Epithelial ovarian tumors pathophysiology

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Hannan Javed, M.D.[2]

Overview

Surface epithelium of ovaries

Surface epithelium of ovaries (OSE), once mistakenly referred as germinal epithelium, consists of single layer of flat to cuboidal epithelial cells. It is characterized by keratin types found in simple epithelium and functions in exchange between peritoneal cavity and the ovaries in addition to ovarian cycle.

Embryogenesis

Celomic epithelium → Peritoneal mesothelium surrounding the ovary → Metaplasia to ovarian surface epithelium[1][2]

  • During embryonic development, surface epithelium of ovaries is a part of celomic epithelium.[2]
  • Celomic epithelium itself is derived from mesothelium and forms lining of intraembryonic celom.[2]
  • The future surface epithelium of ovaries then forms part of gonadal blastema and then undergoes a transformation cycle, multilayered papillary epithelium develops from simple flat to cuboidal epithelium but reverts back to simple flat to cuboidal epithelium by term.[2]
  • It is important to note that ovarian surface epithelium is the part of celomic epithelium that overlies the presumptive gonads and the celomic epithelium in proximity of gonads also gives rise to Mullerian (paramesonephric) ducts, that in future will develop into epthelium of most of the female reproductive tract including oviducts, endometrium and a part of cervix.[2][3]
  • Ovarian surface epithelium has also been postulated to give rise or form a part of ovarian granulosa cells during embryonic development.[2][3]

Structural characteristics of ovarian surface epithelium in human adults

Cell type Surface expression Intercellular connection Basement membrane
  • Single layer
  • squamous-to-cuboidal epithelium
  • Keratin
  • Mucin antigen MUC1
  • 17β-hydroxysteroid dehydrogenase
  • Cilia
  • Simple desmosomes
  • Incomplete tight junctions
  • Integrins
  • Cadherins
  • Loosely attached
  • Tunica albuginea that is less conspicuous of its testicular counterpart
  • Keratin types that are expressed by ovarian surface epithelium are characteristic of simple epithelia such as keratin type 7, 8, 18 and 19.[2][4]
  • Catherins expressed by surface epithelium of ovaries may indicate potential for neoplastic transformation as summarized:[2][4][5][6][7]
    • Surface epithelium of ovaries typically express N-cadherin.
    • E-cadherin is typically expressed in regions where cells are columnar.
    • This selective expression of E-cadherin in regions of metaplastic epithelium may indicate propensity for neoplastic transformation.
    • P-catherin, normally absent in adult surface epithelium of ovaries, is expressed in adenocarcinoma of ovaries.

Functions

  • Two most important functions of human surface epithelium of ovaries are its role in transport and exchange between peritoneal cavity and ovaries, and its function in repair and rupture during ovulation.[2][5][8]
  • At present, its role in ovulatory rupture is not well-understood and is controversial. It is hypothesized that it contributes to follicular rupture through production of proteolytic enzymes.[2][5]
  • Epithelial need and ability of proliferation for repair of rupture and ovulatory defects is well-established and is thought to contribute the most in carcinogenesis of ovarian epithelium tumors.[2]
  • Ovarian surface epithelium undergo epithelio-mesenchymal transformation to replace ovarian stroma in ovulatory repair.[2]
  • The differentiation of surface epithelium of ovaries is, however, different from other epithelia because of its ability of differentiate into ectopic epithelium such as that of epithelium formed by Mullerian ducts.[2]

Role of hormones and growth factors on surface epithelium

Gonadotropin-releasing hormone

and gonadotropins[2] [9]

