Abstract
Objectives
Dickkopf-1 (DKK1) is a secreted protein, known for suppressing the differentiation and activity of bone-building osteoblasts by acting as an inhibitor of Wnt-signalling. Soluble DKK1 (sDKK1) has been proposed as prognostic biomarker for a wide range of malignancies, however, clinical relevance of sDKK1 as potential blood-based marker for ovarian cancer is unknown.
Methods
sDKK1 levels were quantified in a cohort of 150 clinically documented ovarian cancer patients by a commercially available DKK1 ELISA (Biomedica, Vienna, Austria).
Results
Median sDKK1 level was significantly elevated at primary diagnosis of ovarian cancer compared to healthy controls (estimated difference (ED) of 7.75 ng/mL (95% CI: 3.01–12.30 ng/mL, p=0.001)). Higher levels of sDKK1 at diagnosis indicated an increased volume of intraoperative malignant ascites (ED 7.08 pmol/L, 95% CI: 1.46–13.05, p=0.02) and predicted suboptimal debulking surgery (ED 6.88 pmol/L, 95% CI: 1.73–11.87, p=0.01). sDKK1 did not correlate with CA125 and higher sDKK1 levels predicted a higher risk of recurrence and poor survival (PFS: HR=0.507, 95% CI: 0.317–0.809; p=0.004; OS: HR=0.561, 95% CI: 0.320–0.986; p=0.044). Prognostic relevance of sDKK1 was partly sustained in wtBRCA patients (PFS: HR=0.507, 95% CI: 0.317–0.809; p=0.004).
Conclusions
This is the first study demonstrating the prognostic relevance of sDKK1 in ovarian cancer patients, including those with wtBRCA 1/2 status. Our data encourage further evaluation of sDKK1 in ovarian cancer patients, possibly in terms of a therapy monitoring marker or a response predictor for sDKK1-directed targeted therapies.
Funding source: Deutsche Forschungsgemeinschaft
Award Identifier / Grant number: GO 3055/1-1, HO 1875/24-1, 26-1, and 27-1, RA 2151/4-1 and 5-1
Funding source: Deutsche Krebshilfe
Award Identifier / Grant number: 70113573 and as part of the Mildred-Scheel Nachwuchszentrum
Acknowledgments
The authors would like to thank Babett Heschel for her excellent technical assistance.
-
Research funding: The work was funded by the Deutsche Forschungsgemeinschaft to AG (GO 3055/1-1), LCH (HO 1875/24-1, 26-1, and 27-1) and to TDR (RA 2151/4-1 and 5-1) as part of the DFG Schwerpunktprogramm-2084 µBone as well as by the Deutsche Krebshilfe to AG and TDR (#70113573 and as part of the Mildred-Scheel Nachwuchszentrum).
-
Author contributions: TDR, AG, DMK, JDK, PW and LCH made substantial contributions to the conception and design of the study. DMK, AG, JDK, TL, MG, NJ contributed to the experimental work or to the acquisition of clinical samples/data or to the analysis/interpretation of the results. JDK, AG and DMK, TL were involved in drafting the manuscript, creating figures or revising the manuscript. All authors have accepted responsibility for the entire content of this manuscript and approved its submission.
-
Competing interests: Authors state no conflict of interest.
-
Informed consent: Written informed consent was obtained from all study participants and the study was approved by the Local Research Ethics Committee in Dresden (EK74032013).
-
Ethical approval: The study was approved by the Local Research Ethics Committee in Dresden (EK74032013). All study methodologies conformed to the standards set by the Declaration of Helsinki.
