Even in a time with modern medicine and advanced research techniques, cancer is a killer. In the United States, cancer is the second leading cause of death, and one of every four deaths is due to cancer1. Cancer becomes even deadlier when it spreads from its origin to other sites in the body. This is called metastasis. Cancer can metastasize to many different organs, but the lungs are one of the most common metastatic sites2. The full reasons for this are unknown, but a new study has identified one factor that contributes to the prevalence of lung metastases.
Prolyl-hydroxylase domain (PHD) proteins are enzymes that incorporate oxygen into a variety of substances. Through this action, PHDs are suspected to contribute to the production of red blood cells, development of new blood vessels, and cell survival, among others. PHDs also contribute to cell differentiation3.
Cell differentiation is the process by which a cell becomes a more specialized cell4. An example of cell differentiation occurs in the immune system.
All cells of the immune system start life as pluripotent hematopoeitic stem cells. Stem cells are unique in that they have the ability to develop into a wide variety of specialized cells. Through differentiation, hematopoeitic stem cells can become red blood cells or platelets, or they can become cells that fight infections, like B cells or T cells, among several other cell types5.
PHDs influence cell differentiation by promoting the cells of the immune system to differentiate into regulatory T cells6. Most T cells will activate the immune system, but not regulatory T cells. These cells suppress the immune system7.
Suppression of the immune system is important because an overactive immune system can cause disease. The immune system should not fight particles that are harmless, like dust or pollen; nor should it fight cells of the human body. When this happens, diseases like allergies, asthma, or autoimmune disorders occur. Regulatory T cells exist to prevent this from happening8.
However, this has a cost – if the immune system is suppressed too much, it is not as able to fight infections or cancerous cells.
The effects of this can be seen in the lungs. Though PHDs are present in all organs, they need oxygen to function. Thus, in the highly-oxygenated environment of the lungs, PHDs are highly active, resulting in many regulatory T cells. This stops the immune system from unnecessarily attacking the many harmless particles that the lungs are exposed to, but it also gives cancer a greater opportunity to escape destruction by the immune system6.
To show that PHDs contribute to lung metastases, investigators removed PHD genes from mice and injected the mice with cancerous cells. These mice had fewer lung tumors compared to mice who had functional PHD genes6.
Knowing how PHDs affect lung metastases can help to improve cancer treatments. One cancer treatment that is currently used is called adoptive cell transfer. In this treatment, T cells are removed from the patient with cancer. These cells are grown in a laboratory to increase their number, then put back into the patient. These T cells fight cancerous cells, and with a greater number of them, they can do more damage to tumors9. If PHDs could be inhibited in these T cells, the T cells might be better at destroying lung tumors.
To determine the effects of inhibiting PHDs in adoptive cell transfer, researchers tested it in mice. T cells were grown in a chemical that inhibits PHDs, then transferred back into one group of mice. This group showed better clearance of lung metastases, and in addition, tumors growing elsewhere regressed. This resulted in increased survival in this group compared to the group that was injected with normal T cells6.
Though this seems like a promising new development for cancer treatments, it must be researched further, and used cautiously. Inhibition of PHDs should only be targeted in T cells, not in all cell types. Doing so could have negative consequences as some functions of PHDs are beneficial and necessary3,6.
As our knowledge of the immune system grows, so does the opportunity for us to develop better cancer treatments. Perhaps in the future, inhibiting PHDs in adoptive cell transfer will be regularly used in treating lung metastases.
This blog post is based off an original research article. You can read a summary of the article here; however, to read the full article, you will need to purchase it.
1: Cancer prevention and control: Statistics for different kinds of cancer [Internet]. 2016. Atlanta (GA): Centers for Disease Control and Prevention; [cited 2016 Oct 31]. Available from https://www.cdc.gov/cancer/dcpc/data/types.htm
2: Metastatic cancer [Internet]. 2016. Bethesda (MD): National Cancer Institute; [cited 2016 Oct 31]. Available from https://www.cancer.gov/types/metastatic-cancer
3: Fong GH, Takeda K. 2008. Role and regulation of prolyl hydroxylase domain proteins. Cell Death Differ. 15:635-41.
4: Cell differentiation and tissue [Internet]. 2014. Cambridge (MA): Nature Education; [cited 2016 Oct 31]. Available from http://www.nature.com/scitable/topicpage/cell-differentiation-and-tissue-14046412
5: Parham P. 2015. The immune system. 4th ed. New York: Garland Science, Taylor & Francis Group. Part 1-7, Immune system cells with different functions all derive from hematopoeitic stem cells; p 12-6.
6: Clever D, Roychoudhuri R, Constantinides MG, Askenase MH, Sukumar M, Klebanoff CA, Eil RL, Hickman HD, Yu Z, Pan JH, et al. 2016. Oxygen sensing by T cells establishes an immunologically tolerant metastatic niche. Cell 166(5):1117-31.
7: Parham P. 2015. The immune system. 4th ed. New York: Garland Science, Taylor & Francis Group. Glossary; p G:24.
8: Parham P. 2015. The immune system. 4th ed. New York: Garland Science, Taylor & Francis Group. Chapter 14, IgE-mediated immunity and allergy, and Chapter 16, Disruption of healthy tissue by the adaptive immune response. p 401-32, p 473-508.
9: NCI dictionary of cancer terms [Internet]. n.d. Bethesda (MD): National Cancer Institute; [cited 2016 Oct 31]. Available from https://www.cancer.gov/publications/dictionaries/cancer-terms?cdrid=672499