CXCL12 expression by healthy and malignant ovarian epithelial cells
Véronique Machelon, Françoise Gaudin, Sophie Camilleri-Broët, Salam Nasreddine, Laurence Bouchet-Delbos, Eric Pujade-Lauraine, Jerôme Alexandre, Laurence Gladieff, Fernando Arenzana-Seisdedos, Dominique Emilie, Sophie Prévot, Philippe Broët, Karl Balabanian, Véronique Machelon, Françoise Gaudin, Sophie Camilleri-Broët, Salam Nasreddine, Laurence Bouchet-Delbos, Eric Pujade-Lauraine, Jerôme Alexandre, Laurence Gladieff, Fernando Arenzana-Seisdedos, Dominique Emilie, Sophie Prévot, Philippe Broët, Karl Balabanian
Abstract
Background: CXCL12 has been widely reported to play a biologically relevant role in tumor growth and spread. In epithelial ovarian cancer (EOC), CXCL12 enhances tumor angiogenesis and contributes to the immunosuppressive network. However, its prognostic significance remains unclear. We thus compared CXCL12 status in healthy and malignant ovaries, to assess its prognostic value.
Methods: Immunohistochemistry was used to analyze CXCL12 expression in the reproductive tracts, including the ovaries and fallopian tubes, of healthy women, in benign and borderline epithelial tumors, and in a series of 183 tumor specimens from patients with advanced primary EOC enrolled in a multicenter prospective clinical trial of paclitaxel/carboplatin/gemcitabine-based chemotherapy (GINECO study). Univariate COX model analysis was performed to assess the prognostic value of clinical and biological variables. Kaplan-Meier methods were used to generate progression-free and overall survival curves.
Results: Epithelial cells from the surface of the ovary and the fallopian tubes stained positive for CXCL12, whereas the follicles within the ovary did not. Epithelial cells in benign, borderline and malignant tumors also expressed CXCL12. In EOC specimens, CXCL12 immunoreactivity was observed mostly in epithelial tumor cells. The intensity of the signal obtained ranged from strong in 86 cases (47%) to absent in 18 cases (<10%). This uneven distribution of CXCL12 did not reflect the morphological heterogeneity of EOC. CXCL12 expression levels were not correlated with any of the clinical parameters currently used to determine EOC prognosis or with HER2 status. They also had no impact on progression-free or overall survival.
Conclusion: Our findings highlight the previously unappreciated constitutive expression of CXCL12 on healthy epithelia of the ovary surface and fallopian tubes, indicating that EOC may originate from either of these epithelia. We reveal that CXCL12 production by malignant epithelial cells precedes tumorigenesis and we confirm in a large cohort of patients with advanced EOC that CXCL12 expression level in EOC is not a valuable prognostic factor in itself.
Trial registration: ClinicalTrials.gov: NCT00052468.
Figures
References
- Permuth-Wey J, Sellers TA. Epidemiology of ovarian cancer. Methods Mol Biol. 2009;472:413–437. full_text.
- Jemal A, Siegel R, Ward E, Hao Y, Xu J, Murray T, Thun MJ. Cancer statistics, 2008. CA Cancer J Clin. 2008;58(2):71–96. doi: 10.3322/CA.2007.0010.
- Shimizu Y, Kamoi S, Amada S, Akiyama F, Silverberg SG. Toward the development of a universal grading system for ovarian epithelial carcinoma: testing of a proposed system in a series of 461 patients with uniform treatment and follow-up. Cancer. 1998;82(5):893–901. doi: 10.1002/(SICI)1097-0142(19980301)82:5<893::AID-CNCR14>;2-W.
- Shih Ie M, Kurman RJ. Ovarian tumorigenesis: a proposed model based on morphological and molecular genetic analysis. Am J Pathol. 2004;164(5):1511–1518. doi: 10.1016/S0002-9440(10)63708-X.
- Zorn KK, Bonome T, Gangi L, Chandramouli GV, Awtrey CS, Gardner GJ, Barrett JC, Boyd J, Birrer MJ. Gene expression profiles of serous, endometrioid, and clear cell subtypes of ovarian and endometrial cancer. Clin Cancer Res. 2005;11(18):6422–6430. doi: 10.1158/1078-0432.CCR-05-0508.
- Kobel M, Kalloger SE, Boyd N, McKinney S, Mehl E, Palmer C, Leung S, Bowen NJ, Ionescu DN, Rajput A. et al.Ovarian carcinoma subtypes are different diseases: implications for biomarker studies. PLoS Med. 2008;5(12):e232. doi: 10.1371/journal.pmed.0050232.