References
1. Torre, LA, Trabert, B, DeSantis, CE, Miller, KD, Samimi, G, Runowicz, CD, et al.. Ovarian cancer statistics. CA Cancer J Clin 2018;68:284–96. https://doi.org/10.3322/caac.21456.Search in Google Scholar
2. Buys, SS, Partridge, E, Greene, MH, Prorok, PC, Reding, D, Riley, TL, et al.. Ovarian cancer screening in the prostate, lung, colorectal and ovarian (PLCO) cancer screening trial: findings from the initial screen of a randomized trial. Am J Obstet Gynecol 2005;193:1630–9. https://doi.org/10.1016/j.ajog.2005.05.005.Search in Google Scholar
3. du Bois, A, Quinn, M, Thigpen, T, Vermorken, J, Avall-Lundqvist, E, Bookman, M, et al.. 2004 consensus statements on the management of ovarian cancer: final document of the 3rd International Gynecologic Cancer Intergroup Ovarian Cancer Consensus Conference (GCIG OCCC 2004). Ann Oncol 2005;16:viii7–12. https://doi.org/10.1093/annonc/mdi961.Search in Google Scholar
4. Karam, A, Ledermann, JA, Kim, J-W, Sehouli, J, Lu, K, Gourley, C, et al.. Fifth Ovarian Cancer Consensus Conference of the Gynecologic Cancer InterGroup: first-line interventions. Ann Oncol 2017;28:711–7. https://doi.org/10.1093/annonc/mdx011.Search in Google Scholar
5. Stuart, GCE, Kitchener, H, Bacon, M, DuBois, A, Friedlander, M, Ledermann, J, et al.. 2010 Gynecologic Cancer InterGroup (GCIG) consensus statement on clinical trials in ovarian cancer: report from the Fourth Ovarian Cancer Consensus Conference. Int J Gynecol Cancer 2011;21:750–5. https://doi.org/10.1097/igc.0b013e31821b2568.Search in Google Scholar
6. Burger, RA, Brady, MF, Bookman, MA, Fleming, GF, Monk, BJ, Huang, H, et al.. Incorporation of bevacizumab in the primary treatment of ovarian cancer. N Engl J Med 2011;365:2473–83. https://doi.org/10.1056/nejmoa1104390.Search in Google Scholar
7. Ray-Coquard, I, Pautier, P, Pignata, S, Pérol, D, González-Martín, A, Berger, R, et al.. Olaparib plus bevacizumab as first-line maintenance in ovarian cancer. N Engl J Med 2019;381:2416–28. https://doi.org/10.1056/nejmoa1911361.Search in Google Scholar
8. González-Martín, A, Pothuri, B, Vergote, I, DePont Christensen, R, Graybill, W, Mirza, MR, et al.. Niraparib in patients with newly diagnosed advanced ovarian cancer. N Engl J Med 2019;381:2391–402. https://doi.org/10.1056/nejmoa1910962.Search in Google Scholar
9. Wimberger, P, Wehling, M, Lehmann, N, Kimmig, R, Schmalfeldt, B, Burges, A, et al.. Influence of residual tumor on outcome in ovarian cancer patients with FIGO stage IV disease. Ann Surg Oncol 2010;17:1642–8. https://doi.org/10.1245/s10434-010-0964-9.Search in Google Scholar
10. Moore, K, Colombo, N, Scambia, G, Kim, BG, Oaknin, A, Friedlander, M, et al.. Maintenance olaparib in patients with newly diagnosed advanced ovarian cancer. N Engl J Med 2018;379:2495–505. https://doi.org/10.1056/nejmoa1810858.Search in Google Scholar
11. Klotz, DM, Wimberger, P. Overcoming PARP inhibitor resistance in ovarian cancer: what are the most promising strategies? Arch Gynecol Obstet 2020;302:1087–102. https://doi.org/10.1007/s00404-020-05677-1.Search in Google Scholar
12. Oliveira, L, Horvat, N, Andrieu, PIC, Panizza, PSB, Cerri, GG, Viana, PCC. Ovarian cancer staging: what the surgeon needs to know. Br J Radiol 2021;94:20210091. https://doi.org/10.1259/bjr.20210091.Search in Google Scholar
