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Edited by Douglas R. Lowy, National Cancer Institute, Bethesda, MD, and approved May 8, 2012 (received for review February 19, 2012)
Abstract
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.
Footnotes
↵1F.D.M., W.X., and C.P.C. contributed equally to this work.
- ↵2To whom correspondence may be addressed. E-mail: wa.xian{at}imb.a-star.edu.sg or ccrum{at}partners.org.
Author contributions: M.H., M.R.N., F.D.M., W.X., and C.P.C. designed research; M.H., A.L., X.W., M.R.N., M.E.M.-D., S.F., W.X., and C.P.C. performed research; Y.Y., X.W., M.E.M.-D., K.M., S.F., and F.D.M. contributed new reagents/analytic tools; M.H., Y.Y., A.L., X.W., M.R.N., M.E.M.-D., K.M., S.F., F.D.M., W.X., and C.P.C. analyzed data; and M.H., F.D.M., W.X., and C.P.C. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1202684109/-/DCSupplemental.
- Michael Herfsa,b,
- Yusuke Yamamotoc,
- Anna Lauryd,
- Xia Wange,
- Marisa R. Nuccia,
- Margaret E. McLaughlin-Drubinf,
- Karl Müngerf,
- Sarah Feldmang,
- Frank D. McKeonc,e,1,
- Wa Xiana,h,1,2, and
- Christopher P. Cruma,1,2
- aDivision of Women’s and Perinatal Pathology, Department of Pathology, Brigham and Women’s Hospital, Boston, MA 02115;
- bDepartment of Pathology, Groupe Interdisciplinaire de Génoprotéomique Appliquée (GIGA)-Cancer, University of Liege, Liege, Belgium;
- cGenome Institute of Singapore, Agency for Science, Technology and Research (A-STAR), Singapore 138672;
- dDepartment of Pathology, School of Medicine, University of California, Los Angeles, CA 90095;
- eDepartment of Cell Biology, Harvard Medical School, Boston, MA 02115;
- fDepartment of Medicine, Channing Laboratory, Brigham and Women’s Hospital, Boston, MA 02115;
- gDepartment of Obstetrics and Gynecology and Reproductive Biology, Brigham and Women’s Hospital, Boston, MA 02115; and
- hInstitute of Medical Biology, A-STAR, Singapore 138648
Edited by Douglas R. Lowy, National Cancer Institute, Bethesda, MD, and approved May 8, 2012 (received for review February 19, 2012)
Abstract
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.
- gynecology
- oncology
- embryogenesis
Footnotes
↵1F.D.M., W.X., and C.P.C. contributed equally to this work.
- ↵2To whom correspondence may be addressed. E-mail: wa.xian{at}imb.a-star.edu.sg or ccrum{at}partners.org.
Author contributions: M.H., M.R.N., F.D.M., W.X., and C.P.C. designed research; M.H., A.L., X.W., M.R.N., M.E.M.-D., S.F., W.X., and C.P.C. performed research; Y.Y., X.W., M.E.M.-D., K.M., S.F., and F.D.M. contributed new reagents/analytic tools; M.H., Y.Y., A.L., X.W., M.R.N., M.E.M.-D., K.M., S.F., F.D.M., W.X., and C.P.C. analyzed data; and M.H., F.D.M., W.X., and C.P.C. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1202684109/-/DCSupplemental.
The squamocolumnar junction and cervical neoplasia
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