Curiouser and Curiouser: The Links Between Prostate Cancer and Ewing’s Sarcoma
“One in a million.” This is the grave statistic that represents the prevalence of Ewing’s Sarcoma (ES). Affecting children and young adults, those with this rare bone cancer face a difficult challenge, as there is little knowledge and research conducted on the disease. With orphan diseases as rare as ES, finding a treatment is just as uncommon. One would never have thought that one of the most common diseases could be the answer to this difficult task. Over 1.1 million men are diagnosed with prostate cancer every year and scientists have just stumbled upon an astounding new link between the two diseases.1,2 With this new information, a treatment for both prostate cancer and ES may be closer than ever thought possible.
ES was first described by James Ewing in 1921 as a "Diffuse endothelioma of bone."3 Essentially, ES is characterized as cancer cells forming within the bone or soft tissue.3,4 In the early 1980s, researchers were astonished to find that greater than 95% of ES cases shared an identical genetic abnormality, known as a gene translocation.4 They found that this genetic translocation goes on to form a variety of tumours, all classified as Ewing’s Sarcoma Family of Tumours.4 As described by Peter Hollenhorst, co-author of the recent study, "This research shows that the molecular mechanism involved in the development of most prostate cancers is very similar to the molecular mechanism known to cause ES...this mechanism might be used to explore a common treatment for both diseases."5 Therefore, this discovery is the crucial piece in the new link just discovered between ES and prostate cancer.
The two diseases are very different forms of cancers, hence, those with each disease have very different symptoms. ES is a rare bone cancer that is characterized by tumours found at the ends of long bones, most commonly, the thigh bone and pelvis.6,7 Many patients experience pain, swelling and stiffness in the area where the tumour is located, which is commonly passed off as a sports injury as ES is most prevalent in children.6,7 After several weeks, other symptoms may appear such as lumps in the skin, fever, bone pain, weight loss and broken bones.6,7 This is in contrast to prostate cancer, which generally produces very little, if any, signs or symptoms.2 Nonetheless, both diseases are still without a definitive treatment, using a combination of chemotherapy and radiation therapy for each patient.2,6,7 Finding a treatment has been a difficult task for healthcare professionals and researchers and the damaging effects of the current therapies are hard for all patients. Consequently, targeting the cause of both diseases and the underlying genetic similarities may be the key to curing the cancers.
So, what is this genetic similarity, and how does it cause both of these diseases? The current research has highlighted one chromosome translocation that causes both ES and prostate cancer.8 A chromosome translocation results from a breakage within a chromosome, releasing genetic fragments that then go and insert into segments of other chromosomes.6,9,10 Humans usually have a duplicate set of 23 pairs of chromosomes in every cell. These chromosomes hold a person’s entire genetic sequence in the form of genes, which are made up of DNA. Thus, a chromosomal translocation can result in serious consequences, as is the case with ES and prostate cancer.4-6,8 In ES, the chromosome translocation results in gene fusion, where one segment fuses with the other, forming a new mutant gene.4,8-10 This occurs on two specific chromosomes, which encode the Ewing’s Sarcoma gene (EWS) and the FLI1 gene, respectively.4,8 The translocation fuses the EWS and FLI1 gene together, forming the EWS/FLI protein.4,8 The researchers were shocked to discover that this EWS/FLI protein is able to turn on the cancerous ETS (erythroblast transformation-specific) genes.4,8 These ETS genes become proteins that are directly responsible for over 50% of all cases of prostate cancer, which is nearly 500,000 cases of cancer every year, worldwide.1,2,5 To their surprise, the researchers found that the mutated EWS/FLI1 protein directly causes the formation of the oncogenic ETS genes into prostate cancer-causing ETS proteins.8. Even further, EWS/FLI1 only activates the four ETS genes implicated in the cancer, leaving the other 24 ETS genes alone.8,9 Hollenhorst explained the huge significance of these findings, saying that "A molecular mechanism that sets these four genes apart from the ones that don’t trigger cancer has never been identified until now."5,9
So, what do these findings mean for those with ES and prostate cancer? The study looked into this question by conducting several experiments on mice to mimic the relationship between EWS/FLI1 proteins and ETS oncogenes in the formation of prostate cancer and tumour cells.8 The researchers then found the critical relationship between the EWS/FLI1 protein and the activation of ETS proteins, in forming tumours. When researchers inserted the EWS/FLI1 gene into normal human prostate cells, cancerous tumour cells formed in the mice.8 However, without the EWS/FLI1 gene, the tumours were unable to form in the prostate cells.8 Therefore, by inhibiting ETS protein production, the tumours failed to form in the mice, essentially saving them from the cancer. “This is significant because it suggests that any compound that disrupts EWS-ETS interaction would specifically inhibit the function of the four oncogenes and not the others, which play important roles in the healthy function of the body.” explains Hollenhorst.5 He and his colleagues are now in search of the compound that could treat both ES and prostate cancer, saving the lives of millions across the globe. Until then, all of those touched by ES and prostate cancer can remain hopeful that the scientific community is proactively working to understand both diseases and find a final cure for everyone affected.
1. Ferlay J, Soerjomataram I, Ervik M, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D, Bray, F. Cancer Incidence and Mortality Worldwide; IARC Cancer Base website. http://globocan.iarc.fr. Published 2014.
2. Prostate Cancer. Mayo Clinic website. http://www.mayoclinic.org/diseases-conditions/prostate-cancer/basics/treatment/con-20029597. Published 2017.
3. Ewing, James. The classic diffuse endothelioma of bone. Clin Orthop Relat Res. 1921;(185):2-5. https://www.ncbi.nlm.nih.gov/pubmed/6368087.
4. Whang-Peng J, Triche TJ, Knutsen T, Miser JS, Kao-Shan S, Tsai S, et al. Chromosome translocation in peripheral neuroepithelioma. N Enl J of Med. 1984;311:584–585. doi: http://dx.doi.org/10.1016/0165-4608(86)90001.
5. IU research reveals link between molecular mechanisms in prostate cancer and Ewing’s Sarcoma. IU Bloomington News website. http://news.indiana.edu/releases/iu/2016/10/prostate-cancer-ewings-sarcoma-study.shtml. Published October 25, 2016.
6. Randall, L, Calvert, G, Spraker, H, Lessnick, S. Ewing’s Sarcoma. Sarcoma Initiative website. http://sarcomahelp.org/ewings-sarcoma.html. Published 2011.
8. Kedage V, Selvaraj N, Nicholas TR, et al. An Interaction with Ewing’s Sarcoma Breakpoint Protein EWS Defines a Specific Oncogenic Mechanism of ETS Factors Rearranged in Prostate Cancer. Cell Reports. 2016;17(5):1289-1301. doi:10.1016/j.celrep.2016.10.001.
9. Schieszer, John. Molecular Mechanisms In Prostate Cancer Linked To Ewing's Sarcoma. OncoTherapy Network website. http://www.oncotherapynetwork.com/genitourinary-cancer-targets/molecular-mechanisms-prostate-cancer-linked-ewings-sarcoma. Published 2017.
10. Chromosome Translocations. EuroGenTest website. http://www.eurogentest.org/index.php?id=612. Published January 2007.
Cite This Article:
McKee H., Zheng K., Chan G., Ho J. Curiouser and Curiouser: The Links Between Prostate Cancer and Ewing's Sarcoma. Illustrated by P. Taarea. Rare Disease Review. August 2017. DOI:10.13140/RG.2.2.15748.42889.