  • Cell proliferation
Epidermal growth factor (EGF)[2] [4][10][11]
  • Cell proliferation and differentiation
  • Increased survival
Steroids[2] [12][13]
  • Decreased expression of GnRH receptors (estrogen)
  • Regulation of hepatocyte growth factor and epidermal growth factor 9estrogen)
  • Decreased expression of Transfroming growth factor β receptors (5α-dihydrotestosterone)
  • May have direct effect on proliferation stimulation
Fibroblast growth factor (FGF)[2] [14]
  • Cell proliferation
  • Increased survival
Platelet-derived growth factor (PDGF)[2] [15]
  • Cell proliferation
Tissue necrosis factor-α (TNF-α)[2] [16][17]
  • Cell proliferation
  • Increased TNFα expression
Transfroming growth factor β (TGF-β)[2] [18]
  • Decreased growth
Hepatocyte growth factor (HGF)[2] [19][20]
  • Decreased cellular adhesion
  • Increased survival and growth
Cytokines[2] [21][22]
  • Regulation of immune response
  • May increase vasculogenesis and survival

Pathogenesis

Secondary Müllerian system

  • Although ovarian surface epithelium is not a derivative of Müllerian ducts but ovarian epithelial cancers are characterized by presence of Müllerian lesions.[23]
  • Serous carcinoma of ovary is though to originate from fallopian tubes while clear cell, endometrioid, and sero-mucinous carcinomas are thought to have their origin in endometriosis. Similarly Walthard nests potentially give rise to mucinous and Brenner malignant tumors, at least partially. All of these precursors are Müllerian system derivatives..[24][25]
  • Secondary Müllerian system is a hypothesis that tries to explain this apparent enigma of existence of Müllerian epithelial lesions in locations not derived from Müllerian ducts such as ovaries and peritoneal cavity.[26][25]
  • According to this hypothesis, ovarian surface epithelium posses the ability for Müllerian transformation. This potential for transformation stems from close proximity between future ovarian surface epithelium (celomic epithelium) and Müllerian duct system during embryonic development.[24][25]

An attempt to explain the origin of carcinogenesis in sporadic epithelial carcinoma

Proposed

hypothesis

Proposed

Mechanism

For Against
Incessant ovulation
  • Every ovulatory cycle leads to epithelial injury and resultant repairs make cells more susceptible to mutations
  • Increased incidences of ovarian epithelial cancers in advanced age (increased number of cycles)
  • Factors that decrease ovulatory cycles such as oral contraceptive use, pregnancy and breast-feeding decrease the risk for ovarian epithelial cancer
  • Progesterone only oral contraceptives do not inhibit ovulatory cycles but still decrease the risk for ovarian epithelial cancers
  • Polycystic ovarian syndrome (PCOS) decreases the number of ovulatory cycles but increases the risk for ovarian epithelial cancer.
Gonadotropins
  • Follicle-stimulating hormone (FSH) and luteinizing hormone (LH) and human chorionic gonadotropin stimulate ovarian epithelial cells proliferation
  • Resultant increased mitotic activity make cells more susceptible to mutations
  • Higher incidences of epthelial ovarian cancers in women taking infertility drugs in some studies
  • Polycystic ovarian syndrome (PCOS) and infertility increase the risk for ovarian epithelial cancers
  • Progesterone only oral contraceptives decrease the risk for ovarian epithelial cancers
  • Follicle-stimulating hormone (FSH) and luteinizing hormone (LH) are shown to increase cell proliferation in some studies
  • Up-regulation of Cox-1 and Cox-2 and resultant increase in PGE2 by follicle-stimulating hormone (FSH) and luteinizing hormone (LH) has been observed
  • Up-regulation of potential oncogenes in vitro such as EGFR, HER-2, and c-myc, cyclin G2, Meis-1, β-catenin, β-1 integrin, and IGF-1 by Follicle-stimulating hormone (FSH) receptor over-expression
  • Some studies suggest that infertility, rather than gonadotropin drugs treatment, increases the susceptibility to epithelial ovarian cancers
  • No concrete linkage of gonadotropins to malignant transformation of surface epithelial cells of ovaries
  • Proposed hypothesis of gonadotropin role in tumor cell growth and survival rather than origin
Hormonal stimulation
Inflammation

