Viruses to Cancer: A Look at HPV

jan2019

By: Zeynep Kahramanoğlu

Cervical cancer is the fourth most common cancer in women worldwide. The disease is unique because 90% of cervical cancers are caused by human papillomavirus or HPV – mainly a sexually transmitted infection with some evidence of vertical transmission between mother and child, with over 100 different types. “Up to 20% of cancers worldwide are associated with infectious agents, which means one in five is affected,” says Dr. Yuan Chang from the University of Pittsburgh Cancer Institute. Dr. Chang, a multi-award-winning pathologist, is among the 2017 Clarivate Citation Laureates, a list of Nobel prize-worthy scientists, and rightfully so. She co-discovered two out of the seven known cancer-causing viruses: Kaposi’s sarcoma herpesvirus (KSHV) and Merkel cell polyomavirus (MCV). While HPV is a cause of cervical cancer, the majority of women infected will not actually develop the disease. This is because the fundamental goal of a virus’ life cycle is to cause infection, not induce tumours. As such, HPV commonly causes benign warts, but persistent infection with high-risk types is correlated with the development of cervical cancer.

How can a virus cause cancer?

There are many other cancer-causing agents, such as: chemicals, environmental factors, and radiation. The one thing these factors have in common is their ability to alter the individual’s DNA, or host cell DNA. Some viruses, like HPV, integrate their genetic code into the host cell and interfere with the cell’s normal function by modifying important genes involved in its communication abilities. Researchers have found two potent oncoproteins. These oncoproteins, named E6 and E7, have the potential to cause cancer.  The oncoproteins stop tumour suppressors, doing so promotes the uncontrolled growth of cells and more chances for genetic mutations to take place, resulting in cancer. In the small number of women with persistent high-risk HPV infections, there are too many of these oncoproteins. Research into cell pathways involving these viral changes in tumour suppressors are ongoing, in order to discover novel therapeutic targets.

Prevention and diagnosis

In the 1970s, scientist Dr. Harald zur Hausen discovered two HPV strains: HPV 16 and HPV 18 in cervical cancer tumours using DNA technology. From this, the HPV vaccine was born, which targets the worst HPV types. According to the World Health Organization, the vaccine significantly reduces the risk of cervical cancer. Dr. Chang agrees, stating that the vaccine is “very effective and really changed the epidemiology and occurrence of the disease.” Given this success, Dr. Chang now urges for the initiation and development of vaccines for other cancer-causing viruses, like KSHV and MCV. Recently, another possible preventative measure was found in intrauterine devices (IUDs) by researchers at the University of Southern California. IUD use correlated with a reduced rate of cervical cancer, indicating a possible form of protection from the disease. For early diagnosis of cervical cancer, the Pap test, where cells from the cervix are examined for abnormalities, has proved to be the most successful diagnostic tool. Further testing includes a colposcopy (thorough examination of the cervix) or an HPV detection test. Even with these preventative measures and diagnostic tools, early detection remains a challenge and some patients are diagnosed at late stages when the disease is difficult to treat.

Treatments

“We have the technology…we just need the willpower.” – Dr. Yuan Chang, University of Pittsburgh Cancer Institute

Early stages of cervical cancer can be curable with surgery, for instance by hysterectomy (removing the uterus and cervix). Late-stage cervical cancer treatment consists of radiation combined with chemotherapy. Radiation and chemotherapy work by producing high levels of DNA damage in tumour cells that eventually cause these cells to die. Even with these treatments, survival rates of advanced cervical cancer are poor. However, current research is focused on promising developments.

Knowing that HPV causes cervical cancer, therapeutic vaccination and immunological strategies are emerging as possible treatments, with several clinical trials underway. One such therapy take advantage of our body’s immune cells. One class of these cells are T cells, a type of white blood cell that can distinguish between our normal, abnormal and ‘foreign’ cells by interpreting signals from different proteins found on the cell surface, also known as immune cell checkpoints. These immune cell checkpoints are the body’s version of a passport, and your immune cells are the border patrol, looking to see if the cell’s papers are in order. Cancer cells can learn to escape these immune cell checkpoints and trick T cells into recognizing them as ‘normal’, sparing them from T cell attacks. Immune checkpoint inhibitors are an up-and-coming treatment strategy that work by targeting these immune checkpoints. In summary, they work by silencing the cancer cell’s ability to broadcast ‘I am normal’ signals to the rest of the body and helps ensure T cells can carry out their function to eliminate the dangerous cells. Another treatment is therapeutic vaccinations, which work by stimulating immune cells to target and attack HPV-infected cancer cells. Ultimately, the goal of these novel immune therapies is to restore our body’s natural ability to destroy and defend against ‘foreign’ or ‘abnormal’ invasion.

Researchers continue to explore the connections between some viruses and cancers, like HPV and cervical cancer, as well as ways to treat them. When it comes to virus-associated cancers, “We have the technology,” says Dr. Chang, “we just need the willpower.”

Zeynep is a Research Technician in a tumour immunology laboratory. She graduated with a Master’s of Science from Western University where her main thesis focused on the effects of chemotherapy on ovarian cancer. 

Resources:

  1. Liao, J.B. Viruses and human cancer. Yale J Biol Med 79, 115-122 (2006).
  2. Kumar, V., Abbas, A.K., Aster, J.C. & Robbins, S.L. Robbins basic pathology, (Elsevier/Saunders, Philadelphia, PA, 2013).
  3. Basu, P., Mittal, S., Bhadra Vale, D. & Chami Kharaji, Y. Secondary prevention of cervical cancer. Best Pract Res Clin Obstet Gynaecol (2017).
  4. Chang, Y., Moore, P.S. & Weiss, R.A. Human oncogenic viruses: nature and discovery. Philos Trans R Soc Lond B Biol Sci 372(2017).
  5. Kessler, T.A. Cervical Cancer: Prevention and Early Detection. Semin Oncol Nurs 33, 172-183 (2017).
  6. Canadian Cancer Society. Treatments for stage I cervical cancer. (2018).
  7. Borcoman, E. & Le Tourneau, C. Pembrolizumab in cervical cancer: latest evidence and clinical usefulness. Ther Adv Med Oncol 9, 431-439 (2017).
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