Sporadic Epithelial ovarian tumors

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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]

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

Proposed

hypothesis

Proposed

Mechanism

For Against
Incessant ovulation[1][2][3][4][5][6]
  • 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[1][6][7][8][9][10][11]
  • 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 influence[1][5][6][12][13][14]
  • Androgens confer greater risk to epithelial ovarian cancer while progesterone decreases the rik
  • Conditions that result in androgenic excess such as Polycystic ovarian syndrome (PCOS), hirsutism, and acne have been shown to increase the risk for epithelial ovarian cancer
  • Andorgens can stimulate cellular proliferation (androgens are are thought to be pre-dominant in ovarian inclusion cysts)
  • Progesterone only oral contraceptives decrease the risk for ovarian epithelial cancers, possibly through decreased androgens
  • No concrete linkage of androgens to malignant transformation of surface epithelial cells of ovaries
  • No evidence of androgens and their precursors affecting cancer cells growth
Inflammation[1][10][15][16]
  • Cytokines and inflammatory cells are involved in ovulation and repair and increase susceptibility to mutations and carcinogenesis
  • Non-steroidal anti-inflammatory drugs (NSAIDS) and Aminosalicylic acid (ASA) are thought to decrease the risk for epithelial ovarian cancer
  • Chemicals that cause inflammation such as talc and asbestos are shown to be associated with an increased risk for epithelial ovarian cancer
  • Inflammatory pathways and mediators have been observed in tumor pathogenesis and tumor micro-environment
  • No established linkage between talc and asbestos with pathogenesis of epithelial ovarian cancers in animal studies

Obesity a risk factor for epithelial cancer

  • A British study comprising of 1.2 million women found that incidences of epithelial ovarian cancer were higher among women with BMI >30 as compared to women with normal BMI, with risk increasing with incremental increase in BMI. A meta-analysis conducted Olsen et al.also found an increase risk for epithelial ovarian cancer in obese women.[17][18][19]
  • It has been hypothesized that waist to hip ratio provides a better risk determination for epithelial ovarian cancer because of more accuracy in assessing true visceral fat deposition but remains to be validated.[17][20]
  • The time at which women develop obesity during their life may be a key factor for increased risk for epithelial ovarian cancer. Multiple studies indicate that increased BMI in adolescence and/or early adulthood may confer a greater risk for developing epithelial ovarian cancer.[17][21][22]
  • Another study postulates that duration and severity of obesity is also associated with increased risk for epithelial ovarian cancer and few others postulate that association of obesity with epithelial ovarian cancer is greater in premenopausal women than post-menopausal.[17][18][23]
  • Another meta-analysis demonstrated that obesity is associated with not only an increased risk for epithelial ovarian cancer but also with decrease in overall survival and ovarian-cancer specific survival. Another study also showed an increase in ovarian cancer- related mortality in obese women.[17][24][25]

Diabetes mellitus and the risk for epithelial ovarian cancer

  • While conflicting data is present for association of diabetes mellitus and an increased risk for epithelial ovarian cancer, multiple studies, however, demonstrated diabetes as an independent risk factor for increased mortality in epithelial ovarian cancer.[17][26][27][28][29]
  • Findings in some studies indicate a greater risk for epithelial ovarian cancer in diabetic women while some suggest an increased risk only in pre-menopausal women, and some suggest no increase in risk for epithelial ovarian cancer at all.[17][26][27][28]

Metabolic syndrome and the risk for epithelial ovarian cancer.

  • The case for metabolic syndrome to be associated with an increased risk for epithelial ovarian cancer is similar to that of diabetes mellitus. There has been a fewer studies on association between metabolic syndrome and epithelial ovarian cancer and the results are conflicting with some found an increased risk for epithelial ovarian cancer in women with metabolic syndrome while some found no association.[17][30][31]
  • But an association of metabolic syndrome with increased ovarian cancer-related mortality was found in these studies. These studies however had limitation of lack of racial diversity because the study sample comprised only of Caucasian women.[17][31]

Pathogenesis of epithelial ovarian cancer associated with metabolic abnormalities

  • The work on mechanisms linking metabolic abnormalities to epithelial ovarian cancer is not yet complete and the way by which these abnormalities confer a greater risk for epithelial ovarian cancer is not well-understood but several theories have been put forward.
  • The most significant of these theories include role of cytokines and adipokines, immune cells, and aberrant signaling pathways in association with increased risk for epithelial ovarian cancer in women with metabolic derangement.

