[en] Infection by carcinogenic human papillomaviruses (HPV) results in precancers [cervical intraepithelial neoplasia (CIN)] and cancers near the ectoendocervical squamocolumnar (SC) junction of the cervix. However, the specific cells targeted by HPV have not been identified and the cellular origin of cervical cancer remains elusive. In this study, we uncovered a discrete population of SC junctional cells with unique morphology and gene-expression profile. We also demonstrated that the selected junctional biomarkers were expressed by a high percentage of high-grade CIN and cervical cancers associated with carcinogenic HPVs but rarely in ectocervical/transformation zone CINs or those associated with noncarcinogenic HPVs. That the original SC junction immunophenotype was not regenerated at new SC junctions following excision, not induced by expression of viral oncoproteins in foreskin keratinocytes, and not seen in HPV-related precursors of the vagina, vulva, and penis further support the notion that junctional cells are the source of cervical cancer. Taken together, our findings suggest that carcinogenic HPV-related CINs and cervical cancers are linked to a small, discrete cell population that localizes to the SC junction of the cervix, expresses a unique gene expression signature, and is not regenerated after excision. The findings in this study uncover a potential target for cervical cancer prevention, provide insight into the risk assessment of cervical lesions, and establish a model for elucidating the pathway to cervical cancer following carcinogenic HPV infection.
Disciplines :
Oncology
Author, co-author :
Herfs, Michael ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Anatomie et cytologie pathologiques
Yamamoto, Yusuke
Laury, Anna
Wang, Xia
Nucci, Marisa R.
McLaughlin-Drubin, Margaret E.
Munger, Karl
Feldman, Sarah
McKeon, Frank D.
Xian, Wa
Crum, Christopher P.
Language :
English
Title :
A discrete population of squamocolumnar junction cells implicated in the pathogenesis of cervical cancer.
Publication date :
June 2012
Journal title :
Proceedings of the National Academy of Sciences of the United States of America
ISSN :
0027-8424
eISSN :
1091-6490
Publisher :
National Academy of Sciences, Washington, United States - District of Columbia
Dürst M, Gissmann L, Ikenberg H, zur Hausen H (1983) A papillomavirus DNA from a cervical carcinoma and its prevalence in cancer biopsy samples from different geographic regions. Proc Natl Acad Sci USA 80:3812-3815. (Pubitemid 13063146)
Boshart M, et al. (1984) A new type of papillomavirus DNA, its presence in genital cancer biopsies and in cell lines derived from cervical cancer. EMBO J 3:1151-1157.
Crum CP, Ikenberg H, Richart RM, Gissman L (1984) Human papillomavirus type 16 and early cervical neoplasia. N Engl J Med 310:880-883. (Pubitemid 14173180)
Lorincz AT, Lancaster WD, Temple GF (1986) Cloning and characterization of the DNA of a new human papillomavirus from a woman with dysplasia of the uterine cervix. J Virol 58:225-229. (Pubitemid 16021982)
Richart RM (1973) Cervical intraepithelial neoplasia. Pathol Annu 8:301-328.
Marsh M (1956) Original site of cervical carcinoma; topographical relationship of carcinoma of the cervix to the external os and to the squamocolumnar junction. Obstet Gynecol 7:444-452.
de Sanjose S, et al.; Retrospective International Survey and HPV Time Trends Study Group (2010) Human papillomavirus genotype attribution in invasive cervical cancer: A retrospective cross-sectional worldwide study. Lancet Oncol 11:1048-1056.
Schiffman M, et al. (2011) Human papillomavirus testing in the prevention of cervical cancer. J Natl Cancer Inst 103:368-383.
Koutsky LA, et al.; Proof of Principle Study Investigators (2002) A controlled trial of a human papillomavirus type 16 vaccine. N Engl J Med 347:1645-1651. (Pubitemid 35340782)
Kines RC, Thompson CD, Lowy DR, Schiller JT, Day PM (2009) The initial steps leading to papillomavirus infection occur on the basement membrane prior to cell surface binding. Proc Natl Acad Sci USA 106:20458-20463.
Arbeit JM, Howley PM, Hanahan D (1996) Chronic estrogen-induced cervical and vaginal squamous carcinogenesis in human papillomavirus type 16 transgenic mice. Proc Natl Acad Sci USA 93:2930-2935. (Pubitemid 26114341)
McCance DJ, Kopan R, Fuchs E, Laimins LA (1988) Human papillomavirus type 16 alters human epithelial cell differentiation in vitro. Proc Natl Acad Sci USA 85:7169-7173.
Wang X, et al. (2011) Residual embryonic cells as precursors of a Barrett's-like metaplasia. Cell 145:1023-1035.
Martens JE, et al. (2009) Distribution pattern and marker profile show two subpopulations of reserve cells in the endocervical canal. Int J Gynecol Pathol 28:381-388.
Sano T, Oyama T, Kashiwabara K, Fukuda T, Nakajima T (1998) Expression status of p16 protein is associated with human papillomavirus oncogenic potential in cervical and genital lesions. Am J Pathol 153:1741-1748. (Pubitemid 28550662)
Klaes R, et al. (2001) Overexpression of p16(INK4A) as a specific marker for dysplastic and neoplastic epithelial cells of the cervix uteri. Int J Cancer 92:276-284. (Pubitemid 32225381)
Keating JT, et al. (2001) Ki-67, cyclin E, and p16INK4 are complimentary surrogate biomarkers for human papilloma virus-related cervical neoplasia. Am J Surg Pathol 25:884-891. (Pubitemid 32594981)
Wright TC, Jr., et al.; 2006 American Society for Colposcopy and Cervical Pathology-sponsored Consensus Conference (2007) 2006 consensus guidelines for the management of women with abnormal cervical cancer screening tests. Am J Obstet Gynecol 197:346-355.
Galgano MT, et al. (2010) Using biomarkers as objective standards in the diagnosis of cervical biopsies. Am J Surg Pathol 34:1077-1087.
Reich O, Pickel H, Lahousen M, Tamussino K, Winter R (2001) Cervical intraepithelial neoplasia III: Long-term outcome after cold-knife conization with clear margins. Obstet Gynecol 97:428-430. (Pubitemid 32184706)
Richart RM, et al. (1980) An analysis of "long-term" follow-up results in patients with cervical intraepithelial neoplasia treated by cryotherapy. Am J Obstet Gynecol 137: 823-826. (Pubitemid 10046460)
Mork J, et al. (2001) Human papillomavirus infection as a risk factor for squamous-cell carcinoma of the head and neck. N Engl J Med 344:1125-1131. (Pubitemid 32285233)
D'Souza G, et al. (2007) Case-control study of human papillomavirus and oropharyngeal cancer. N Engl J Med 356:1944-1956. (Pubitemid 46740304)
Palefsky JM, et al. (2011) HPV vaccine against anal HPV infection and anal intraepithelial neoplasia. N Engl J Med 365:1576-1585.
Crum CP, Cibas ES, Rose PG, Peters WA, III (2011) Cervical squamous neoplasia. Diagnostic Gynecologic and Obstetric Pathology, eds Crum CP, Nucci MR, Lee KR (Elsevier, Philadelphia), pp 269-298.
Tate JE, et al. (1996) A comparison of early (E7) and late (L1) primer-mediated amplification of papillomaviral DNA in cervical neoplasia. Mol Cell Probes 10:347-351. (Pubitemid 26372354)
Senoo M, Pinto F, Crum CP, McKeon F (2007) p63 Is essential for the proliferative potential of stem cells in stratified epithelia. Cell 129:523-536. (Pubitemid 46660965)
