Epithelial ovarian cancer

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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]

Possible genetic alteration in epithelial ovarian cancers
Protein Normal function Result of mutation
Epidermal growth factor receptor (HER-1)[1][2]
  • Promotes cell proliferation
  • Opposes apoptosis
  • Regulates differentiation
  • Activating mutation
  • Increased cellular proliferation
  • Inhibition of apoptosis
Human Epidermal Growth Factor Receptor 2 (HER-2)[1][2]
  • Promotes cell prolifeartion
  • Inhibition of apoptosis
  • Regulates differentiation
  • Activating mutation
  • Increased cellular proliferation
  • Inhibition of apoptosis
Non-receptor tyrosine kinase Src[3][4] Involved in regulation of
  • Gene transcription
  • Angiogenesis
  • Cellular adhesion
  • Cellular proliferation
  • Activating mutation
  • Increased angiogenesis
  • Decreased cellular adhesion
  • Increased tumor metastasis
  • Increased cellular proliferation
CSF-1/fms[5][6][7]
  • Increased macrophage survival
  • Increased macrophage proliferation
  • Increased macrophage differentiation
  • Activating mutation
  • Stimulation of tumor cell proliferation
  • Increased angiogenesis
  • Promotes tumor invasion
  • Increased metastasis
  • Decreased anoikis
Insulin-like growth factor/receptor ILGF/ILGFR[8][9][10]
  • Promotes growth
  • Increased survival
  • Activating mutation
  • Increased proliferation
  • Enhanced survival
  • Suppression of cell cycle regulators
k-ras[11][12]
  • Cellular proliferation
  • Cell survival
  • Activating mutation
  • Increased proliferation
  • Enhanced survival
b-raf[13][14]
  • Cellular proliferation
  • Cellular differentiation
  • Activating mutation
  • Increased proliferation
  • Enhanced growth
TGF-β[15][16][17]
  • May function as a tumor suppressor and a promoter
  • Promotes growth arrest
  • Maintains cellular homeostasis
  • Increased proliferation
  • Decreased apoptosis
  • Epithelial-to-mesenchymal transition
  • Sustained angiogenesis
  • Evasion of immune surveillance
  • Metastasis
myc[18][19][20]
  • Derives cellular proliferation
  • Increased growth
  • Cell-cycle mediator
  • Inhibits apoptosis
  • Stem-cell renewal
  • Activating mutation
  • Increased proliferation
  • Decreased apoptosis
  • Increased metabolism in tumor cells
Cyclin D/Cdk4/6[21][22][23]
  • Cell-cycle mediator
  • Controls G1 length
  • Activating mutation
  • Decreased G1 length
  • Increased proliferation
  • Increased angiogenesis
Cyclin E/Cdk2[24][25][26]
  • Cellular proliferation
  • Cell-cycle mediator
  • Assembly of the pre-replication complex
  • Promotes G0 to cell cycle entry
  • Promotes G1 to S phase transition
  • Decreased apoptosis
  • Activating mutation
  • Increased cellular proliferation
  • Impaired apoptosis
  • Increased cellular survival
Cyclin B/Cdk1[27][28][29]
  • Cell-cycle mediator
  • promotes G2 to M phase transition
  • Activating mutation
  • Increased cellular proliferation
  • Promotes malignant transformation
p16[30][31][32]
  • Member of the INK4 family of CDK inhibitors
  • Inhibits Cyclin D/Cdk4/6
  • Decreased G1 to S phase transition
  • Lost or downregulated
  • Decreased G1 length
  • Increased proliferation
  • Increased angiogenesis
p27 (kip-1)[33][34][35]
  • Inhibitor of Cyclin E/Cdk2
