Pancreatic cancer is one of the tumors with a relatively high degree of hypoxia. Cancer cells exhibit complex metabolic adaptability in the severely hypoxic and nutrient-restricted tumor microenvironment. The hypoxic microenvironment of tumors is a major factor influencing the sensitivity of pancreatic cancer to radiotherapy. Hyperbaric oxygen, as an important adjuvant therapy, can directly improve intra-tumoral oxygen tension and has been widely used in the treatment of various diseases caused by hypoxia. Current research indicates that hyperbaric oxygen can enhance the radiotherapy sensitivity of pancreatic cancer by increasing intracellular oxygen tension, thereby improving the efficacy of pancreatic cancer radiotherapy. However, the underlying sensitization mechanisms are not yet fully understood. This article provides a review of recent research on the application of hyperbaric oxygen in sensitizing pancreatic cancer to radiotherapy based on the relationship between tumor development and hypoxia, as well as the mechanisms of hyperbaric oxygen-enhanced radiotherapy sensitivity.
Research on the tumor microenvironment began in 1889 when Paget proposed the "seed and soil" hypothesis, suggesting that tumor cell growth, as "seeds," requires an adapted growth environment or "soil." In 1984, Moulder and Rockwell assessed the hypoxic state of tumors using electrodes, exogenous markers, or upregulation of endogenous hypoxia-related molecules, demonstrating that hypoxia is a common feature of animal solid tumors, human tumor xenografts, and human cancers. In 2000, Koong et al. used polarographic oxygen sensors to first indicate that pancreatic cancer belongs to typical hypoxic solid tumors. In 2011, Hanahan and Weinberg summarized the ten hallmarks of cancer, highlighting hypoxia as a crucial characteristic of the tumor microenvironment, elucidating its significant role in tumor development.
Hypoxia induces adaptive responses in tumor cells, influencing tumor proliferation, differentiation, angiogenesis, energy metabolism, chemotherapy resistance, radiation resistance, and poorer patient prognosis. Hypoxia is closely associated with various aspects of tumor biology:
Hypoxia and reactive oxygen species (ROS)
Hypoxia enhances the release of high-activity ROS clusters, inducing DNA damage and genomic instability, promoting the carcinogenic transformation of normal cells.
Hypoxia and metabolic reprogramming
Under hypoxic conditions, cancer cells undergo a shift towards glycolysis, changing the metabolic process from oxidative phosphorylation to anaerobic glycolysis, facilitating rapid cancer cell proliferation and exacerbating tumor hypoxia.
Hypoxia and angiogenesis
Hypoxia promotes the secretion of vascular endothelial growth factor (VEGF) and fibroblast growth factor by tumor cells, inducing the formation of new blood vessels, allowing tumor expansion. The rapidly generated vascular network is often structurally disordered and dysfunctional, further intensifying hypoxia.
Hypoxia and tumor cell proliferation and apoptosis
Hypoxia induces the upregulation of hypoxia-inducible factor-1α (HIF-1α), erythropoietin, and VEGF, promoting cancer cell proliferation, while also activating or inhibiting certain oncogenes or tumor suppressor genes, reducing cell apoptosis.
Hypoxia and cancer stem cell (CSC) properties
Hypoxia activates various signaling pathways in CSCs, leading to the acquisition of a CSC phenotype by cancer cells. Hypoxia-induced autophagy, by balancing ROS levels in the microenvironment and maintaining oxidative homeostasis, can regulate the induction and maintenance of pancreatic cancer cell stemness, potentially influencing pancreatic cancer cell stemness.
Studies on the effects of oxygen on microbial, plant, cellular, and animal radiation responses date back to the 1950s. Subsequent research found that when oxygen partial pressure drops below approximately 20 mmHg, cells develop resistance to radiation damage. Hypoxia is currently considered a major negative factor affecting tumor radiation responses. Higher radiation doses, three times that of normoxic cells, are required to eradicate hypoxic tumor cells. Hyperbaric oxygen therapy directly addresses tissue hypoxia, making it an early application in radiotherapy sensitization. Early studies focused on whether hyperbaric oxygen had a carcinogenic effect, but it was later confirmed that hyperbaric oxygen does not stimulate tumor growth and recurrence. In fact, it has tumor-suppressive effects in certain cancers. Recent clinical trial data shows that hyperbaric oxygen can enhance the efficacy of radiotherapy for head and neck tumors, gliomas, and cervical cancer, but the results are not ideal for skin cancer and bladder cancer. Moreover, related studies have found that at pressures exceeding 2 absolute atmospheres, hyperbaric oxygen can reduce late radiation injuries to the head and neck, bones, prostate, and bladder, improving patient prognosis. Li et al. also pointed out that patients with conditions such as radiation enteritis, brain injury, skin damage, lung injury, and xerostomia can benefit from hyperbaric oxygen therapy. In summary, hyperbaric oxygen not only increases radiotherapy sensitivity in some tumor treatments but also reduces adverse reactions to radiation in certain cases.