References

  1. ↑ Saad AF, Hu W, Sood AK (December 2010). "Microenvironment and pathogenesis of epithelial ovarian cancer". Horm Cancer. 1 (6): 277–90. doi:10.1007/s12672-010-0054-2. PMC 3199131. PMID 21761359.
  2. ↑ 2.00 2.01 2.02 2.03 2.04 2.05 2.06 2.07 2.08 2.09 2.10 2.11 2.12 2.13 2.14 2.15 2.16 2.17 2.18 2.19 2.20 2.21 Auersperg N, Wong AS, Choi KC, Kang SK, Leung PC (April 2001). "Ovarian surface epithelium: biology, endocrinology, and pathology". Endocr. Rev. 22 (2): 255–88. doi:10.1210/edrv.22.2.0422. PMID 11294827.
  3. ↑ 3.0 3.1 Yoshinaga K, Hess DL, Hendrickx AG, Zamboni L (January 1988). "The development of the sexually indifferent gonad in the prosimian, Galago crassicaudatus crassicaudatus". Am. J. Anat. 181 (1): 89–105. doi:10.1002/aja.1001810110. PMID 3348150.
  4. ↑ 4.0 4.1 4.2 Siemens CH, Auersperg N (March 1988). "Serial propagation of human ovarian surface epithelium in tissue culture". J. Cell. Physiol. 134 (3): 347–56. doi:10.1002/jcp.1041340305. PMID 2450877.
  5. ↑ 5.0 5.1 5.2 Kruk PA, Uitto VJ, Firth JD, Dedhar S, Auersperg N (November 1994). "Reciprocal interactions between human ovarian surface epithelial cells and adjacent extracellular matrix". Exp. Cell Res. 215 (1): 97–108. doi:10.1006/excr.1994.1320. PMID 7525326.
  6. ↑ Davies BR, Worsley SD, Ponder BA (January 1998). "Expression of E-cadherin, alpha-catenin and beta-catenin in normal ovarian surface epithelium and epithelial ovarian cancers". Histopathology. 32 (1): 69–80. PMID 9522220.
  7. ↑ Sundfeldt K, Piontkewitz Y, Ivarsson K, Nilsson O, Hellberg P, Brännström M, Janson PO, Enerback S, Hedin L (June 1997). "E-cadherin expression in human epithelial ovarian cancer and normal ovary". Int. J. Cancer. 74 (3): 275–80. PMID 9221804.
  8. ↑ Osterholzer HO, Streibel EJ, Nicosia SV (August 1985). "Growth effects of protein hormones on cultured rabbit ovarian surface epithelial cells". Biol. Reprod. 33 (1): 247–58. PMID 3933584.
  9. ↑ Davies BR, Finnigan DS, Smith SK, Ponder BA (April 1999). "Administration of gonadotropins stimulates proliferation of normal mouse ovarian surface epithelium". Gynecol. Endocrinol. 13 (2): 75–81. PMID 10399050.
  10. ↑ Rodriguez GC, Berchuck A, Whitaker RS, Schlossman D, Clarke-Pearson DL, Bast RC (March 1991). "Epidermal growth factor receptor expression in normal ovarian epithelium and ovarian cancer. II. Relationship between receptor expression and response to epidermal growth factor". Am. J. Obstet. Gynecol. 164 (3): 745–50. PMID 2003535.
  11. ↑ Evangelou A, Jindal SK, Brown TJ, Letarte M (February 2000). "Down-regulation of transforming growth factor beta receptors by androgen in ovarian cancer cells". Cancer Res. 60 (4): 929–35. PMID 10706107.
  12. ↑ Kang SK, Choi KC, Tai CJ, Auersperg N, Leung PC (February 2001). "Estradiol regulates gonadotropin-releasing hormone (GnRH) and its receptor gene expression and antagonizes the growth inhibitory effects of GnRH in human ovarian surface epithelial and ovarian cancer cells". Endocrinology. 142 (2): 580–8. doi:10.1210/endo.142.2.7982. PMID 11159828.
  13. ↑ Liu Y, Lin L, Zarnegar R (September 1994). "Modulation of hepatocyte growth factor gene expression by estrogen in mouse ovary". Mol. Cell. Endocrinol. 104 (2): 173–81. PMID 7988745.