  • Mediates cell cycle arrest
  • Decreased G1 to S phase transition
  • May act as oncogen and promote proliferation
  • Lost or dysregulated
  • Increase in cell proliferation
  • Impaired apoptosis
p21 (WAF-1)[36][37][38]
  • Inhibits cyclin-dependant kinases
  • Cell-cycle arrest
  • Decreased proliferation
  • Promotes cellular differentiation
  • May inhibit/promote apoptosis
  • May act as oncogen and promote proliferation
  • Lost or dysregulated
  • Increase in cell proliferation
  • Decreased cellular differentiation
  • Decreased apoptosis
  • Correlates positively
    • tumour grade
    • invasiveness
    • aggressiveness
NFκB[39][40][41]
  • A transcription factor involved in regulation of
    • immune response to inflammation
    • expression of cytokines, chemokines, and adhesion molecules
    • cell cycle
    • apoptosis
  • May function as a tumor suppressor and a promoter
  • Dysregulated
  • Increased angiogenesis
  • Enhanced tumor growth
  • Induces resistance to chemotherapy by acting as anti-apoptosis
NOEY(ARHI)[42][43][44]
  • Inhibits cell growth
  • Induces apoptosis
  • Inhibits tumor cells migration through chemotaxis and haptotaxis
  • Inactivating mutation
  • Enhanced tumor growth
  • Decreased apoptosis
  • Increased chances for metastasis
PIP3/Akt[45]
  • Akt is activated by PIP3 and plays a role in
    • regulation of cellular growth
    • cell cycle progression
    • regulation of glucose metabolism
    • genome stability
    • gene transcription
    • protein synthesis
    • neovascularization
    • promotes cell survival by blocking apoptosis
  • Activating mutations
  • Increased cellular proliferation
  • Increased survival
  • Increased migration
  • Increased invasion
  • Chemotherapy resistance
  • Decreased apoptosis
  • May promote angiogenesis
PTEN
p53
BRCA1
BRCA2
MLH1/MSH2
Fas ligand
HLA-G
hTERT
VEGF/VEGFR
IL-8
EphA2
MMPs
αvβ3
FAK
E-cadherin

References

  1. ↑ 1.0 1.1 Wee P, Wang Z (May 2017). "Epidermal Growth Factor Receptor Cell Proliferation Signaling Pathways". Cancers (Basel). 9 (5). doi:10.3390/cancers9050052. PMC 5447962. PMID 28513565.
  2. ↑ 2.0 2.1 Iqbal N, Iqbal N (2014). "Human Epidermal Growth Factor Receptor 2 (HER2) in Cancers: Overexpression and Therapeutic Implications". Mol Biol Int. 2014: 852748. doi:10.1155/2014/852748. PMC 4170925. PMID 25276427.
  3. ↑ Zan L, Wu H, Jiang J, Zhao S, Song Y, Teng G, Li H, Jia Y, Zhou M, Zhang X, Qi J, Wang J (July 2011). "Temporal profile of Src, SSeCKS, and angiogenic factors after focal cerebral ischemia: correlations with angiogenesis and cerebral edema". Neurochem. Int. 58 (8): 872–9. doi:10.1016/j.neuint.2011.02.014. PMC 3100427. PMID 21334414.
  4. ↑ Reinecke JB, Katafiasz D, Naslavsky N, Caplan S (April 2014). "Regulation of Src trafficking and activation by the endocytic regulatory proteins MICAL-L1 and EHD1". J. Cell. Sci. 127 (Pt 8): 1684–98. doi:10.1242/jcs.133892. PMC 3986674. PMID 24481818.
  5. ↑ 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.
  6. ↑ Dwyer AR, Greenland EL, Pixley FJ (June 2017). "Promotion of Tumor Invasion by Tumor-Associated Macrophages: The Role of CSF-1-Activated Phosphatidylinositol 3 Kinase and Src Family Kinase Motility Signaling". Cancers (Basel). 9 (6). doi:10.3390/cancers9060068. PMC 5483887. PMID 28629162.
