Science Center of obstetrics, gynecology and perinatology named after academician V.I. Kulakov, Moscow, Russian Federation
*Corresponding author: Prof. Eugeniya A. Kogan, PhD, ScD. Head of the 1st Department of Pathology; Science Center of obstetrics, gynecology and perinatology named after academician V.I. Kulakov. Moscow, Russian Federation. E-mail: email@example.com
Published: September 24, 2013
Background: Spheroid cell structures (SCS) described in cell culture are used to study cell-cell and cell-matrix interactions. However, the role of the SCS in the repair process in vivo remains unexplored.
The aim of the study was to examine the cellular composition of the spherical structures and their functional significance in the repair of the squamous epithelium in human papilloma virus-associated chronic cervicitis (HPV-CC).
Methods and Results: The cytology and biopsy materials from 223 patients with HPV-CC were subjected to molecular testing for HPV DNA by Real-Time Polymerase Chain Reaction (Real-Time PCR) with genotyping and chromogenic in situ hybridization (CISH), as well as immunocytological and immunohistochemical analyses of p16INK4A, Ki67, SMA, Vimentin, CD34, E-cadherin, Oct4, CD44, CKW markers. In the stem cell niche zone, these spheroid structures were discovered having proliferative activity and showing signs of producing stem cells involved in the repair of the cervical mucosa in HPV-CC.
Conclusion: The persistence of the HPV in the stem cell niche zone cells in the cervix determines the chronization of inflammation in this area, with the ability to perform pathological repair. The immunophenotype of the spheroid cell structures in the HPV-CC includes cells with signs of stem cells (‘stemness’) and the mesenchymal-epithelial transition.
1. Lord EM, Penney DP, Sutherland RM, Cooper RAJr. Morphological and functional characteristics of cells infiltrating and destroying tumor multicellular spheroids in vivo. Virchows Arch B Cell Pathol Incl Mol Pathol 1979; 31(2):103-16.
2. Sutherland RM, Durand RE. Radiation response of muiticell spheroids – an in vitro tumour model. Curr Top Radiat Res Q 1976; 11(1):87-139.
3. Umanskii IuA, Semenova-Kobzar' RA, Kushko Lla. 3-dimensional growth (spheroid formation) of tumor cells in diffusion chambers. Tsitologiia 1975; 27(5):557-9. [Article in Russian]
4. Saburina IN. Epithelial-mesenchymal plasticity of multipotent mesenchymal stromal cells in normal and pathological conditions (experimental study). Doctoral Dissertations Abstract. Moscow, 2010. [Abstract in Russian].
5. Greco KV, Iqbal AJ, Rattazzi L, Nalesso G, Moradi-Bidhendi N, Moore AR, et al. High density micromass cultures of a human chondrocyte cell line: a reliable assay system to reveal the modulatory functions of pharmacological agents. Biochem Pharmacol 201; 82(12):1919-1929.
6. Klopp AH, Lacerda L, Gupta A, Debeb BG, Solley T, Li L, et al. Mesenchymal stem cells promote mammosphere formation and decrease E-cadherin in normal and malignant breast cells. PloS ONE 2010; 5(8): e12180.
7. Rivron NC, Rouwkema J, Truckenmuller R, Karperien M, de Boer J, van Blitterswijk CA. Tissue assembly and organization: developmental mechanisms in microfabricated tissues. Biomaterials 2009; 30(28): 4851-8.
8. von der Mark K, Gauss V, von der Mark H, Müller P. Relationship between cell shape and type of collagen synthesised as chondrocytes lose their cartilage phenotype in culture. Nature 1977; 267(5611):531-2.
9. Bierwolf J, Lutgehetmann M, Feng K, Erbes J, Deichmann S, Toronyi E, et al. Primary rat hepatocyte culture on 3D nanofibrous polymer scaffolds for toxicology and pharmaceutical research. Biotechnol Bioeng 2011; 108(1):141-50.
10. Kuch V, Schreiber C, Thiele W, Umansky V, Sleeman JP. Tumor-initiating properties of breast cancer and melanoma cells in vivo are not invariably reflected by spheroid formation in vitro, but can be increased by long-term culturing as adherent monolayers. Int J Cancer 2013; 132(3):E94-105.