13. Glinka, A, Wu, W, Delius, H, Monaghan, AP, Blumenstock, C, Niehrs, C. Dickkopf-1 is a member of a new family of secreted proteins and functions in head induction. Nature 1998;391:357–62. https://doi.org/10.1038/34848.Search in Google Scholar
14. Baron, R, Kneissel, M. WNT signaling in bone homeostasis and disease : from human mutations to treatments. Nat Med 2013;19:179–92. https://doi.org/10.1038/nm.3074.Search in Google Scholar
15. Tian, E, Zhan, F, Walker, R, Rasmussen, E, Ma, Y, Barlogie, B, et al.. The role of the Wnt-signalling antagonist DKK1 in the development of osteolytic lesions in multiple myeloma. N Engl J Med 2003;349:2438–94. https://doi.org/10.1056/NEJMoa030847.Search in Google Scholar
16. Hall, CL, Daignault, SD, Shah, RB, Pienta, KJ, Keller, ET. Dickkopf-1 expression increases early in prostate cancer development and decreases during progression from primary tumor to metastasis. Prostate 2008;68:1396–404. https://doi.org/10.1002/pros.20805.Search in Google Scholar
17. Qin, W, Xu, W-H, Shao, Z-M, Yang, C, Liu, Z-B. Expression of Dickkopf-1 and beta-catenin related to the prognosis of breast cancer patients with triple negative phenotype. PLoS One 2012;7:e37624. https://doi.org/10.1371/journal.pone.0037624.Search in Google Scholar
18. Voorzanger-Rousselot, N, Goehrig, D, Journe, F, Doriath, V, Body, JJ, Clézardin, P, et al.. Increased Dickkopf-1 expression in breast cancer bone metastases. Br J Cancer 2007;97:964–70. https://doi.org/10.1038/sj.bjc.6603959.Search in Google Scholar
19. Voorzanger-Rousselot, N, Journe, F, Doriath, V, Body, JJ, Garnero, P. Assessment of circulating Dickkopf-1 with a new two-site immunoassay in healthy subjects and women with breast cancer and bone metastases. Calcif Tissue Int 2009;84:348–54. https://doi.org/10.1007/s00223-009-9225-y.Search in Google Scholar
20. Jaschke, N, Hofbauer, LC, Göbel, A, Rachner, TD. Evolving functions of Dickkopf-1 in cancer and immunity. Cancer Lett 2020;482:1–7. https://doi.org/10.1016/j.canlet.2020.03.031.Search in Google Scholar
21. Choi, SH, Kim, H, Lee, HG, Kim, BK, Park, JY, Kim, DY, et al.. Dickkopf-1 induces angiogenesis via VEGF receptor 2 regulation independent of the Wnt signaling pathway. Oncotarget 2017;8:58974–84. https://doi.org/10.18632/oncotarget.19769.Search in Google Scholar
22. Krause, U, Ryan, DM, Clough, BH, Gregory, CA. An unexpected role for a Wnt-inhibitor: Dickkopf-1 triggers a novel cancer survival mechanism through modulation of aldehyde-dehydrogenase-1 activity. Cell Death Dis 2014;5:e1093. https://doi.org/10.1038/cddis.2014.67.Search in Google Scholar
23. Hall, CL, Zhang, H, Baile, S, Ljungman, M, Kuhstoss, S, Keller, ET. p21CIP-1/WAF-1 induction is required to inhibit prostate cancer growth elicited by deficient expression of the Wnt inhibitor Dickkopf-1. Cancer Res 2010;70:9916–26. https://doi.org/10.1158/0008-5472.can-10-0440.Search in Google Scholar
24. Haas, MS, Kagey, MH, Heath, H, Schuerpf, F, Newman, W, Rottman, JB. mDKN-01, a novel anti-DKK1 monoclonal antibody, enhances innate immune responses in the tumor microenvironment. Mol Cancer Res 2020;19:717–25. https://doi.org/10.1158/1541-7786.MCR-20-0799.Search in Google Scholar
