What is hypoxia and why study it?
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Hypoxia is the deprivation of oxygen supply. It is usually discussed in the context of brain injury, as the brain relies on a constant supply of oxygenated blood to survive and function correctly. Insufficient levels of oxygen can result in lifelong damage, and in some cases, death.
It has been extensively studied concerning its impact on the brain, however, there is another sign of hypoxia, and this is the relationship between hypoxia, the starvation of oxygen, and the development of cancerous cells.
The rapid growth of a tumor leads to the depletion of its oxygen supply. This results in a reduction in oxygen supply to certain areas of the tumor, which is significantly lower than the level of supply to healthy tissue.
The rapid proliferation of cells that occurs in growing tumors creates regions known as hypoxic microenvironments, where oxygen is being consumed rapidly due to the increasing number of cells in the area, and available oxygen is prevented from being able to diffuse deep within the tissue.
As a result, cancer cells have been seen to alter their metabolism to support further growth in the absence of sufficient oxygen. Hypoxia has also been linked with increased migratory and metastatic behavior in cancer.
Because of its implications in the growth and development of tumors, the study of hypoxia in this environment has become crucial to deepening our understanding of how cancer progresses, as well as in helping to develop new and improved treatments.
The significance of hypoxia in cancer treatment
As discussed above, tumor hypoxia is known to be significant in tumor progression and predisposes tumors to metastasis. Also, it is key to the resistance of the tumor to therapy, as research has shown that tumor hypoxia also has the impact of reducing responsiveness to radiation and chemotherapy.
Evidence has uncovered that hypoxia in tumor cells is linked with resistance to ionizing radiation. For this reason, hypoxia has become a key focus of research, with dozens of clinical and lab studies having been conducted over the last few decades, dedicated to understanding hypoxia’s influence on the success of radiation therapy.
The results of these studies have supported the idea that systems that can accurately detect the hypoxic regions of the tumor would open the door to new and innovative treatments that could be developed to improve tumor response to treatment.
By the end of the last decade, several methods had been developed to detect tumor hypoxia, however, clinical studies had provided mostly ambiguous results due to failures in the selection of suitable sample groups. There was, therefore, no “gold standard” approach for measuring tumor hypoxia.
Experts agreed that an ideal biomarker of hypoxia was required to create a reliable, “gold standard” method of looking at tumor hypoxia. Work that had attempted to find one had been limited by extreme spatial and temporal heterogeneities in oxygen levels of tissue because of the complicated behavior of cellular oxygen consumption.
Finding markers of hypoxia
In recent years, a large number of studies have looked into potential markers of tumor hypoxia. In 2015, a team of researchers highlighted the markers of hypoxia in soft tissue sarcoma.
They found an over-expression of HIF‑1α and CA9 to be related with poor prognosis, and that over-expression of HIF‑1α was an independent unfavorable prognostic factor in soft tissue sarcoma.
In the same year, a team at the Washington University School of Medicine in St Louis found that hypoxia has the effect of stimulating complex cell signaling networks in cancer cells. They highlighted the HIF, PI3K, MAPK, and NFĸB pathways as those that are activated.
These pathways are known to interact with each other and generate both positive and negative feedback loops, which can either boost or reduce hypoxic effects.
A multitude of studies has concluded that the proteins HIF-1α, BNIP3, PDK1, and GLUT1 can be used as markers to detect hypoxia. HIF-1a has been found to become stabilized under hypoxia, where it then moves into the cell’s nucleus and increases the rate of transcription of genes that control oxygen delivery, helping the cancerous cells adapt to a lack of oxygen.
BNIP3 becomes induced by HIF-1α during hypoxia, and it is associated with cell survival and tumor progression. The PDK1 protein is also induced under hypoxia, and it is known to play a role in maintaining ATP production. Finally, the GLUT1 glucose transporter is induced by HIF-1α3 under hypoxia.
In addition, the markers CAIX, LDH-5, MCT1, and MCT4 have also found to be up-regulated under hypoxic conditions.
Using hypoxia markers in cancer therapy
Several proteins have been identified as being over-expressed during hypoxia in cancerous cells. These proteins are considered as potential biomarkers of hypoxia and have the potential to be recognized through various imagining techniques, such as immunostaining, PET, SPECT and immunohistochemical staining.
Research is still underway as to how these markers can be fully exploited to measure hypoxia in tumors, and how this information can be used to develop new and more targeted therapies and management techniques.
- Kim, J., Choi, K., Lee, I., Choi, Y., Kim, W., Shin, D., Kim, K., Lee, J., Kim, J. and Sol, M. (2015). Expression of hypoxia markers and their prognostic significance in soft tissue sarcoma. Oncology Letters, 9(4), pp.1699-1706. https://www.spandidos-publications.com/10.3892/ol.2015.2914
- Rademakers, S., Lok, J., van der Kogel, A., Bussink, J. and Kaanders, J. (2011). Metabolic markers in relation to hypoxia; staining patterns and colocalization of pimonidazole, HIF-1α, CAIX, LDH-5, GLUT-1, MCT1, and MCT4. BMC Cancer, 11(1). https://bmccancer.biomedcentral.com/articles/10.1186/1471-2407-11-167
- Muz, B., de la Puente, P., Azab, F. and Azab, A. (2015). The role of hypoxia in cancer progression, angiogenesis, metastasis, and resistance to therapy. Hypoxia, p.83. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5045092/