- Song H, Ramus SJ, Tyrer J, Bolton KL, Gentry-Maharaj A, Wozniak E, Anton-Culver H, Chang-Claude J, Cramer DW, DiCioccio R. et al.A genome-wide association study identifies a new ovarian cancer susceptibility locus on 9p22.2. Nat Genet. 2009;41(9):996–1000. doi: 10.1038/ng.424.
- Schwartz DR, Kardia SL, Shedden KA, Kuick R, Michailidis G, Taylor JM, Misek DE, Wu R, Zhai Y, Darrah DM. et al.Gene expression in ovarian cancer reflects both morphology and biological behavior, distinguishing clear cell from other poor-prognosis ovarian carcinomas. Cancer Res. 2002;62(16):4722–4729.
- White NM, Mathews M, Yousef GM, Prizada A, Popadiuk C, Dore JJ. KLK6 and KLK13 predict tumor recurrence in epithelial ovarian carcinoma. Br J Cancer. 2009;101(7):1107–1113. doi: 10.1038/sj.bjc.6605280.
- Balkwill F. Cancer and the chemokine network. Nat Rev Cancer. 2004;4(7):540–550. doi: 10.1038/nrc1388.
- Barbieri F, Bajetto A, Florio T. Role of chemokine network in the development and progression of ovarian cancer: a potential novel pharmacological target. J Oncol. 2010;2010:426956.
- Lazennec G, Richmond A. Chemokines and chemokine receptors: new insights into cancer-related inflammation. Trends Mol Med. 2010;16(3):133–144. doi: 10.1016/j.molmed.2010.01.003.
- Wilson J, Balkwill F. The role of cytokines in the epithelial cancer microenvironment. Semin Cancer Biol. 2002;12(2):113–120. doi: 10.1006/scbi.2001.0419.
- Kryczek I, Wei S, Keller E, Liu R, Zou W. Stromal derived factor (SDF-1/CXCL12) and human tumor pathogenesis. Am J Physiol Cell Physiol. 2007;292:C987–95. doi: 10.1152/ajpcell.00406.2006.
- Zou W, Machelon V, Coulomb-L'Hermine A, Borvak J, Nome F, Isaeva T, Wei S, Krzysiek R, Durand-Gasselin I, Gordon A. et al.Stromal-derived factor-1 in human tumors recruits and alters the function of plasmacytoid precursor dendritic cells. Nat Med. 2001;7(12):1339–1346. doi: 10.1038/nm1201-1339.
- Scotton CJ, Wilson JL, Scott K, Stamp G, Wilbanks GD, Fricker S, Bridger G, Balkwill FR. Multiple actions of the chemokine CXCL12 on epithelial tumor cells in human ovarian cancer. Cancer Res. 2002;62(20):5930–5938.
- Kryczek I, Lange A, Mottram P, Alvarez X, Cheng P, Hogan M, Moons L, Wei S, Zou L, Machelon V. et al.CXCL12 and vascular endothelial growth factor synergistically induce neoangiogenesis in human ovarian cancers. Cancer Res. 2005;65(2):465–472.
- Scotton CJ, Wilson JL, Milliken D, Stamp G, Balkwill FR. Epithelial cancer cell migration: a role for chemokine receptors? Cancer Res. 2001;61(13):4961–4965.
- Kajiyama H, Shibata K, Terauchi M, Ino K, Nawa A, Kikkawa F. Involvement of SDF-1alpha/CXCR4 axis in the enhanced peritoneal metastasis of epithelial ovarian carcinoma. Int J Cancer. 2008;122(1):91–99. doi: 10.1002/ijc.23083.
- Barbolina MV, Kim M, Liu Y, Shepard J, Belmadani A, Miller RJ, Shea LD, Stack MS. Microenvironmental regulation of chemokine (C-X-C-motif) receptor 4 in ovarian carcinoma. Mol Cancer Res. 2010;8(5):653–664. doi: 10.1158/1541-7786.MCR-09-0463.
- Pils D, Pinter A, Reibenwein J, Alfanz A, Horak P, Schmid BC, Hefler L, Horvat R, Reinthaller A, Zeillinger R. et ovarian cancer the prognostic influence of HER2/neu is not dependent on the CXCR4/SDF-1 signalling pathway. Br J Cancer. 2007;96(3):485–491. doi: 10.1038/sj.bjc.6603581.
- Jiang YP, Wu XH, Shi B, Wu WX, Yin GR. Expression of chemokine CXCL12 and its receptor CXCR4 in human epithelial ovarian cancer: an independent prognostic factor for tumor progression. Gynecol Oncol. 2006;103(1):226–233. doi: 10.1016/j.ygyno.2006.02.036.
- Auersperg N, Wong AS, Choi KC, Kang SK, Leung PC. Ovarian surface epithelium: biology, endocrinology, and pathology. Endocr Rev. 2001;22(2):255–288. doi: 10.1210/er.22.2.255.
