Cervical cancer is one of the leading causes of cancer-related death in women in sub-Saharan Africa. Extensive evidence has shown that cervical cancer and its precursor lesions are caused by Human papillomavirus (HPV) infection. Although the vast majority of HPV infections are naturally resolved, failure to eradicate infected cells has been shown to promote viral persistence and tumorigenesis. Furthermore, following neoplastic transformation, exposure of cervical epithelial cells to inflammatory mediators either directly or via the systemic circulation may enhance progression of the disease. It is well recognised that seminal plasma contains an abundance of inflammatory mediators, which are identified as regulators of tumour growth. Here we investigated the role of seminal plasma in regulating neoplastic cervical epithelial cell growth and tumorigenesis. Using HeLa cervical adenocarcinoma cells, we found that seminal plasma (SP) induced the expression of the inflammatory enzymes, prostaglandin endoperoxide synthase (PTGS1 and PTGS2), cytokines interleukin (IL) -6, and -11 and vascular endothelial growth factor-A(VEGF-A). To investigate the role of SP on tumour cell growth in vivo, we xenografted HeLa cells subcutaneously into the dorsal flank of nude mice. Intra-peritoneal administration of SP rapidly and significantly enhanced the tumour growth rate and size of HeLa cell xenografts in nude mice. As observed in vitro, we found that SP induced expression of inflammatory PTGS enzymes, cytokines and VEGF-A in vivo. Furthermore we found that SP enhances blood vessel size in HeLa cell xenografts. Finally we show that SP-induced cytokine production, VEGF-A expression and cell proliferation are mediated via the induction of the inflammatory PTGS pathway.
References
[1]
Arbyn M, Castellsague X, de Sanjose S, Bruni L, Saraiya M, et al. (2011) Worldwide burden of cervical cancer in 2008. Ann Oncol 22: 2675–2686.
[2]
Anorlu RI (2008) Cervical cancer: the sub-Saharan African perspective. Reprod Health Matters 16: 41–49.
[3]
Canadas MP, Videla S, Darwich L, Tarrats A, Pinol M, et al. (2010) Human papillomavirus HPV-16, 18, 52 and 58 integration in cervical cells of HIV-1-infected women. J Clin Virol 48: 198–201.
[4]
Al-Daraji WI, Smith JH (2009) Infection and cervical neoplasia: facts and fiction. Int J Clin Exp Pathol 2: 48–64.
[5]
Boccardo E, Lepique AP, Villa LL (2010) The role of inflammation in HPV carcinogenesis. Carcinogenesis 31: 1905–1912.
[6]
Subbaramaiah K, Dannenberg AJ (2007) Cyclooxygenase-2 transcription is regulated by human papillomavirus 16 E6 and E7 oncoproteins: evidence of a corepressor/coactivator exchange. Cancer Res 67: 3976–3985.
[7]
Jabbour HN, Sales KJ, Catalano RD, Norman JE (2009) Inflammatory pathways in female reproductive health and disease. Reproduction 138: 903–919.
[8]
Coussens LM, Werb Z (2002) Inflammation and cancer. Nature 420: 860–867.
[9]
Goswami B, Rajappa M, Sharma M, Sharma A (2008) Inflammation: its role and interplay in the development of cancer, with special focus on gynecological malignancies. Int J Gynecol Cancer 18: 591–599.
[10]
Ryu HS, Chang KH, Yang HW, Kim MS, Kwon HC, et al. (2000) High cyclooxygenase-2 expression in stage IB cervical cancer with lymph node metastasis or parametrial invasion. Gynecol Oncol 76: 320–325.
[11]
Sales KJ, Katz AA, Davis M, Hinz S, Soeters RP, et al. (2001) Cyclooxygenase-2 expression and prostaglandin E2 synthesis are up- regulated in carcinomas of the cervix: a possible autocrine/paracrine regulation of neoplastic cell function via EP2/EP4 receptors. J Clin Endocrinol Metab 86: 2243–2249.
