Researchers Identify Origin of Cervical Cancer Caused by Human Papillomavirus

Researchers have identified a population of cells in the uterine cervix that appears to give rise to dysplasia and cancer caused by human papillomavirus (HPV), according to a report in the June 11, 2012, Proceedings of the National Academy of Sciences.

Oncogenic HPV types such as 16 and 18 can cause anogenital malignancies including cervical and anal cancer. People with HIV tend to carry more HPV types, are less likely to spontaneously clear the virus, and are at higher risk for precancerous cell abnormalities. Invasive cervical cancer is considered an AIDS-defining condition, and many believe that anal cancer should be as well.

Cervical intraepithelial neoplasia (CIN) -- which can progress to cancer if left untreated -- typically occurs at the squamocolumnar junction, where the squamous cells covering the outside of the cervix meet the columnar cells that make up the inner cervical lining. The precise cellular origin of cervical cancer, however, is poorly understood.

Michael Herfs from Brigham and Women's Hospital in Boston and an international team of colleagues discovered a distinct population of squamocolumnar junction cells with a unique structure and gene expression profile. They also found that these cells did not regenerate after surgical excision.

This information may help clinicians differentiate between benign and dangerous precancerous lesions, and potentially could guide decisions about the best course of treatment. 

Below is an edited excerpt from a press release issued by Brigham and Women's describing the research and its findings in more detail.

Identifying the Origins of Cervical Cancer

Researchers from Brigham and Women's Hospital uncover a population of cells that are targeted by the cancer-causing Human Papillomaviruses (HPV).

Juen 11, 2012 -- Virtually all cervical cancers are caused by HPV infections, with just two HPV types, 16 and 18, responsible for about 70 percent of all cases, according to the National Cancer Institute. Scientists have presumed for decades that the cervical cancers that develop from HPV infection arise in a specific location in the cervix. Now, new research from Brigham and Women's Hospital (BWH) in close collaboration with Harvard Medical School and the Agency for Science Technology and Research in Singapore finds that a specific population of cells that are found only in the region of the cervix called the "squamo-columnar junction" can become cancerous when infected with HPV while other cells in the cervix apparently do not. This research is published online the week of June 11 in the Proceedings of the National Academy of Sciences (PNAS).

"We have discovered a discrete population of cells that are located in a specific area of the cervix that could be responsible for most, if not all, of HPV-associated cervical cancers," said Christopher Crum, MD, director, Women's and Perinatal Pathology at BWH and a senior author on the paper.

Xian Wa, PhD, Assistant Professor of Medicine at the National University of Singapore and Frank McKeon, PhD, Professor of Cell Biology at Harvard Medical School are also senior authors of the PNAS research paper. A prior discovery published in 2011 by the Xian/McKeon group on the origins of cancer in the esophagus set the stage for the current study.

Dr. Crum and Michael Herfs, PhD, a research fellow from the University of Liège and the lead author in the study, collaborated with the Xian/Mckeon laboratory to show that these cells have a unique gene expression that is also found in the cells of aggressive tumors of the cervix. This knowledge could potentially allow clinicians to differentiate benign from potentially dangerous precancerous lesions in the cervix and guide therapy. 

Additionally, the investigators noted that when the cells are removed from the cervix, which typically happens when treating precancers, they do not regenerate. They believe this opens up intriguing prospects for cancer prevention.

"The removal of these cells in young women before they are subject to HPV infection or precancerous changes could potentially reduce the risk of cervical cancer, but further research is needed to evaluate the benefits and risks of this potential therapy," said the authors. Additionally, Crum noted that the discovery of these cells could promote more meaningful cell models to further study cervical cancer.

This research was funded by Defense Advanced Research Projects Agency, the National Institutes of Health (grants RC1 HL100767, R01-GM83348 and R21CA124688), the Singapore-Massachusetts Institute of Technology Alliance for Research and Technology, the European Research Council, Agence de Nationale, the Institute of Medical Biology; and the Genome Institute of Singapore of the Agency for Science, Technology and Research as well as the Department of Defense (W81XWH-10-1-0289).

6/19/12

Reference

M Herfs, Y Yamamoto, A Laury, et al. A discrete population of squamocolumnar junction cells implicated in the pathogenesis of cervical cancer. Proceedings of the National Academy of Sciences USA. June 11, 2012 (Epub ahead of print).

Other Sources

Brigham and Women's Hospital. Identifying the Origins of Cervical Cancer. Press release. June 11, 2012.

Agency for Science, Technology and Research. Groundbreaking Discovery of the Cellular Origin of Cervical Cancer. Press release. June 12, 2012.