{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,28]],"date-time":"2026-08-28T12:44:45Z","timestamp":1787921085852,"version":"build-2784847793"},"reference-count":93,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2019,5,2]],"date-time":"2019-05-02T00:00:00Z","timestamp":1556755200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>RANK ligand (RANKL) is a member of the tumor necrosis factor alpha superfamily of cytokines. It is the only known ligand binding to a membrane receptor named receptor activator of nuclear factor-kappa B (RANK), thereby triggering recruitment of tumor necrosis factor (TNF) receptor associated factor (TRAF) adaptor proteins and activation of downstream pathways. RANK\/RANKL signaling is controlled by a decoy receptor called osteoprotegerin (OPG), but also has additional more complex levels of regulation. The existing literature on RANK\/RANKL signaling in cervical cancer was reviewed, particularly focusing on the effects on the microenvironment. RANKL and RANK are frequently co-expressed in cervical cancer cells lines and in carcinoma of the uterine cervix. RANKL and OPG expression strongly increases during cervical cancer progression. RANKL is directly secreted by cervical cancer cells, which may be a mechanism they use to create an immune suppressive environment. RANKL induces expression of multiple activating cytokines by dendritic cells. High RANK mRNA levels and high immunohistochemical OPG expression are significantly correlated with high clinical stage, tumor grade, presence of lymph node metastases, and poor overall survival. Inhibition of RANKL signaling has a direct effect on tumor cell proliferation and behavior, but also alters the microenvironment. Abundant circumstantial evidence suggests that RANKL inhibition may (partially) reverse an immunosuppressive status. The use of denosumab, a monoclonal antibody directed to RANKL, as an immunomodulatory strategy is an attractive concept which should be further explored in combination with immune therapy in patients with cervical cancer.<\/jats:p>","DOI":"10.3390\/ijms20092183","type":"journal-article","created":{"date-parts":[[2019,5,7]],"date-time":"2019-05-07T03:15:46Z","timestamp":1557198946000},"page":"2183","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":29,"title":["RANK-RANKL Signaling in Cancer of the Uterine Cervix: A Review"],"prefix":"10.3390","volume":"20","author":[{"given":"Peter A.","family":"van Dam","sequence":"first","affiliation":[{"name":"Multidisciplinary Oncologic Center Antwerp (MOCA), Antwerp University Hospital, B2650 Edegem, Belgium"},{"name":"Center for Oncological Research (CORE), University of Antwerp, B2610 Wilrijk, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yannick","family":"Verhoeven","sequence":"additional","affiliation":[{"name":"Multidisciplinary Oncologic Center Antwerp (MOCA), Antwerp University Hospital, B2650 Edegem, Belgium"},{"name":"Center for Oncological Research (CORE), University of Antwerp, B2610 Wilrijk, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2873-3364","authenticated-orcid":false,"given":"Julie","family":"Jacobs","sequence":"additional","affiliation":[{"name":"Center for Oncological Research (CORE), University of Antwerp, B2610 Wilrijk, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7771-1239","authenticated-orcid":false,"given":"An","family":"Wouters","sequence":"additional","affiliation":[{"name":"Center for Oncological Research (CORE), University of Antwerp, B2610 Wilrijk, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wiebren","family":"Tjalma","sequence":"additional","affiliation":[{"name":"Multidisciplinary Oncologic Center Antwerp (MOCA), Antwerp University Hospital, B2650 Edegem, Belgium"},{"name":"Center for Oncological Research (CORE), University of Antwerp, B2610 Wilrijk, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Filip","family":"Lardon","sequence":"additional","affiliation":[{"name":"Center for Oncological Research (CORE), University of Antwerp, B2610 Wilrijk, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tim","family":"Van den Wyngaert","sequence":"additional","affiliation":[{"name":"Center for Oncological Research (CORE), University of Antwerp, B2610 Wilrijk, Belgium"},{"name":"Department of Nuclear Medicine, Antwerp University Hospital, B2650 Edegem, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0697-7667","authenticated-orcid":false,"given":"Jonatan","family":"Dewulf","sequence":"additional","affiliation":[{"name":"Center for Oncological Research (CORE), University of Antwerp, B2610 Wilrijk, Belgium"},{"name":"Department of Nuclear Medicine, Antwerp University Hospital, B2650 Edegem, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9255-3435","authenticated-orcid":false,"given":"Evelien","family":"Smits","sequence":"additional","affiliation":[{"name":"Center for Oncological Research (CORE), University of Antwerp, B2610 Wilrijk, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C\u00e9cile","family":"Colpaert","sequence":"additional","affiliation":[{"name":"Multidisciplinary Oncologic Center Antwerp (MOCA), Antwerp University Hospital, B2650 Edegem, Belgium"},{"name":"Department of Histopathology, Antwerp University Hospital, B2650 Edegem, Belgium"},{"name":"Department of Histopathology, Gasthuiszusters Antwerpen (GZA) Hospitals, B2610 Wilrijk, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8802-7352","authenticated-orcid":false,"given":"Hans","family":"Prenen","sequence":"additional","affiliation":[{"name":"Multidisciplinary Oncologic Center Antwerp (MOCA), Antwerp University Hospital, B2650 Edegem, Belgium"},{"name":"Center for Oncological Research (CORE), University of Antwerp, B2610 Wilrijk, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marc","family":"Peeters","sequence":"additional","affiliation":[{"name":"Multidisciplinary Oncologic Center Antwerp (MOCA), Antwerp University Hospital, B2650 Edegem, Belgium"},{"name":"Center for Oncological Research (CORE), University of Antwerp, B2610 Wilrijk, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3881-6692","authenticated-orcid":false,"given":"Martin","family":"Lammens","sequence":"additional","affiliation":[{"name":"Multidisciplinary Oncologic Center Antwerp (MOCA), Antwerp University Hospital, B2650 Edegem, Belgium"},{"name":"Department of Histopathology, Antwerp University Hospital, B2650 Edegem, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuan Bich","family":"Trinh","sequence":"additional","affiliation":[{"name":"Multidisciplinary Oncologic Center Antwerp (MOCA), Antwerp University Hospital, B2650 Edegem, Belgium"},{"name":"Center for Oncological Research (CORE), University of Antwerp, B2610 Wilrijk, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2019,5,2]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"87","DOI":"10.3322\/caac.21262","article-title":"Global cancer statistics 2012","volume":"65","author":"Torre","year":"2015","journal-title":"CA Cancer J. 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