- Karst AM, Drapkin R. Ovarian cancer pathogenesis: a model in evolution. J Oncol. 2010;2010:932371.
- Camilleri-Broet S, Hardy-Bessard AC, Le Tourneau A, Paraiso D, Levrel O, Leduc B, Bain S, Orfeuvre H, Audouin J, Pujade-Lauraine E. HER-2 overexpression is an independent marker of poor prognosis of advanced primary ovarian carcinoma: a multicenter study of the GINECO group. Ann Oncol. 2004;15(1):104–112. doi: 10.1093/annonc/mdh021.
- Tuefferd M, Couturier J, Penault-Llorca F, Vincent-Salomon A, Broet P, Guastalla JP, Allouache D, Combe M, Weber B, Pujade-Lauraine E. et al.HER2 status in ovarian carcinomas: a multicenter GINECO study of 320 patients. PLoS One. 2007;2(11):e1138. doi: 10.1371/journal.pone.0001138.
- du Bois A, Herrstedt J, Hardy-Bessard AC, Muller HH, Harter P, Kristensen G, Joly F, Huober J, Avall-Lundqvist E, Weber B. et al.Phase III trial of carboplatin plus paclitaxel with or without gemcitabine in first-line treatment of epithelial ovarian cancer. J Clin Oncol. 2010;28:4162–4169. doi: 10.1200/JCO.2009.27.4696.
- Drapkin R, Crum CP, Hecht JL. Expression of candidate tumor markers in ovarian carcinoma and benign ovary: evidence for a link between epithelial phenotype and neoplasia. Hum Pathol. 2004;35(8):1014–1021. doi: 10.1016/j.humpath.2004.04.014.
- Redjimi N, Gaudin F, Touboul C, Emilie D, Pallardy M, Biola-Vidamment A, Fernandez H, Prevot S, Balabanian K, Machelon V. Identification of glucocorticoid-induced leucine zipper as a key regulator of tumor cell proliferation in epithelial ovarian cancer. Mol Cancer. 2009;8:83. doi: 10.1186/1476-4598-8-83.
- Coulomb-L'Hermin A, Amara A, Schiff C, Durand-Gasselin I, Foussat A, Delaunay T, Chaouat G, Capron F, Ledee N, Galanaud P. et al.Stromal cell-derived factor 1 (SDF-1) and antenatal human B cell lymphopoiesis: expression of SDF-1 by mesothelial cells and biliary ductal plate epithelial cells. Proc Natl Acad Sci USA. 1999;96(15):8585–8590.
- Balabanian K, Couderc J, Bouchet-Delbos L, Amara A, Berrebi D, Foussat A, Baleux F, Portier A, Durand-Gasselin I, Coffman RL. et al.Role of the chemokine stromal cell-derived factor 1 in autoantibody production and nephritis in murine lupus. J Immunol. 2003;170(6):3392–3400.
- Kryczek I, Frydman N, Gaudin F, Krzysiek R, Fanchin R, Emilie D, Chouaib S, Zou W, Machelon V. The chemokine SDF-1/CXCL12 contributes to T lymphocyte recruitment in human pre-ovulatory follicles and coordinates with lymphocytes to increase granulosa cell survival and embryo quality. Am J Reprod Immunol. 2005;54(5):270–283. doi: 10.1111/j.1600-0897.2005.00307.x.
- Orimo A, Gupta PB, Sgroi DC, Arenzana-Seisdedos F, Delaunay T, Naeem R, Carey VJ, Richardson AL, Weinberg RA. Stromal fibroblasts present in invasive human breast carcinomas promote tumor growth and angiogenesis through elevated SDF-1/CXCL12 secretion. Cell. 2005;121(3):335–348. doi: 10.1016/j.cell.2005.02.034.
- Levanon K, Ng V, Piao HY, Zhang Y, Chang MC, Roh MH, Kindelberger DW, Hirsch MS, Crum CP, Marto JA. et al.Primary ex vivo cultures of human fallopian tube epithelium as a model for serous ovarian carcinogenesis. Oncogene. 2010;29(8):1103–1113. doi: 10.1038/onc.2009.402.
- Naora H, Montell DJ. Ovarian cancer metastasis: integrating insights from disparate model organisms. Nat Rev Cancer. 2005;5(5):355–366. doi: 10.1038/nrc1611.
- Wendt MK, Johanesen PA, Kang-Decker N, Binion DG, Shah V, Dwinell MB. Silencing of epithelial CXCL12 expression by DNA hypermethylation promotes colonic carcinoma metastasis. Oncogene. 2006;25(36):4986–4997. doi: 10.1038/sj.onc.1209505.