  7. ↑ Abraham D, Zins K, Sioud M, Lucas T, Schäfer R, Stanley ER, Aharinejad S (March 2010). "Stromal cell-derived CSF-1 blockade prolongs xenograft survival of CSF-1-negative neuroblastoma". Int. J. Cancer. 126 (6): 1339–52. doi:10.1002/ijc.24859. PMC 3222589. PMID 19711348.
  8. ↑ Laron Z (October 2001). "Insulin-like growth factor 1 (IGF-1): a growth hormone". MP, Mol. Pathol. 54 (5): 311–6. PMC 1187088. PMID 11577173.
  9. ↑ Weroha SJ, Haluska P (June 2012). "The insulin-like growth factor system in cancer". Endocrinol. Metab. Clin. North Am. 41 (2): 335–50, vi. doi:10.1016/j.ecl.2012.04.014. PMC 3614012. PMID 22682634.
  10. ↑ Lukanova A, Lundin E, Toniolo P, Micheli A, Akhmedkhanov A, Rinaldi S, Muti P, Lenner P, Biessy C, Krogh V, Zeleniuch-Jacquotte A, Berrino F, Hallmans G, Riboli E, Kaaks R (October 2002). "Circulating levels of insulin-like growth factor-I and risk of ovarian cancer". Int. J. Cancer. 101 (6): 549–54. doi:10.1002/ijc.10613. PMID 12237896.
  11. ↑ Prior IA, Lewis PD, Mattos C (May 2012). "A comprehensive survey of Ras mutations in cancer". Cancer Res. 72 (10): 2457–67. doi:10.1158/0008-5472.CAN-11-2612. PMC 3354961. PMID 22589270.
  12. ↑ Franklin WA, Haney J, Sugita M, Bemis L, Jimeno A, Messersmith WA (January 2010). "KRAS mutation: comparison of testing methods and tissue sampling techniques in colon cancer". J Mol Diagn. 12 (1): 43–50. doi:10.2353/jmoldx.2010.080131. PMC 2797717. PMID 20007845.
  13. ↑ Estep AL, Palmer C, McCormick F, Rauen KA (December 2007). "Mutation analysis of BRAF, MEK1 and MEK2 in 15 ovarian cancer cell lines: implications for therapy". PLoS ONE. 2 (12): e1279. doi:10.1371/journal.pone.0001279. PMC 2093994. PMID 18060073.
  14. ↑ Grisham RN, Iyer G, Garg K, Delair D, Hyman DM, Zhou Q, Iasonos A, Berger MF, Dao F, Spriggs DR, Levine DA, Aghajanian C, Solit DB (February 2013). "BRAF mutation is associated with early stage disease and improved outcome in patients with low-grade serous ovarian cancer". Cancer. 119 (3): 548–554. doi:10.1002/cncr.27782. PMC 3961140. PMID 22930283.
  15. ↑ Alsina-Sanchís E, Figueras A, Lahiguera A, Gil-Martín M, Pardo B, Piulats JM, Martí L, Ponce J, Matias-Guiu X, Vidal A, Villanueva A, Viñals F (July 2017). "TGFβ Controls Ovarian Cancer Cell Proliferation". Int J Mol Sci. 18 (8). doi:10.3390/ijms18081658. PMC 5578048. PMID 28758950.
  16. ↑ Principe DR, Doll JA, Bauer J, Jung B, Munshi HG, Bartholin L, Pasche B, Lee C, Grippo PJ (February 2014). "TGF-β: duality of function between tumor prevention and carcinogenesis". J. Natl. Cancer Inst. 106 (2): djt369. doi:10.1093/jnci/djt369. PMC 3952197. PMID 24511106.
  17. ↑ Bierie B, Moses HL (February 2010). "Transforming growth factor beta (TGF-beta) and inflammation in cancer". Cytokine Growth Factor Rev. 21 (1): 49–59. doi:10.1016/j.cytogfr.2009.11.008. PMC 2834863. PMID 20018551.