25. Goldstein, SD, Trucco, M, Guzman, WB, Hayashi, M, Loeb, DM. A monoclonal antibody against the Wnt signaling inhibitor Dickkopf-1 inhibits osteosarcoma metastasis in a preclinical model. Oncotarget 2016;7:21114–23. https://doi.org/10.18632/oncotarget.8522.Search in Google Scholar
26. Huang, J, Lu, T, Kuang, W. Prognostic role of Dickkopf-1 in patients with cancer. Medicine (Baltim) 2020;99:e20388. https://doi.org/10.1097/md.0000000000020388.Search in Google Scholar
27. Zhou, SJ, Zhuo, SR, Yang, XQ, Qin, CX, Wang, ZL. Serum Dickkopf-1 expression level positively correlates with a poor prognosis in breast cancer. Diagn Pathol 2014;9:161–4. https://doi.org/10.1186/s13000-014-0161-4.Search in Google Scholar
28. Rachner, TD, Thiele, S, Göbel, A, Browne, A, Fuessel, S, Erdmann, K, et al.. High serum levels of Dickkopf-1 are associated with a poor prognosis in prostate cancer patients. BMC Cancer 2014;14:649. https://doi.org/10.1186/1471-2407-14-649.Search in Google Scholar
29. Kaiser, M, Mieth, M, Liebisch, P, Oberländer, R, Rademacher, J, Jakob, C, et al.. Serum concentrations of DKK-1 correlate with the extent of bone disease in patients with multiple myeloma. Eur J Haematol 2008;80:490–4. https://doi.org/10.1111/j.1600-0609.2008.01065.x.Search in Google Scholar
30. Heath, DJ, Chantry, AD, Buckle, CH, Coulton, L, Shaughnessy, JD, Evans, HR, et al.. Inhibiting Dickkopf-1 (Dkkl) removes suppression of bone formation and prevents the development of osteolytic bone disease in multiple myeloma. J Bone Miner Res 2009;24:425–36. https://doi.org/10.1359/jbmr.081104.Search in Google Scholar
31. Fulciniti, M, Tassone, P, Hideshima, T, Vallet, S, Nanjappa, P, Ettenberg, SA, et al.. Anti-DKK1 mAb (BHQ880) as a potential therapeutic agent for multiple myeloma. Blood 2009;114:371–9. https://doi.org/10.1182/blood-2008-11-191577.Search in Google Scholar
32. Zhang, C, Guo, X, Peltzer, K, Ma, W, Qi, L, Zhang, Y, et al.. The prevalence, associated factors for bone metastases development and prognosis in newly diagnosed ovarian cancer: a large population based real-world study. J Cancer 2019;10:3133–9. https://doi.org/10.7150/jca.30335.Search in Google Scholar
33. FIGO Committee on Gynecologic Oncology. Current FIGO staging for cancer of the vagina, fallopian tube, ovary, and gestational trophoblastic neoplasia. Int J Gynecol Obstet 2009;105:3–4. https://doi.org/10.1016/j.ijgo.2008.12.015.Search in Google Scholar
34. Prat, J, FIGO Committee on Gynecologic Oncology. Staging classification for cancer of the ovary, fallopian tube, and peritoneum. Int J Gynecol Obstet 2014;124:1–5. https://doi.org/10.1016/j.ijgo.2013.10.001.Search in Google Scholar
35. Harter, P, Hauke, J, Heitz, F, Reuss, A, Kommoss, S, Marmé, F, et al.. Prevalence of deleterious germline variants in risk genes including BRCA1/2 in consecutive ovarian cancer patients (AGO-TR-1). Galli A, editor. PLoS One 2017;12:e0186043. https://doi.org/10.1371/journal.pone.0186043.Search in Google Scholar