[12]
Sales KJ, Katz AA, Howard B, Soeters RP, Millar RP, et al. (2002) Cyclooxygenase-1 is up-regulated in cervical carcinomas: autocrine/paracrine regulation of cyclooxygenase-2, prostaglandin e receptors, and angiogenic factors by cyclooxygenase-1. Cancer Res 62: 424–432.
[13]
Oh JM, Kim SH, Lee YI, Seo M, Kim SY, et al. (2009) Human papillomavirus E5 protein induces expression of the EP4 subtype of prostaglandin E2 receptor in cyclic AMP response element-dependent pathways in cervical cancer cells. Carcinogenesis 30: 141–149.
[14]
Smith WL, DeWitt DL, Garavito RM (2000) CYCLOOXYGENASES: structural, cellular, and molecular biology. Annu Rev Biochem 69: 145–182.
[15]
Battersby S, Sales KJ, Williams AR, Anderson RA, Gardner S, et al. (2007) Seminal plasma and prostaglandin E2 up-regulate fibroblast growth factor 2 expression in endometrial adenocarcinoma cells via E-series prostanoid-2 receptor-mediated transactivation of the epidermal growth factor receptor and extracellular signal-regulated kinase pathway. Hum Reprod 22: 36–44.
[16]
Muller M, Sales KJ, Katz AA, Jabbour HN (2006) Seminal plasma promotes the expression of tumorigenic and angiogenic genes in cervical adenocarcinoma cells via the E-series prostanoid 4 receptor. Endocrinology 147: 3356–3365.
[17]
Sales KJ, Katz AA, Millar RP, Jabbour HN (2002) Seminal plasma activates cyclooxygenase-2 and prostaglandin E2 receptor expression and signalling in cervical adenocarcinoma cells. Mol Hum Reprod 8: 1065–1070.
[18]
Ness RB, Grainger DA (2008) Male reproductive proteins and reproductive outcomes. Am J Obstet Gynecol 198: 620 e621–624.
[19]
Fung KY, Glode LM, Green S, Duncan MW (2004) A comprehensive characterization of the peptide and protein constituents of human seminal fluid. Prostate 61: 171–181.
[20]
Robertson SA, Guerin LR, Moldenhauer LM, Hayball JD (2009) Activating T regulatory cells for tolerance in early pregnancy - the contribution of seminal fluid. J Reprod Immunol 83: 109–116.
[21]
Robertson SA (2005) Seminal plasma and male factor signalling in the female reproductive tract. Cell Tissue Res 322: 43–52.
[22]
Robertson SA, Guerin LR, Bromfield JJ, Branson KM, Ahlstrom AC, et al. (2009) Seminal fluid drives expansion of the CD4+CD25+ T regulatory cell pool and induces tolerance to paternal alloantigens in mice. Biol Reprod 80: 1036–1045.
[23]
Moldenhauer LM, Diener KR, Thring DM, Brown MP, Hayball JD, et al. (2009) Cross-presentation of male seminal fluid antigens elicits T cell activation to initiate the female immune response to pregnancy. J Immunol 182: 8080–8093.
[24]
Sharkey DJ, Tremellen KP, Jasper MJ, Gemzell-Danielsson , Robertson SA (2012) Seminal Fluid induces leukocyte recruitment and cytokine and chemokine mRNA expression in the human cervix after coitus. J Immunol. In Press.
[25]
Jeremias J, David SS, Toth M, Witkin SS (1997) Induction of messenger RNA for the 70 kDa heat shock protein in HeLa cells and the human endocervix following exposure to semen: Implications for antisperm antibody production and susceptibility to sexually transmitted infections. Hum Reprod 12: 1915–1919.
[26]
Jeremias J, Witkin SS (1999) Effect of human seminal fluid on production of messenger ribonucleic acid for metalloproteinase 2 and metalloproteinase 9 in cervical epithelial carcinoma cells. Am J Obstet Gynecol 181: 591–595.