  18. ↑ Miller DM, Thomas SD, Islam A, Muench D, Sedoris K (October 2012). "c-Myc and cancer metabolism". Clin. Cancer Res. 18 (20): 5546–53. doi:10.1158/1078-0432.CCR-12-0977. PMC 3505847. PMID 23071356.
  19. ↑ Dang CV (March 2012). "MYC on the path to cancer". Cell. 149 (1): 22–35. doi:10.1016/j.cell.2012.03.003. PMC 3345192. PMID 22464321.
  20. ↑ Aughey GN, Grice SJ, Liu JL (February 2016). "The Interplay between Myc and CTP Synthase in Drosophila". PLoS Genet. 12 (2): e1005867. doi:10.1371/journal.pgen.1005867. PMC 4759343. PMID 26889675.
  21. ↑ Neumeister P, Pixley FJ, Xiong Y, Xie H, Wu K, Ashton A, Cammer M, Chan A, Symons M, Stanley ER, Pestell RG (May 2003). "Cyclin D1 governs adhesion and motility of macrophages". Mol. Biol. Cell. 14 (5): 2005–15. doi:10.1091/mbc.02-07-0102. PMC 165093. PMID 12802071.
  22. ↑ Dong P, Zhang C, Parker BT, You L, Mathey-Prevot B (2018). "Cyclin D/CDK4/6 activity controls G1 length in mammalian cells". PLoS ONE. 13 (1): e0185637. doi:10.1371/journal.pone.0185637. PMC 5757913. PMID 29309421.
  23. ↑ Khleif SN, DeGregori J, Yee CL, Otterson GA, Kaye FJ, Nevins JR, Howley PM (April 1996). "Inhibition of cyclin D-CDK4/CDK6 activity is associated with an E2F-mediated induction of cyclin kinase inhibitor activity". Proc. Natl. Acad. Sci. U.S.A. 93 (9): 4350–4. PMC 39540. PMID 8633069.
  24. ↑ Honda R, Lowe ED, Dubinina E, Skamnaki V, Cook A, Brown NR, Johnson LN (February 2005). "The structure of cyclin E1/CDK2: implications for CDK2 activation and CDK2-independent roles". EMBO J. 24 (3): 452–63. doi:10.1038/sj.emboj.7600554. PMC 548659. PMID 15660127.
  25. ↑ Choudhary GS, Tat TT, Misra S, Hill BT, Smith MR, Almasan A, Mazumder S (July 2015). "Cyclin E/Cdk2-dependent phosphorylation of Mcl-1 determines its stability and cellular sensitivity to BH3 mimetics". Oncotarget. 6 (19): 16912–25. doi:10.18632/oncotarget.4857. PMC 4627281. PMID 26219338.
  26. ↑ Won KA, Reed SI (August 1996). "Activation of cyclin E/CDK2 is coupled to site-specific autophosphorylation and ubiquitin-dependent degradation of cyclin E". EMBO J. 15 (16): 4182–93. PMC 452142. PMID 8861947.
  27. ↑ Sun X, Zhangyuan G, Shi L, Wang Y, Sun B, Ding Q (May 2017). "Prognostic and clinicopathological significance of cyclin B expression in patients with breast cancer: A meta-analysis". Medicine (Baltimore). 96 (19): e6860. doi:10.1097/MD.0000000000006860. PMC 5428614. PMID 28489780.
  28. ↑ Huang Y, Sramkoski RM, Jacobberger JW (2013). "The kinetics of G2 and M transitions regulated by B cyclins". PLoS ONE. 8 (12): e80861. doi:10.1371/journal.pone.0080861. PMC 3851588. PMID 24324638.
  29. ↑ Lindqvist A, van Zon W, Karlsson Rosenthal C, Wolthuis RM (May 2007). "Cyclin B1-Cdk1 activation continues after centrosome separation to control mitotic progression". PLoS Biol. 5 (5): e123. doi:10.1371/journal.pbio.0050123. PMC 1858714. PMID 17472438.
