This project is based on the discovery of a specific cell population in the uterine cervix that the investigators propose to be the target of cancer causing human papillomaviruses (HPV) and the origin of cervical cancer. These cells are located at the squamo-columnar (S-C) junction of the cervix and their share attributes with preinvasive and invasive HPV-associated cervical neoplasms links support their role as progenitor cells. This project is designed to expand this investigation to accomplish three tasks. The first is to clarify the biologic differences of early cervical precancers with S-C junction specific attributes to better define the parameters that increase the empirical risk of eventually developing invasive cancer. Understanding these differences will permit a more precise classification of cervical precancers and reduce the likelihood of over-treatment and its reproductive sequelae. A related goal is to map the geography of these specialized S-C junction cells in the cervix to determine its influence on origin and successful removal of precancers. The second task is to grow these S-C junction cells in culture and determine both how they differentiate and if they express unique biomarkers relative to their surrounding cellular environment. Because the S-C junction is vulnerable to cancer causing HPV infections, these biomarkers could be exploited to devise novel therapies to selectively remove the S-C junction cells preemptively (for cancer prevention) via targeted therapy. The third task is to generate a transgenic animal model (mouse) in which a precise mimic of human cervical cancer could be generated at the S-C junction by introducing carcinogenic HPV-related oncogenes. Such models do not currently exist and their successful development could be an important advance in the creation of mouse models of human cervical cancer that could be used to test new therapeutics.
Successful completion of this project will result in a major improvement in our ability to accurately determine which individuals with cervical precancers merit therapy and expand their treatment options. Moreover, new cell culture and, in particular, animal models of cervical cancer would provide important opportunities to test new therapies in a preclinical setting with a high relevance to human disease.
|Mirkovic, Jelena; Howitt, Brooke E; Roncarati, Patrick et al. (2015) Carcinogenic HPV infection in the cervical squamo-columnar junction. J Pathol 236:265-71|
|Herfs, Michael; Somja, Joan; Howitt, Brooke E et al. (2015) Unique recurrence patterns of cervical intraepithelial neoplasia after excision of the squamocolumnar junction. Int J Cancer 136:1043-52|
|Yang, Eric J; Quick, Matthew C; Hanamornroongruang, Suchanan et al. (2015) Microanatomy of the cervical and anorectal squamocolumnar junctions: a proposed model for anatomical differences in HPV-related cancer risk. Mod Pathol 28:994-1000|
|Conner, James R; Meserve, Emily; Pizer, Ellen et al. (2014) Outcome of unexpected adnexal neoplasia discovered during risk reduction salpingo-oophorectomy in women with germ-line BRCA1 or BRCA2 mutations. Gynecol Oncol 132:280-6|
|Ning, Gang; Bijron, Jonathan G; Yamamoto, Yusuke et al. (2014) The PAX2-null immunophenotype defines multiple lineages with common expression signatures in benign and neoplastic oviductal epithelium. J Pathol 234:478-87|
|Herfs, Michael; Parra-Herran, Carlos; Howitt, Brooke E et al. (2013) Cervical squamocolumnar junction-specific markers define distinct, clinically relevant subsets of low-grade squamous intraepithelial lesions. Am J Surg Pathol 37:1311-8|
|Crum, Christopher P; Herfs, Michael; Ning, Gang et al. (2013) Through the glass darkly: intraepithelial neoplasia, top-down differentiation, and the road to ovarian cancer. J Pathol 231:402-12|