[27]
Klemmt L, Scialli AR (2005) The transport of chemicals in semen. Birth Defects Res B Dev Reprod Toxicol 74: 119–131.
[28]
Catalano RD, Wilson MR, Boddy SC, McKinlay AT, Sales KJ, et al. (2011) Hypoxia and prostaglandin e receptor 4 signalling pathways synergise to promote endometrial adenocarcinoma cell proliferation and tumour growth. PLoS One 6: e19209.
[29]
Sales KJ, Jabbour HN (2003) Cyclooxygenase enzymes and prostaglandins in pathology of the endometrium. Reproduction 126: 559–567.
[30]
Jabbour HN, Sales KJ (2004) Prostaglandin receptor signalling and function in human endometrial pathology. Trends Endocrinol Metab 15: 398–404.
[31]
Ponten J, Adami HO, Bergstrom R, Dillner J, Friberg LG, et al. (1995) Strategies for global control of cervical cancer. Int J Cancer 60: 1–26.
[32]
Harlan LC, Bernstein AB, Kessler LG (1991) Cervical cancer screening: who is not screened and why? Am J Public Health 81: 885–890.
[33]
Chan JK, Monk BJ, Brewer C, Keefe KA, Osann K, et al. (2003) HPV infection and number of lifetime sexual partners are strong predictors for ‘natural’ regression of CIN 2 and 3. Br J Cancer 89: 1062–1066.
[34]
Schiffman MH, Brinton LA (1995) The epidemiology of cervical carcinogenesis. Cancer 76: 1888–1901.
[35]
Sales KJ, Jabbour HN (2003) Cyclooxygenase enzymes and prostaglandins in reproductive tract physiology and pathology. Prostaglandins Other Lipid Mediat 71: 97–117.
Wallace AE, Sales KJ, Catalano RD, Anderson RA, Williams AR, et al. (2009) Prostaglandin F2alpha-F-Prostanoid Receptor Signaling Promotes Neutrophil Chemotaxis via Chemokine (C-X-C Motif) Ligand 1 in Endometrial Adenocarcinoma. Cancer Res 69: 5726–5733.
[38]
Takehara H, Iwamoto J, Mizokami Y, Takahashi K, Ootubo T, et al. (2006) Involvement of cyclooxygenase-2-prostaglandin E2 pathway in interleukin-8 production in gastric cancer cells. Dig Dis Sci 51: 2188–2197.
Eustace D, Han X, Gooding R, Rowbottom A, Riches P, et al. (1993) Interleukin-6 (IL-6) functions as an autocrine growth factor in cervical carcinomas in vitro. Gynecol Oncol 50: 15–19.
[41]
Fujimoto J, Sakaguchi H, Aoki I, Tamaya T (2000) Clinical implications of expression of interleukin 8 related to angiogenesis in uterine cervical cancers. Cancer Res 60: 2632–2635.
[42]
Venkatakrishnan G, Salgia R, Groopman JE (2000) Chemokine receptors CXCR-1/2 activate mitogen-activated protein kinase via the epidermal growth factor receptor in ovarian cancer cells. J Biol Chem 275: 6868–6875.
[43]
Watson JM, Sensintaffar JL, Berek JS, Martinez-Maza O (1990) Constitutive production of interleukin 6 by ovarian cancer cell lines and by primary ovarian tumor cultures. Cancer Res 50: 6959–6965.
[44]
Sales KJ, Grant V, Cook IH, Maldonado-Perez D, Anderson RA, et al. (2010) Interleukin-11 in endometrial adenocarcinoma is regulated by prostaglandin F2alpha-F-prostanoid receptor interaction via the calcium-calcineurin-nuclear factor of activated T cells pathway and negatively regulated by the regulator of calcineurin-1. Am J Pathol 176: 435–445.