11. Wei B, Han XY, Qi CL, Zhang S, Zheng ZH, Huang Y, et al. Coaction of spheroid-derived stem-like cells and endothelial progenitor cells promotes development of colon cancer. PLoS One 2012; 7(6):e39069.
12. Kurioka D, Takagi A, Yoneda M, Hirokawa Y, Shiraishi T, Watanabe M. Multicellular spheroid culture models: applications in prostate cancer research and therapeutics. J Cancer Sci Ther 2011; 3(3):060-065.
13. Fennema E, Rivron N, Rouwkema J, van Blitterswijk C, de Boer J. Spheroid culture as a tool for creating 3D complex tissues. Trends Biotechnol 2013; 31(2):108-15.
14. Kogan EA, Faizullina NM, Demura SA, Demura TA, Israilova AKh, Kozachenko A.V. Remodeling of an endocervical stem cell niche in HPV-associated precancer and microinvasive cancer of the cervix uteri. Obstet & Gynecol 2012; 7:54-8. [Article in Russian].
15. Buitrago-Perez A, Garaulet G, Vazquez-Carballo A, Paramio JM, Garcia-Escudero R. Molecular signature of HPV-induced carcinogenesis: pRb, p53 and gene expression profiling. Curr Genomics 2009; 10(1):26–34.
16. Castle PE, Stoler MH, Wright TC Jr, Sharma A, Wright TL, Behrens CM. Performance of carcinogenic human papillomavirus (HPV) testing and HPV16 or HPV18 genotyping for cervical cancer screening of women aged 25 years and older: a subanalysis of the ATHENA study. Lancet Oncol 2011; 12(9):880-90.
17. Rijkaart DC, Berkhof J, Rozendaal L, van Kemenade FJ, Bulkmans NW, Heideman DA, et al. Human papillomavirus testing for the detection for high-grade cervical intraepithelial neoplasia and cancer: final results of the POBASCAM randomized controlled trial. Lancet Oncol 2012; 13(1):78-88.
18. Giatromanolaki A, Sivridis E, Papazoglou D, Koukourakis MI, Maltezos E. Human papillomavirus in endometrial adenocarcinomas: infectious agent or a mere “Passenger”? Infect Dis Obstet Gynecol 2007; 2007:60549.
19. Wang X, Dai J. Concise review: isoforms of OCT4 contribute to the confusing diversity in stem cell biology. Stem Cells 2010; 28(5):.885-93.
20. Malpica A, Deavers MT, Euscher E. Biopsy interpretation of the uterine cervix and corpus. Philadelphia: Wolters Kluwer Health/Lippincott Williams &Wilkins; 2010.
21. Wright TC, Ronnett BM, Ferenczy A et al. Bening deseases of the cervix. Precancerous lesions of the cervix. In book: “Blaustein’s Pathology of the Female Genital Tract”. Editors: Ellenson LH, Kurman RJ, Ronnett BM. New York; London: Springer, 2011. Chapter 4-5:155-252.
22. Baak JPA, Stoler MH, Bean SM, et al. Cervical precancer (intraepithelial neoplasia), including functional biomarkers and colposcopy. In book: Robboy’s pathology of the female reproductive tract. Robboy SJ, Bentley RC, Russell P, Anderson MC, Mutter GL, Prat J. Elsevier Health Sciences, 2009; Chapter 8:189-226.
23. Stewart CJR, McCluggage WG. Epithelial–mesenchymal transition in carcinomas of the female genital tract. Histopathology 2013; 62(1):31-43.
24. Hellner K, Mar J, Fang F, Quackenbush J, Munger K. HPV16E7 oncogene expression in normal human epithelial cells causes molecular changes indicative of an epithelial to mesenchymal transition. Virology 2009; 391(1):57–63.
25. Cheng YM, Chou CY, Hsu YC, Chen MJ, Wing LY. The role of human papillomavirus type 16 E6/E7 oncoproteins in cervical epithelial–mesenchymal transition and carcinogenesis. Oncol Lett 2012; 3(3):667–671.
26. Lee MY, Shen MR. Epithelial–mesenchymal transition in cervical carcinoma. Am J Transl Res 2012; 4(1):1–13.
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