36. Kast, K, Rhiem, K, Wappenschmidt, B, Hahnen, E, Hauke, J, Bluemcke, B, et al.. Prevalence of BRCA1/2 germline mutations in 21 401 families with breast and ovarian cancer. J Med Genet 2016;53:465–71. https://doi.org/10.1136/jmedgenet-2015-103672.Search in Google Scholar
37. Link, T, Passek, S, Wimberger, P, Frank, K, Vassileva, YD, Kramer, M, et al.. Serum calretinin as an independent predictor for platinum resistance and prognosis in ovarian cancer. Int J Cancer 2020;146:2608–18. https://doi.org/10.1002/ijc.32676.Search in Google Scholar
38. Link, T, Kuhlmann, JD, Kobelt, D, Herrmann, P, Vassileva, YD, Kramer, M, et al.. Clinical relevance of circulating MACC1 and S100A4 transcripts for ovarian cancer. Mol Oncol 2019;13:1268–79. https://doi.org/10.1002/1878-0261.12484.Search in Google Scholar
39. Shizhuo, W, Tao, J, Shulan, Z, Bing, Z. The expression and significance of Dickkopf-1 in epithelial ovarian carcinoma. Int J Biol Markers 2009;24:165–70. https://doi.org/10.1177/172460080902400306.Search in Google Scholar
40. Wang, S, Zhang, S. Dickkopf-1 is frequently overexpressed in ovarian serous carcinoma and involved in tumor invasion. Clin Exp Metastasis 2011;28:581–91. https://doi.org/10.1007/s10585-011-9393-9.Search in Google Scholar
41. Zhang, R, Lin, HM, Broering, R, Shi, XD, Yu, XH, Xu, LB, et al.. Dickkopf-1 contributes to hepatocellular carcinoma tumorigenesis by activating the wnt/β-catenin signaling pathway. Signal Transduct Targeted Ther 2019;4:1–10. https://doi.org/10.1038/s41392-019-0082-5.Search in Google Scholar
42. Zhu, G, Song, J, Chen, W, Yuan, D, Wang, W, Chen, X, et al.. Expression and role of Dickkopf-1 (Dkk1) in tumors: from the cells to the patients. Cancer Manag Res 2021;13:659–75. https://doi.org/10.2147/cmar.s275172.Search in Google Scholar
43. Rachner, TD, Göbel, A, Benad-Mehner, P, Hofbauer, LC, Rauner, M. Dickkopf-1 as a mediator and novel target in malignant bone disease. Cancer Lett 2014;346:172–7. https://doi.org/10.1016/j.canlet.2014.01.010.Search in Google Scholar
44. D’Amico, L, Mahajan, S, Capietto, A-HH, Yang, Z, Zamani, A, Ricci, B, et al.. Dickkopf-related protein 1 (Dkk1) regulates the accumulation and function of myeloid derived suppressor cells in cancer. J Exp Med 2016;213:827–40. https://doi.org/10.1084/jem.20150950.Search in Google Scholar
45. Smadja, DM, d’Audigier, C, Weiswald, LB, Badoual, C, Dangles-Marie, V, Mauge, L, et al.. The Wnt antagonist Dickkopf-1 increases endothelial progenitor cell angiogenic potential. Arterioscler Thromb Vasc Biol 2010;30:2544–52. https://doi.org/10.1161/atvbaha.110.213751.Search in Google Scholar
46. Baert, T, Vankerckhoven, A, Riva, M, Van Hoylandt, A, Thirion, G, Holger, G, et al.. Myeloid derived suppressor cells: key drivers of immunosuppression in ovarian cancer. Front Immunol 2019;10:1273. https://doi.org/10.3389/fimmu.2019.01273.Search in Google Scholar
47. Salim, H, Zong, D, Haag, P, Novak, M, Mork, B, Lewensohn, R, et al.. DKK1 is a potential novel mediator of cisplatin-refractoriness in non-small cell lung cancer cell lines. BMC Cancer 2015;15:628. https://doi.org/10.1186/s12885-015-1635-9.Search in Google Scholar
Supplementary Material
The online version of this article offers supplementary material (https://doi.org/10.1515/cclm-2021-0504).
© 2021 Walter de Gruyter GmbH, Berlin/Boston