The mechanisms by which hyperbaric oxygen increases radiotherapy sensitivity include the following aspects：
Improvement of tumor cell hypoxia
Hyperbaric oxygen can increase blood oxygen content, enhance oxygen diffusion radius, and improve the hypoxic state of tumor cells. Studies by Becker and Kinoshita used oxygen electrodes and magnetic resonance imaging to measure tumor tissue oxygen tension before and after hyperbaric oxygen therapy. The results showed that hyperbaric oxygen could increase intratumoral oxygen tension, and this effect could be sustained for a certain period even after leaving the hyperbaric oxygen environment. Research has found that hyperbaric oxygen can partially reverse the vascular structural abnormalities induced by hypoxia, reducing vessel density and curvature, and improving tumor hypoxia by improving the hypoxic microenvironment and stromal microenvironment.
Induction of tumor cell cycle arrest
Hyperbaric oxygen can induce cell cycle synchronization, causing more tumor cells to be in the radiation-sensitive G2/M phase, enhancing tumor cell radiation sensitivity. Hyperbaric oxygen can also release CSCs from G0/G1 phase cell arrest, induce cells to enter the G2/M phase, accumulate in this phase, and promote cancer cell proliferation inhibition and apoptosis. Compared to other cell cycle phases, G2/M phase cells are more sensitive to radiation, which can enhance tumor cell radiation damage.
Induction of tumor cell apoptosis
Hyperbaric oxygen induces the overexpression of apoptosis-inducing genes such as p53 and Bax, and the downregulation of apoptosis-inhibiting genes such as Bcl-2 and Ras, promoting tumor cell apoptosis. Studies by Wei et al. found that hyperbaric oxygen reduced the Bcl-2/Bax ratio, increasing cell apoptosis. Wang et al. also found that hyperbaric oxygen significantly reduced the elevated lactate dehydrogenase activity caused by hypoxia, restored the decreased E-cadherin/N-cadherin ratio and epithelial-mesenchymal transition phenotype induced by hypoxia, and inhibited the expression of GRP78 protein, demonstrating anti-proliferative and pro-apoptotic effects.
Previous studies have suggested that the combination of hyperbaric oxygen and radiotherapy can improve the hypoxic microenvironment of certain tumors, increase their radiotherapy sensitivity, reduce radiation adverse reactions, but whether it benefits pancreatic cancer radiotherapy patients is still a debated focus.
Early research primarily focused on the adverse reaction rate, clinical response rate, and short-term efficacy of the combination of hyperbaric oxygen and pancreatic cancer radiotherapy. In 2005, Ren et al. divided 56 advanced pancreatic cancer patients into treatment and control groups. The treatment group received 1 hour of oxygen inhalation in a hyperbaric oxygen chamber at 2 absolute atmospheres before each radiotherapy session, followed immediately by whole-body gamma knife treatment. The control group received only whole-body gamma knife treatment. Both groups had equivalent dose lines covering 50%-90% of the target, with a planned target volume coverage of over 95%, a single dose of 3-6 Gy, repeated treatments 6-12 times, and a total dose of 30-42 Gy, with treatment every other day. The results showed that the clinical response rate and the objective remission rate three months after treatment were 85.7% and 78.6%, respectively, for the treatment group, and 60.7% and 53.6% for the control group. There were no significant differences in adverse reactions such as blood routine, liver and kidney function, and digestive tract reactions between the two groups. This indicated that combined hyperbaric oxygen and gamma knife treatment did not increase adverse reactions to radiation therapy, improved the clinical response rate and short-term efficacy, and enhanced the quality of life for patients.