- Zhou W, Jiang Z, Liu N, Xu F, Wen P, Liu Y, Zhong W, Song X, Chang X, Zhang X. et al.Down-regulation of CXCL12 mRNA expression by promoter hypermethylation and its association with metastatic progression in human breast carcinomas. J Cancer Res Clin Oncol. 2009;135(1):91–102. doi: 10.1007/s00432-008-0435-x.
- Akishima-Fukasawa Y, Nakanishi Y, Ino Y, Moriya Y, Kanai Y, Hirohashi S. Prognostic significance of CXCL12 expression in patients with colorectal carcinoma. Am J Clin Pathol. 2009;132(2):202–210. doi: 10.1309/AJCPK35VZJEWCUTL.
- Liang JJ, Zhu S, Bruggeman R, Zaino R, Evans D, Fleming JB, Gomez HF, Zander DS, Wang H. High levels of expression of human stromal cell-derived factor-1 are associated with worse prognosis in patients with stage II pancreatic ductal adenocarcinoma. Cancer Epidemiol Biomarkers Prev. 2010;19(10):2598–2604. doi: 10.1158/1055-9965.EPI-10-0405.
- Hassan S, Ferrario C, Saragovi U, Quenneville L, Gaboury L, Baccarelli A, Salvucci O, Basik M. The influence of tumor-host interactions in the stromal cell-derived factor-1/CXCR4 ligand/receptor axis in determining metastatic risk in breast cancer. Am J Pathol. 2009;175(1):66–73. doi: 10.2353/ajpath.2009.080948.
- Sasaki K, Natsugoe S, Ishigami S, Matsumoto M, Okumura H, Setoyama T, Uchikado Y, Kita Y, Tamotsu K, Hanazono K. et al.Expression of CXCL12 and its receptor CXCR4 in esophageal squamous cell carcinoma. Oncol Rep. 2009;21(1):65–71.
- Gelmini S, Mangoni M, Castiglione F, Beltrami C, Pieralli A, Andersson KL, Fambrini M, Taddei GL, Serio M, Orlando C. The CXCR4/CXCL12 axis in endometrial cancer. Clin Exp Metastasis. 2009;26(3):261–268. doi: 10.1007/s10585-009-9240-4.
- Gilbert DC, Chandler I, McIntyre A, Goddard NC, Gabe R, Huddart RA, Shipley J. Clinical and biological significance of CXCL12 and CXCR4 expression in adult testes and germ cell tumours of adults and adolescents. J Pathol. 2009;217(1):94–102. doi: 10.1002/path.2436.
- Barbero S, Bonavia R, Bajetto A, Porcile C, Pirani P, Ravetti JL, Zona GL, Spaziante R, Florio T, Schettini G. Stromal cell-derived factor 1 alpha stimulates human glioblastoma cell growth through the activation of both extracellular signal-regulated kinases 1/2 and Akt. Cancer Res. 2003;63(8):1969–1974.
- Lis R, Touboul C, Mirshahi P, Ali F, Mathew S, Nolan DJ, Maleki TM, Abdalla SA, Raynaud CM, Querleu D. et al.Tumor associated mesenchymal stem cells protects ovarian cancer cells from hyperthermia through CXCL12. Int J Cancer. 2010;128:715–725. doi: 10.1002/ijc.25619.
- Laguri C, Arenzana-Seisdedos F, Lortat-Jacob H. Relationships between glycosaminoglycan and receptor binding sites in chemokines-the CXCL12 example. Carbohydr Res. 2008;343(12):2018–2023. doi: 10.1016/j.carres.2008.01.047.
- Balabanian K, Lagane B, Infantino S, Chow KY, Harriague J, Moepps B, Arenzana-Seisdedos F, Thelen M, Bachelerie F. The chemokine SDF-1/CXCL12 binds to and signals through the orphan receptor RDC1 in T lymphocytes. J Biol Chem. 2005;280(42):35760–35766. doi: 10.1074/jbc.M508234200.
- Thelen M, Thelen S. CXCR7, CXCR4 and CXCL12: an eccentric trio ? J Neuroimmunol. 2008;198(1-2):9–13. doi: 10.1016/j.jneuroim.2008.04.020.
- Burns JM, Summers BC, Wang Y, Melikian A, Berahovich R, Miao Z, Penfold ME, Sunshine MJ, Littman DR, Kuo CJ. et al.A novel chemokine receptor for SDF-1 and I-TAC involved in cell survival, cell adhesion, and tumor development. J Exp Med. 2006;203(9):2201–2213. doi: 10.1084/jem.20052144.
- Mirisola V, Zuccarino A, Bachmeier BE, Sormani MP, Falter J, Nerlich A, Pfeffer U. CXCL12/SDF1 expression by breast cancers is an independent prognostic marker of disease-free and overall survival. Eur J Cancer. 2009;45(14):2579–2587. doi: 10.1016/j.ejca.2009.06.026.
Source: PubMed