Cytokines and adipokines

The role of cytokines and adipokines in epithelial ovarian cancer
Cytokines and adipokines Association with metabolic abnormalities Proposed mechanism in initiation and progression of epithelial ovarian cancer
Tissue necrosis factor-α[17][32][33][34]
  • Produced by immune cells (macrophages), tumor cells and fat cells
  • Shown to be elevated in obesity and diabetes mellitus
  • Promotes matrix metalloproteinases that contribute to carcinognesis and increased risk for tumor cell invasion and metastasis
  • Promotes tumor cells growth by acting as paracrine and autocrine growth factor
  • Promotes angiogenesis that contribute to tumor progression
  • Promotes cell survival
  • Promotes cell proliferation
  • Inhibits apoptosis
  • Acts to decrease adiponectin levels by decreasing its production
  • Promotes aromatase expression in adipose tissues
  • Promotes insulin resistance
  • Promotes inflammation
  • A positive correlation of tissue necrosis factor-α levels with tumor grade of epithelial ovarian cancer
  • Elevated levels shown to be associated with decreased overall survival
Leptin[17][35][36][37][38]
  • Produced by adipocytes
  • Shown to be elevated in obesity and produced by tumor cells
  • Leptin receptors expressed by tumor cells
  • Inhibits natural killer function by decreasing
    • toxicity towards tumor cells
    • perforin production
    • interferon-γ secretion
  • Promotes secretion of interleukin-6 and tissue necrosis factor-α by monocytes
  • Promotes tumor cells growth and invasion
  • Promotes resistance to apoptosis
  • Promotes tumor cells proliferation
  • Promotes expression of cyclin-D that increases tumor cells growth and survival
  • Promotes tumor cells migration
  • Shown to decrease progression-free survival in epithelial ovarian tumors
IL-6[17][37][39]
  • Produced by immune cells (macrophages), tumor cells and fat cells
  • Shown to be elevated in obesity and diabetes mellitus
  • Reactive oxygen species associated with an increased level of interlekin-6
  • Promotes angiogenesis
  • Associated with increased aromatase that leads to elevated levels of estrogen
  • Inhibits apoptosis by increasing expression of anti-apoptotic proteins
  • Promotes resistance to chemotherapy
  • Promotes inflammation
  • Associated with increased levels of C-reactive protein
  • Response prediction to bevacizumab therapy
C reactive protein (CRP)[17][34]
  • Produced by liver
  • Shown to be elevated in obesity and diabetes mellitus
  • Shown to be associated with an increased risk for developing epithelial ovarian cancer
Monocyte chemotactic protein-1 (MCP-1)[17][35][40]
  • Produced by ovarian tumor cells
  • Induced by hypoxia inducible factor (levels elevated in obesity)
  • Elevated levels observed in obesity
  • Promotes monocytes recruitment
  • Associated with increased density of tumor associated macrophages
  • May play a role in angiogenesis
Adiponectin[17][20][41][42]
  • Produced by mature fat cells
  • Shown to be decreased in obesity and diabetes mellitus
  • Anti-tumor effects lost/decreased in obesity and diabetes mellitus that include
  • insulin sensitivity
  • Inhibition of inflammation
  • inhibition of tumor growth
  • inhibition of angiogenesis
  • inhibition of tissue necrosis factor-α signaling

