. There are over 100 types of cancer, affecting every organ and tissue in the body. Cancer occurs when abnormal cells divide uncontrollably, often destroying surrounding healthy cells. This cellular invasion can spread throughout the entire body, no matter where the source of the tumors begin. As these abnormal cells spread, they can deplete the body of its essential nutrients and resources, oxygen being one.
Traditional cancer treatments include surgery to remove tumors (lumps of abnormal cells or tissues that clump together), chemotherapy and radiation. Chemo and Radiation are both designed to poison the cancerous cells that have spread throughout the body. While technology is starting to get to a point where these procedures can be targeted at specific affected tissue, there is still often a lot of collateral damage done to healthy cells and tissues during the process. Many patients treated with chemo or radiation suffer extreme symptoms such as weight loss, hair loss, digestive issues, extreme pain, fatigue, immune suppression, immobility and much more.
Unfortunately, a large portion of cancer deaths are related to the side effects from the treatments.
Hyperbaric Oxygen Therapy has gained traction as an adjunctive modality in the treatment and symptom management of cancer. Cancerous cells are anaerobic, meaning they thrive in oxygen-poor environments. Research is showing that flooding cancer cells with oxygen can make them easier to kill with chemo or radiation. Some experts also believe that the pressure of hyperbaric therapy can help push chemo through the body faster, leaving less time for healthy tissue to be poisoned. There are many published studies showing hyperbaric therapy’s ability to heal post-radiation damage inside the burned tissues and organs as well. Anecdotally, many patients report that their time in the chamber helps relieve pain, increase appetite, and boosts energy levels.
Background: Tumor hypoxia is relevant for tumor growth, metabolism, resistance to chemotherapy and metastasis. We have previously shown that hyperoxia, using hyperbaric oxygen treatment (HBOT), attenuates tumor growth and shifts the phenotype from mesenchymal to epithelial (MET) in the DMBA-induced mammary tumor model. This study describes the effect of HBOT on tumor growth, angiogenesis, chemotherapy efficacy and metastasis in a triple negative MDA-MB-231 breast cancer model, and evaluates tumor growth using a triple positive BT-474 breast cancer model.
Materials and methods: 5 x 105 cancer cells were injected s.c. in the groin area of NOD/SCID female mice. The BT-474 group was supplied with Progesterone and Estradiol pellets 2-days prior to tumor cell injection. Mice were divided into controls (1 bar, pO2 = 0.2 bar) or HBOT (2.5 bar, pO2 = 2.5 bar, 90 min, every third day until termination of the experiments). Treatment effects were determined by assessment of tumor growth, proliferation (Ki67-staining), angiogenesis (CD31-staining), metastasis (immunostaining), EMT markers (western blot), stromal components collagen type I, Itgb1 and FSP1 (immunostaining) and chemotherapeutic efficacy (5FU).
Results: HBOT significantly suppressed tumor growth in both the triple positive and negative tumors, and both MDA-MB-231 and BT-474 showed a decrease in proliferation after HBOT. No differences were found in angiogenesis or 5FU efficacy between HBOT and controls. Nevertheless, HBOT significantly reduced both numbers and total area of the metastastatic lesions, as well as reduced expression of N-cadherin, Axl and collagen type I measured in the MDA-MB-231 model. No change in stromal Itgb1 and FSP1 was found in either tumor model.
Conclusion: Despite the fact that behavior and prognosis of the triple positive and negative subtypes of cancer are different, the HBOT had a similar suppressive effect on tumor growth, indicating that they share a common oxygen dependent anti-tumor mechanism. Furthermore, HBOT significantly reduced the number and area of metastatic lesions in the triple negative model as well as a significant reduction in the EMT markers N-cadherin, Axl and density of collagen type I.
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Hypoxia, which is commonly observed in many solid tumors, is a major impediment to chemo- or radiation therapy. Hypoxia is also known to overexpress/activate signal transducer and activator of transcription 3 (STAT3) leading to tumor progression as well as drug resistance. We hypothesized that increased oxygenation of the hypoxic tumor may have an inhibitory effect on STAT3 activation and hence tumor-growth inhibition. Mice containing human ovarian cancer xenograft tumor were exposed to hyperbaric oxygen (HBO; 100% oxygen; 2 atm; 90-min duration) daily, for up to 21 days. Mice exposed to HBO showed a significant reduction in tumor volume, with no effect on body weight. STAT3 (Tyr 705) activation and cyclin-D1 protein/mRNA levels were significantly decreased up on HBO exposure. Interestingly, HBO exposure, in combination with weekly administration of cisplatin, also significantly reduced the tumor volume; however, this group of mice had drastically reduced body weight when compared to other groups. While conventional wisdom might suggest that increased oxygenation of tumors would promote tumor growth, the results of the present study indicated otherwise. Hyperoxia appears to inhibit STAT3 activation, which is a key step in the ovarian tumor progression. The study may have important implications for the treatment of ovarian cancer in the clinic.
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