  30. ↑ Yoon N, Yoon G, Park CK, Kim HS (October 2016). "Stromal p16 expression is significantly increased in malignant ovarian neoplasms". Oncotarget. 7 (40): 64665–64673. doi:10.18632/oncotarget.11660. PMC 5323106. PMID 27572321.
  31. ↑ Sano T, Oyama T, Kashiwabara K, Fukuda T, Nakajima T (December 1998). "Expression status of p16 protein is associated with human papillomavirus oncogenic potential in cervical and genital lesions". Am. J. Pathol. 153 (6): 1741–8. doi:10.1016/S0002-9440(10)65689-1. PMC 1866324. PMID 9846965.
  32. ↑ Felix AS, Sherman ME, Hewitt SM, Gunja MZ, Yang HP, Cora RL, Boudreau V, Ylaya K, Lissowska J, Brinton LA, Wentzensen N (2015). "Cell-cycle protein expression in a population-based study of ovarian and endometrial cancers". Front Oncol. 5: 25. doi:10.3389/fonc.2015.00025. PMC 4321403. PMID 25709969.
  33. ↑ Lee J, Kim SS (November 2009). "The function of p27 KIP1 during tumor development". Exp. Mol. Med. 41 (11): 765–71. doi:10.3858/emm.2009.41.11.102. PMC 2788730. PMID 19887899.
  34. ↑ Roy S, Singh RP, Agarwal C, Siriwardana S, Sclafani R, Agarwal R (June 2008). "Downregulation of both p21/Cip1 and p27/Kip1 produces a more aggressive prostate cancer phenotype". Cell Cycle. 7 (12): 1828–35. doi:10.4161/cc.7.12.6024. PMC 2744498. PMID 18583941.
  35. ↑ Miskimins WK, Wang G, Hawkinson M, Miskimins R (August 2001). "Control of cyclin-dependent kinase inhibitor p27 expression by cap-independent translation". Mol. Cell. Biol. 21 (15): 4960–7. doi:10.1128/MCB.21.15.4960-4967.2001. PMC 87223. PMID 11438653.
  36. ↑ Abbas T, Dutta A (June 2009). "p21 in cancer: intricate networks and multiple activities". Nat. Rev. Cancer. 9 (6): 400–14. doi:10.1038/nrc2657. PMC 2722839. PMID 19440234.
  37. ↑ Dash BC, El-Deiry WS (April 2005). "Phosphorylation of p21 in G2/M promotes cyclin B-Cdc2 kinase activity". Mol. Cell. Biol. 25 (8): 3364–87. doi:10.1128/MCB.25.8.3364-3387.2005. PMC 1069593. PMID 15798220.
  38. ↑ Shi Y, Zou M, Farid NR, al-Sedairy ST (November 1996). "Evidence of gene deletion of p21 (WAF1/CIP1), a cyclin-dependent protein kinase inhibitor, in thyroid carcinomas". Br. J. Cancer. 74 (9): 1336–41. PMC 2074763. PMID 8912526.
  39. ↑ Lawrence T (December 2009). "The nuclear factor NF-kappaB pathway in inflammation". Cold Spring Harb Perspect Biol. 1 (6): a001651. doi:10.1101/cshperspect.a001651. PMC 2882124. PMID 20457564.
  40. ↑ Yang G, Xiao X, Rosen DG, Cheng X, Wu X, Chang B, Liu G, Xue F, Mercado-Uribe I, Chiao P, Du X, Liu J (April 2011). "The biphasic role of NF-kappaB in progression and chemoresistance of ovarian cancer". Clin. Cancer Res. 17 (8): 2181–94. doi:10.1158/1078-0432.CCR-10-3265. PMC 3152795. PMID 21339307.