Immune cells

  • Immune cells may have a pro or anti-tumor effect, depending on the cell type. Metabolic risk factors may alter these cell types and their functions to have a promoter effect in initiation and progression of epithelial ovarian tumors.[17]
  • The table below provides a short overview of possible role of immune cells in pathogenesis of epithelial ovarian tumors.[17]
The role of immune cells in epithelial ovarian cancer
Cell type Link with metabolic risk factors Possible role in pathogenesis
Dendritic cells[43][44][45]
  • Tumor stroma-derived factor 1 (SDF-1) recruits dendritic cells
  • Interleukin 10 by tumor cells leads to alteration in dendritic cells differentiation
  • These specific subtypes induced by tumor cells cytokines are less efficient in T-cells activation
  • Interact with programmed death-ligand 1 (PD-L1) to decrease T-cells effector function
Macrophages[40][46][47][48][49]
  • Two populations:
    • (1) M1 → classically activated tumor associated macrophages
    • (2) M2 → alternatively activated tumor associated macrophages
  • Studies indicate decreased M1 subpopulation in obese patients leading to ↓ M1/M2 ratio
  • Interferon gamma induce differentiation of macrophages into M1 subpopulation
  • Differentiation of macrophages into M2 subpopulation is possibly promoted by
    • transforming growth factor-beta
    • interleukin-4
    • interleukin-10
    • interleukin-13
    • colony stimulating factor-1
  • M1
    • inhibit tumor progression
    • promote inflammation through production of cytokines
    • cytotoxic to tumor cell
    • produce and release reactive oxygen species (ROS)
  • M2
    • promote tumor cells growth
    • promote angiogenesis
    • promote invasion and metastasis
    • promote tissue repair
    • inhibits immune system
    • produce C-C motif chemokine 22 (CCL22)
Natural killer cells[50][51]
  • Leptin may inhibit cytotoxic activity and interferon-γ production by natural killer cells
  • Mucin 16, Cell Surface Associated (MUC16) suppresses natural killer cells function
  • Increased natural killer cells activity in peripheral blood → increased progression free survival
  • Higher number of natural killer cells in peritoneal/pleural fluids → poor prognosis
B-cells[49][52][53]
  • Animal model studies indicate an up to threefold increase in B cells population in tumor cells in obese patients
  • Higher B cells tumor population associated with poorer prognosis
  • Promote angiogenesis
T-cells[50][54][55][56]
  • Interaction with programmed death-ligand 1 (PD-L1) inhibits CD4+ and CD8+ cells function
  • Transforming growth factor-β inhibits cytotoxic function of CD8+ cells
  • C-C motif chemokine 22 (CCL22) recruits regulatory T cells to the tumor
  • CD4+ cells
    • produce interleukin-17 that may have an anti-tumor role
  • CD8+ cells
    • increased number is associated with increased survival
  • Regulatory T-cells
    • release interleukin-10 and transforming growth factor-β that inhibit anti-tumor function of T-cells
    • inhibit cytotoxic function of CD8+ T cells

Hormones, signaling pathways in pathogenesis of epithelial ovarian cancer and their link with metabolic risk factors

  • Hormones and signaling pathways that may play a role in pathogenesis of epithelial ovarian cancer with link to metabolic abnormalities are summarized below in table:[17]
Possible role of hormones and signal transduction pathways in relation to metabolic abnormalities
Hormone Link with metabolic risk factors Possible role in pathogenesis
Hypoxia inducible factor (HIF)[35][32][57][58]
  • Increased in obesity due to relative hypoxia
  • Promotes growth and survival by increased production/expression of
    • interleukin-6
    • tissue necrosis factor
    • monocyte chemoattractant protein-1 (MCP-1)
    • erythropoietin
    • vascular endothelial growth factor and vascular endothelial growth factor receptors
    • glucose transporters
    • glycolytic enzymes
  • Promotes inflammation through increased expression of cytokines and recruitment of macrophages
  • Leads to increased C-X-C chemokine receptor type 4 (CXCR-4) that leads to increased density of tumor associated macrophages
  • Promotes angiogenesis
  • Promotes pro-fibrotic pathway, resulting in altered extra-cellular matrix
Vascular endothelial growth factor (VEGF)[49][59]
  • Increased levels observed in obesity
  • Promotes angiogenesis
  • Promotes tumor cells growth
  • Promotes metastasis
Insulin-like growth factor 1 (IGF-1)[35][27][60][61]
  • Increased levels observed in obesity
  • Increased levels in diabetes mellitus patients
  • Promotes tumor cells growth
  • Promotes angiogenesis
  • Inhibits apoptosis
  • Decreases sex hormone binding globulin, leading to increased levels of biologically available estrogen
  • Associated with increased levels of hypoxia inducible factor (HIF)
  • Correlates negatively with survival
Estrogen[35][62][63]
  • Increased levels observed in obesity
  • Promotes tumor cells growth through action as a mitogen
  • Associated with increased expression of insulin-like growth factor 1 (IGF-1) receptors

