RANK-RANKL Signaling in Cancer of the Uterine Cervix: A Review

• Published in: International journal of molecular sciences Vol. 20; no. 9; p. 2183
• Main Authors: van Dam, Peter A, Verhoeven, Yannick, Jacobs, Julie, Wouters, An, Tjalma, Wiebren, Lardon, Filip, Van den Wyngaert, Tim, Dewulf, Jonatan, Smits, Evelien, Colpaert, Cécile, Prenen, Hans, Peeters, Marc, Lammens, Martin, Trinh, Xuan Bich
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 02-05-2019; MDPI
• Subjects: Activation; Activator protein 1; Adaptor proteins; AKT protein; Apolipoprotein B; Apoptosis; Aspartic acid; c-Jun protein; Carcinogenesis; Carcinogens; Cdc4 protein; Cell cycle; Cervical cancer; checkpoint inhibition; Chemotherapy; Chromatin; Cytokines; Deregulation; Disease; ErbB-3 protein; Estrogens; Fibroblast growth factor receptor 1; Fibroblast growth factor receptor 3; Fibroblast growth factor receptors; Forkhead protein; Growth factors; Homology; Human papillomavirus; Hypoxia-inducible factor 1; immunotherapy; Keratin; Kinases; Ligands; Medical prognosis; microenvironment; mRNA; Mutagenesis; Mutation; Patients; Polypeptides; Proteins; Radiation therapy; RANK; RANKL; Review; Sarcoma; Signal transduction; Squamous cell carcinoma; Transcription factors; Tumor necrosis factor-TNF; Uterus; microenvironment; RANKL; RANK; cervical cancer; checkpoint inhibition; immunotherapy
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms20092183

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.