  14. ↑ Basilico C, Moscatelli D (1992). "The FGF family of growth factors and oncogenes". Adv. Cancer Res. 59: 115–65. PMID 1381547.
  15. ↑ Dabrow MB, Francesco MR, McBrearty FX, Caradonna S (October 1998). "The effects of platelet-derived growth factor and receptor on normal and neoplastic human ovarian surface epithelium". Gynecol. Oncol. 71 (1): 29–37. doi:10.1006/gyno.1998.5121. PMID 9784315.
  16. ↑ Wu S, Rodabaugh K, Martinez-Maza O, Watson JM, Silberstein DS, Boyer CM, Peters WP, Weinberg JB, Berek JS, Bast RC (March 1992). "Stimulation of ovarian tumor cell proliferation with monocyte products including interleukin-1, interleukin-6, and tumor necrosis factor-alpha". Am. J. Obstet. Gynecol. 166 (3): 997–1007. PMID 1550178.
  17. ↑ Wu S, Boyer CM, Whitaker RS, Berchuck A, Wiener JR, Weinberg JB, Bast RC (April 1993). "Tumor necrosis factor alpha as an autocrine and paracrine growth factor for ovarian cancer: monokine induction of tumor cell proliferation and tumor necrosis factor alpha expression". Cancer Res. 53 (8): 1939–44. PMID 8385577.
  18. ↑ Berchuck A, Rodriguez G, Olt G, Whitaker R, Boente MP, Arrick BA, Clarke-Pearson DL, Bast RC (February 1992). "Regulation of growth of normal ovarian epithelial cells and ovarian cancer cell lines by transforming growth factor-beta". Am. J. Obstet. Gynecol. 166 (2): 676–84. PMID 1536252.
  19. ↑ Parrott JA, Skinner MK (March 2000). "Expression and action of hepatocyte growth factor in human and bovine normal ovarian surface epithelium and ovarian cancer". Biol. Reprod. 62 (3): 491–500. PMID 10684788.
  20. ↑ Gulati R, Peluso JJ (May 1997). "Opposing actions of hepatocyte growth factor and basic fibroblast growth factor on cell contact, intracellular free calcium levels, and rat ovarian surface epithelial cell viability". Endocrinology. 138 (5): 1847–56. doi:10.1210/endo.138.5.5137. PMID 9112378.
  21. ↑ Ziltener HJ, Maines-Bandiera S, Schrader JW, Auersperg N (September 1993). "Secretion of bioactive interleukin-1, interleukin-6, and colony-stimulating factors by human ovarian surface epithelium". Biol. Reprod. 49 (3): 635–41. PMID 7691194.
  22. ↑ Marth C, Zeimet AG, Herold M, Brumm C, Windbichler G, Müller-Holzner E, Offner F, Feichtinger H, Zwierzina H, Daxenbichler G (September 1996). "Different effects of interferons, interleukin-1beta and tumor necrosis factor-alpha in normal (OSE) and malignant human ovarian epithelial cells". Int. J. Cancer. 67 (6): 826–30. doi:10.1002/(SICI)1097-0215(19960917)67:6<826::AID-IJC12>3.0.CO;2-#. PMID 8824555.
  23. ↑ Devouassoux-Shisheboran M, Genestie C (January 2015). "Pathobiology of ovarian carcinomas". Chin J Cancer. 34 (1): 50–5. doi:10.5732/cjc.014.10273. PMC 4302089. PMID 25556618.
  24. ↑ 24.0 24.1 Devouassoux-Shisheboran M, Genestie C (January 2015). "Pathobiology of ovarian carcinomas". Chin J Cancer. 34 (1): 50–5. doi:10.5732/cjc.014.10273. PMC 4302089. PMID 25556618.
  25. ↑ 25.0 25.1 25.2 Lauchlan SC (July 1984). "Metaplasias and neoplasias of Müllerian epithelium". Histopathology. 8 (4): 543–57. PMID 6090303.
  26. ↑ Devouassoux-Shisheboran M, Genestie C (January 2015). "Pathobiology of ovarian carcinomas". Chin J Cancer. 34 (1): 50–5. doi:10.5732/cjc.014.10273. PMC 4302089. PMID 25556618.
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