As research progressed, studies began to focus on the improvement of pancreatic tumor tissue hypoxia and the impact on related tumor markers. In 2015, Lu and Shi selected 68 stage II-IV pancreatic cancer patients, divided them into an observation group (35 cases) and a control group (33 cases), and both groups were treated with stereotactic radiotherapy. The observation group received 1 hour of hyperbaric oxygen treatment before each radiotherapy session. Comparing the changes in tumor size before and 3 months after radiotherapy, the observation group showed significantly increased arterial oxygen tension and oxygen saturation after hyperbaric oxygen treatment. Based on the evaluation of short-term efficacy, the observation group had a statistically significant higher objective remission rate (65.71%) than the control group (45.45%). Tumor markers CA125, CEA, and CA19-9 showed no significant differences between the two groups before radiotherapy, but both levels decreased after radiotherapy, with the observation group lower than the control group. The overall incidence of acute radiation reactions in the digestive system was 42.86% in the observation group and 63.64% in the control group, with a statistically significant difference. This suggested that hyperbaric oxygen treatment before radiotherapy could improve tumor cell hypoxia, enhance the short-term efficacy of pancreatic cancer radiotherapy, and reduce acute radiation damage.
Recent studies have further focused on the intrinsic mechanisms of hyperbaric oxygen enhancing pancreatic cancer radiotherapy sensitivity. In 2019, An et al. selected 84 patients with advanced pancreatic cancer and divided them into an observation group and a control group. Both groups underwent stereotactic radiotherapy, with the observation group receiving hyperbaric oxygen treatment before radiotherapy. The results showed that both groups had decreased levels of CA19-9, HIF-1α, and VEGF after treatment, with the observation group having a higher decrease in CA19-9 than the control group. The clinical overall response rate in the observation group was 64.28%, significantly higher than the 40.48% in the control group. The observation group also had significantly lower rates of bone marrow suppression, liver function damage, and gastrointestinal reactions than the control group. This suggested that hyperbaric oxygen-assisted radiotherapy could increase the sensitivity of pancreatic cancer cells to radiation by downregulating CA19-9, HIF-1α, and VEGF levels, improving clinical efficacy, and reducing adverse reactions, contributing to an improved quality of life for patients.
Currently, research on the signaling pathways associated with CSC (Cancer Stem Cells) and the radiotherapy sensitivity of pancreatic cancer has become a new frontier in pancreatic cancer studies. CSCs exhibit characteristics such as self-renewal, multi-directional differentiation, strong tumorigenicity, and resistance to cancer treatments, often leading to cancer metastasis, recurrence, radiotherapy failure, and poor prognosis. They are considered a major factor influencing tumor radioresistance.
Studies have identified several signaling pathways related to the radioresistance of pancreatic cancer CSCs, including the NF-κB signaling pathway, Wnt/β-catenin signaling pathway, PI3K/AKT/mTOR signaling pathway, Notch signaling pathway, Hedgehog signaling pathway, and TGF-β signaling pathway. The NF-κB pathway, in particular, plays a crucial role in how tumor cells respond to ionizing radiation, serving as one of the DNA damage repair mechanisms and being associated with tumor invasive growth, anti-apoptosis, and radioresistance. Research suggests that the inactivation of the STAT3/NF-κB signaling transduction may play a crucial role in inducing radio sensitivity in pancreatic cancer cells.
The Wnt/β-catenin signaling pathway is involved in the regulation of processes such as cell proliferation, migration, apoptosis inhibition, and dedifferentiation. It has garnered attention in increasing sensitivity to radiotherapy in pancreatic cancer. Studies have shown that targeting and inhibiting FAM83A can affect the activity of the Wnt/β-catenin signaling pathway, enhancing the radio sensitivity of pancreatic cancer cells.
Additionally, the PI3K/AKT/mTOR signaling pathway is implicated in the regulation of critical cancer markers. Genomic analysis of pancreatic ductal adenocarcinoma patients reveals abnormal activation of PI3K/AKT/mTOR pathway components. Loss of the tumor suppressor gene ARID1A, through the activation of the PI3K/AKT pathway, has also been shown to enhance radioresistance in pancreatic cancer.
In summary, research on hyperbaric oxygen therapy to enhance the radiotherapy sensitivity of pancreatic cancer is still in the exploratory stage. While hyperbaric oxygen has shown high potential and prospects for improving the hypoxic microenvironment of tumor cells and increasing radio sensitivity in pancreatic cancer, the lack of high-level evidence is a major obstacle to its widespread application. Furthermore, the inconvenience, inefficiency, and potential complications associated with hyperbaric oxygen therapy in radiotherapy applications, along with the variability in hyperbaric oxygen price, highlight the need for further research to enhance its convenience and safety in sensitizing pancreatic cancer to radiotherapy. Understanding the molecular mechanisms behind hyperbaric oxygen therapy enhancing radio sensitivity in pancreatic cancer is expected to promote its clinical application.
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