  41. ↑ Charbonneau B, Block MS, Bamlet WR, Vierkant RA, Kalli KR, Fogarty Z, Rider DN, Sellers TA, Tworoger SS, Poole E, Risch HA, Salvesen HB, Kiemeney LA, Baglietto L, Giles GG, Severi G, Trabert B, Wentzensen N, Chenevix-Trench G, Whittemore AS, Sieh W, Chang-Claude J, Bandera EV, Orlow I, Terry K, Goodman MT, Thompson PJ, Cook LS, Rossing MA, Ness RB, Narod SA, Kupryjanczyk J, Lu K, Butzow R, Dörk T, Pejovic T, Campbell I, Le ND, Bunker CH, Bogdanova N, Runnebaum IB, Eccles D, Paul J, Wu AH, Gayther SA, Hogdall E, Heitz F, Kaye SB, Karlan BY, Anton-Culver H, Gronwald J, Hogdall CK, Lambrechts D, Fasching PA, Menon U, Schildkraut J, Pearce CL, Levine DA, Kjaer SK, Cramer D, Flanagan JM, Phelan CM, Brown R, Massuger LF, Song H, Doherty JA, Krakstad C, Liang D, Odunsi K, Berchuck A, Jensen A, Lubinski J, Nevanlinna H, Bean YT, Lurie G, Ziogas A, Walsh C, Despierre E, Brinton L, Hein A, Rudolph A, Dansonka-Mieszkowska A, Olson SH, Harter P, Tyrer J, Vitonis AF, Brooks-Wilson A, Aben KK, Pike MC, Ramus SJ, Wik E, Cybulski C, Lin J, Sucheston L, Edwards R, McGuire V, Lester J, du Bois A, Lundvall L, Wang-Gohrke S, Szafron LM, Lambrechts S, Yang H, Beckmann MW, Pelttari LM, Van Altena AM, van den Berg D, Halle MK, Gentry-Maharaj A, Schwaab I, Chandran U, Menkiszak J, Ekici AB, Wilkens LR, Leminen A, Modugno F, Friel G, Rothstein JH, Vergote I, Garcia-Closas M, Hildebrandt MA, Sobiczewski P, Kelemen LE, Pharoah PD, Moysich K, Knutson KL, Cunningham JM, Fridley BL, Goode EL (February 2014). "Risk of ovarian cancer and the NF-κB pathway: genetic association with IL1A and TNFSF10". Cancer Res. 74 (3): 852–61. doi:10.1158/0008-5472.CAN-13-1051. PMC 3946482. PMID 24272484.
  42. ↑ Badgwell DB, Lu Z, Le K, Gao F, Yang M, Suh GK, Bao JJ, Das P, Andreeff M, Chen W, Yu Y, Ahmed AA, S-L Liao W, Bast RC (January 2012). "The tumor-suppressor gene ARHI (DIRAS3) suppresses ovarian cancer cell migration through inhibition of the Stat3 and FAK/Rho signaling pathways". Oncogene. 31 (1): 68–79. doi:10.1038/onc.2011.213. PMC 3170676. PMID 21643014.
  43. ↑ Yu Y, Xu F, Peng H, Fang X, Zhao S, Li Y, Cuevas B, Kuo WL, Gray JW, Siciliano M, Mills GB, Bast RC (January 1999). "NOEY2 (ARHI), an imprinted putative tumor suppressor gene in ovarian and breast carcinomas". Proc. Natl. Acad. Sci. U.S.A. 96 (1): 214–9. PMC 15119. PMID 9874798.
  44. ↑ Albanese C, Johnson J, Watanabe G, Eklund N, Vu D, Arnold A, Pestell RG (October 1995). "Transforming p21ras mutants and c-Ets-2 activate the cyclin D1 promoter through distinguishable regions". J. Biol. Chem. 270 (40): 23589–97. PMID 7559524.
  45. ↑ Hemmings BA, Restuccia DF (September 2012). "PI3K-PKB/Akt pathway". Cold Spring Harb Perspect Biol. 4 (9): a011189. doi:10.1101/cshperspect.a011189. PMC 3428770. PMID 22952397.
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