References

  1. ↑ 1.0 1.1 1.2 1.3 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. ↑ Riman T, Dickman PW, Nilsson S, Correia N, Nordlinder H, Magnusson CM, Persson IR (August 2002). "Risk factors for invasive epithelial ovarian cancer: results from a Swedish case-control study". Am. J. Epidemiol. 156 (4): 363–73. PMID 12181107.
  3. ↑ Gwinn ML, Lee NC, Rhodes PH, Layde PM, Rubin GL (1990). "Pregnancy, breast feeding, and oral contraceptives and the risk of epithelial ovarian cancer". J Clin Epidemiol. 43 (6): 559–68. PMID 2348208.
  4. ↑ Nasca PC, Greenwald P, Chorost S, Richart R, Caputo T (May 1984). "An epidemiologic case-control study of ovarian cancer and reproductive factors". Am. J. Epidemiol. 119 (5): 705–13. PMID 6539067.
  5. ↑ 5.0 5.1 Risch HA (December 1998). "Hormonal etiology of epithelial ovarian cancer, with a hypothesis concerning the role of androgens and progesterone". J. Natl. Cancer Inst. 90 (23): 1774–86. PMID 9839517.
  6. ↑ 6.0 6.1 6.2 Schildkraut JM, Schwingl PJ, Bastos E, Evanoff A, Hughes C (October 1996). "Epithelial ovarian cancer risk among women with polycystic ovary syndrome". Obstet Gynecol. 88 (4 Pt 1): 554–9. PMID 8841217.
  7. ↑ Choi KC, Kang SK, Tai CJ, Auersperg N, Leung PC (May 2002). "Follicle-stimulating hormone activates mitogen-activated protein kinase in preneoplastic and neoplastic ovarian surface epithelial cells". J. Clin. Endocrinol. Metab. 87 (5): 2245–53. doi:10.1210/jcem.87.5.8506. PMID 11994371.
  8. ↑ Lau MT, Wong AS, Leung PC (July 2010). "Gonadotropins induce tumor cell migration and invasion by increasing cyclooxygenases expression and prostaglandin E(2) production in human ovarian cancer cells". Endocrinology. 151 (7): 2985–93. doi:10.1210/en.2009-1318. PMID 20392831.
  9. ↑ Choi JH, Choi KC, Auersperg N, Leung PC (November 2004). "Overexpression of follicle-stimulating hormone receptor activates oncogenic pathways in preneoplastic ovarian surface epithelial cells". J. Clin. Endocrinol. Metab. 89 (11): 5508–16. doi:10.1210/jc.2004-0044. PMID 15531506.
  10. ↑ 10.0 10.1 Ness RB, Cottreau C (September 1999). "Possible role of ovarian epithelial inflammation in ovarian cancer". J. Natl. Cancer Inst. 91 (17): 1459–67. PMID 10469746.
  11. ↑ Zheng W, Lu JJ, Luo F, Zheng Y, Feng Y, Felix JC, Lauchlan SC, Pike MC (January 2000). "Ovarian epithelial tumor growth promotion by follicle-stimulating hormone and inhibition of the effect by luteinizing hormone". Gynecol. Oncol. 76 (1): 80–8. doi:10.1006/gyno.1999.5628. PMID 10620446. Vancouver style error: initials (help)
  12. ↑ Rosenberg L, Palmer JR, Zauber AG, Warshauer ME, Lewis JL, Strom BL, Harlap S, Shapiro S (April 1994). "A case-control study of oral contraceptive use and invasive epithelial ovarian cancer". Am. J. Epidemiol. 139 (7): 654–61. PMID 8166126.
  13. ↑ Edmondson RJ, Monaghan JM, Davies BR (March 2002). "The human ovarian surface epithelium is an androgen responsive tissue". Br. J. Cancer. 86 (6): 879–85. doi:10.1038/sj.bjc.6600154. PMC 2364138. PMID 11953818.