[45]
Sales KJ, Maldonado-Perez D, Grant V, Catalano RD, Wilson MR, et al. (2009) Prostaglandin F2alpha-F-prostanoid receptor regulates CXCL8 expression in endometrial adenocarcinoma cells via the calcium-calcineurin-NFAT pathway. Biochim Biophys Acta 1793: 1917–1928.
[46]
Ney PG (1986) The intravaginal absorption of male generated hormones and their possible effect on female behaviour. Med Hypotheses 20: 221–231.
[47]
Liu L, Liu C, Lou F, Zhang G, Wang X, et al. (2011) Activation of telomerase by seminal plasma in malignant and normal cervical epithelial cells. J Pathol 225: 203–211.
[48]
Sharkey DJ, Macpherson AM, Tremellen KP, Robertson SA (2007) Seminal plasma differentially regulates inflammatory cytokine gene expression in human cervical and vaginal epithelial cells. Mol Hum Reprod 13: 491–501.
[49]
Denison FC, Grant VE, Calder AA, Kelly RW (1999) Seminal plasma components stimulate interleukin-8 and interleukin-10 release. Mol Hum Reprod 5: 220–226.
[50]
Robertson SA, Mau VJ, Tremellen KP, Seamark RF (1996) Role of high molecular weight seminal vesicle proteins in eliciting the uterine inflammatory response to semen in mice. J Reprod Fertil 107: 265–277.
[51]
Takano H, Harigaya K, Ishii G, Sugaya Y, Soeta S, et al. (1996) Interleukin-6 (IL-6) production in carcinoma of the cervix. Arch Gynecol Obstet 258: 25–33.
[52]
Robertson SA, Mayrhofer G, Seamark RF (1992) Uterine epithelial cells synthesize granulocyte-macrophage colony- stimulating factor and interleukin-6 in pregnant and nonpregnant mice. Biol Reprod 46: 1069–1079.
[53]
Guidi AJ, Abu-Jawdeh G, Berse B, Jackman RW, Tognazzi K, et al. (1995) Vascular permeability factor (vascular endothelial growth factor) expression and angiogenesis in cervical neoplasia. J Natl Cancer Inst 87: 1237–1245.
[54]
Cheng WF, Chen CA, Lee CN, Chen TM, Hsieh FJ, et al. (1999) Vascular endothelial growth factor in cervical carcinoma. Obstet Gynecol 93: 761–765.
[55]
Darai E, Bringuier AF, Walker-Combrouze F, Fauconnier A, Couvelard A, et al. (1998) CD31 expression in benign, borderline, and malignant epithelial ovarian tumors: an immunohistochemical and serological analysis. Gynecol Oncol 71: 122–127.
[56]
Horak ER, Leek R, Klenk N, LeJeune S, Smith K, et al. (1992) Angiogenesis, assessed by platelet/endothelial cell adhesion molecule antibodies, as indicator of node metastases and survival in breast cancer. Lancet 340: 1120–1124.
[57]
Yamazaki K, Abe S, Takekawa H, Sukoh N, Watanabe N, et al. (1994) Tumor angiogenesis in human lung adenocarcinoma. Cancer 74: 2245–2250.
[58]
Fregene TA, Khanuja PS, Noto AC, Gehani SK, Van Egmont EM, et al. (1993) Tumor-associated angiogenesis in prostate cancer. Anticancer Res 13: 2377–2381.
[59]
Mazibrada J, Ritta M, Mondini M, De Andrea M, Azzimonti B, et al. (2008) Interaction between inflammation and angiogenesis during different stages of cervical carcinogenesis. Gynecol Oncol 108: 112–120.
[60]
Quigley JP, Deryugina EI (2012) Combating angiogenesis early: potential of targeting tumor-recruited neutrophils in cancer therapy. Future Oncol 8: 5–8.
[61]
Aumuller G, Riva A (1992) Morphology and functions of the human seminal vesicle. Andrologia 24: 183–196.