  14. ↑ Seeger H, Wallwiener D, Mueck AO (2006). "Is there a protective role of progestogens on the proliferation of human ovarian cancer cells in the presence of growth factors?". Eur. J. Gynaecol. Oncol. 27 (2): 139–41. PMID 16620055.
  15. ↑ Altinoz MA, Korkmaz R (2004). "NF-kappaB, macrophage migration inhibitory factor and cyclooxygenase-inhibitions as likely mechanisms behind the acetaminophen- and NSAID-prevention of the ovarian cancer". Neoplasma. 51 (4): 239–47. PMID 15254653.
  16. ↑ Heller DS, Westhoff C, Gordon RE, Katz N (May 1996). "The relationship between perineal cosmetic talc usage and ovarian talc particle burden". Am. J. Obstet. Gynecol. 174 (5): 1507–10. PMID 9065120.
  17. ↑ 17.00 17.01 17.02 17.03 17.04 17.05 17.06 17.07 17.08 17.09 17.10 17.11 17.12 17.13 17.14 17.15 17.16 17.17 Craig ER, Londoño AI, Norian LA, Arend RC (December 2016). "Metabolic risk factors and mechanisms of disease in epithelial ovarian cancer: A review". Gynecol. Oncol. 143 (3): 674–683. doi:10.1016/j.ygyno.2016.10.005. PMC 5689410. PMID 27751590.
  18. ↑ 18.0 18.1 Reeves GK, Pirie K, Beral V, Green J, Spencer E, Bull D (December 2007). "Cancer incidence and mortality in relation to body mass index in the Million Women Study: cohort study". BMJ. 335 (7630): 1134. doi:10.1136/bmj.39367.495995.AE. PMC 2099519. PMID 17986716.
  19. ↑ Olsen CM, Green AC, Whiteman DC, Sadeghi S, Kolahdooz F, Webb PM (March 2007). "Obesity and the risk of epithelial ovarian cancer: a systematic review and meta-analysis". Eur. J. Cancer. 43 (4): 690–709. doi:10.1016/j.ejca.2006.11.010. PMID 17223544.
  20. ↑ 20.0 20.1 Renehan AG, Tyson M, Egger M, Heller RF, Zwahlen M (February 2008). "Body-mass index and incidence of cancer: a systematic review and meta-analysis of prospective observational studies". Lancet. 371 (9612): 569–78. doi:10.1016/S0140-6736(08)60269-X. PMID 18280327.
  21. ↑ Lubin F, Chetrit A, Freedman LS, Alfandary E, Fishler Y, Nitzan H, Zultan A, Modan B (January 2003). "Body mass index at age 18 years and during adult life and ovarian cancer risk". Am. J. Epidemiol. 157 (2): 113–20. PMID 12522018.
  22. ↑ Engeland A, Tretli S, Bjørge T (August 2003). "Height, body mass index, and ovarian cancer: a follow-up of 1.1 million Norwegian women". J. Natl. Cancer Inst. 95 (16): 1244–8. PMID 12928351.
  23. ↑ Arnold M, Jiang L, Stefanick ML, Johnson KC, Lane DS, LeBlanc ES, Prentice R, Rohan TE, Snively BM, Vitolins M, Zaslavsky O, Soerjomataram I, Anton-Culver H (August 2016). "Duration of Adulthood Overweight, Obesity, and Cancer Risk in the Women's Health Initiative: A Longitudinal Study from the United States". PLoS Med. 13 (8): e1002081. doi:10.1371/journal.pmed.1002081. PMC 4987008. PMID 27529652.
  24. ↑ Protani MM, Nagle CM, Webb PM (July 2012). "Obesity and ovarian cancer survival: a systematic review and meta-analysis". Cancer Prev Res (Phila). 5 (7): 901–10. doi:10.1158/1940-6207.CAPR-12-0048. PMID 22609763.
  25. ↑ Nagle CM, Dixon SC, Jensen A, Kjaer SK, Modugno F, deFazio A, Fereday S, Hung J, Johnatty SE, Fasching PA, Beckmann MW, Lambrechts D, Vergote I, Van Nieuwenhuysen E, Lambrechts S, Risch HA, Rossing MA, Doherty JA, Wicklund KG, Chang-Claude J, Goodman MT, Ness RB, Moysich K, Heitz F, du Bois A, Harter P, Schwaab I, Matsuo K, Hosono S, Goode EL, Vierkant RA, Larson MC, Fridley BL, Høgdall C, Schildkraut JM, Weber RP, Cramer DW, Terry KL, Bandera EV, Paddock L, Rodriguez-Rodriguez L, Wentzensen N, Yang HP, Brinton LA, Lissowska J, Høgdall E, Lundvall L, Whittemore A, McGuire V, Sieh W, Rothstein J, Sutphen R, Anton-Culver H, Ziogas A, Pearce CL, Wu AH, Webb PM (September 2015). "Obesity and survival among women with ovarian cancer: results from the Ovarian Cancer Association Consortium". Br. J. Cancer. 113 (5): 817–26. doi:10.1038/bjc.2015.245. PMC 4559823. PMID 26151456.
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  27. ↑ 27.0 27.1 27.2 Vrachnis N, Iavazzo C, Iliodromiti Z, Sifakis S, Alexandrou A, Siristatidis C, Grigoriadis C, Botsis D, Creatsas G (February 2016). "Diabetes mellitus and gynecologic cancer: molecular mechanisms, epidemiological, clinical and prognostic perspectives". Arch. Gynecol. Obstet. 293 (2): 239–46. doi:10.1007/s00404-015-3858-z. PMID 26338721.
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  33. ↑ Naylor MS, Stamp GW, Foulkes WD, Eccles D, Balkwill FR (May 1993). "Tumor necrosis factor and its receptors in human ovarian cancer. Potential role in disease progression". J. Clin. Invest. 91 (5): 2194–206. doi:10.1172/JCI116446. PMC 288222. PMID 8387543.
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  35. ↑ 35.0 35.1 35.2 35.3 35.4 Park J, Morley TS, Kim M, Clegg DJ, Scherer PE (August 2014). "Obesity and cancer--mechanisms underlying tumour progression and recurrence". Nat Rev Endocrinol. 10 (8): 455–465. doi:10.1038/nrendo.2014.94. PMC 4374431. PMID 24935119.
  36. ↑ Uddin S, Bu R, Ahmed M, Abubaker J, Al-Dayel F, Bavi P, Al-Kuraya KS (September 2009). "Overexpression of leptin receptor predicts an unfavorable outcome in Middle Eastern ovarian cancer". Mol. Cancer. 8: 74. doi:10.1186/1476-4598-8-74. PMC 2754986. PMID 19765303.
  37. ↑ 37.0 37.1 Chen C, Chang YC, Lan MS, Breslin M (March 2013). "Leptin stimulates ovarian cancer cell growth and inhibits apoptosis by increasing cyclin D1 and Mcl-1 expression via the activation of the MEK/ERK1/2 and PI3K/Akt signaling pathways". Int. J. Oncol. 42 (3): 1113–9. doi:10.3892/ijo.2013.1789. PMID 23354006.
  38. ↑ Kato S, Abarzua-Catalan L, Trigo C, Delpiano A, Sanhueza C, García K, Ibañez C, Hormazábal K, Diaz D, Brañes J, Castellón E, Bravo E, Owen G, Cuello MA (August 2015). "Leptin stimulates migration and invasion and maintains cancer stem-like properties in ovarian cancer cells: an explanation for poor outcomes in obese women". Oncotarget. 6 (25): 21100–19. doi:10.18632/oncotarget.4228. PMC 4673253. PMID 26053184.
  39. ↑ Gastl G, Plante M (2001). "Bioactive interleukin-6 levels in serum and ascites as a prognostic factor in patients with epithelial ovarian cancer". Methods Mol. Med. 39: 121–3. doi:10.1385/1-59259-071-3:121. PMID 21340762.
  40. ↑ 40.0 40.1 Colvin EK (2014). "Tumor-associated macrophages contribute to tumor progression in ovarian cancer". Front Oncol. 4: 137. doi:10.3389/fonc.2014.00137. PMC 4047518. PMID 24936477.
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