O eixo RANK-RANKL no câncer de pênis: associações com o HPV e com a invasão tumoral e perspectivas para terapias anti-RANKL
DOI:
https://doi.org/10.11606/issn.2176-7262.rmrp.2025.227715Palavras-chave:
Imunoterapia, Estadiamento tumoral, Câncer de pênis, Microambiente tumoralResumo
Objetivos- A sinalização mediada pelo receptor ativador do fator nuclear kappa B (RANK) depende do seu ligante (RANKL). A sobre-expressão de RANKL está associada com mau prognóstico em tumores sólidos, nomeadamente em tumores induzidos pelo papilomavírus humano (HPV). Neste contexto, os fármacos anti-RANKL podem aumentar a eficácia de imunoterapias, se usados em combinação. Este trabalho testou a hipótese de que os níveis de expressão de RANK/RANKL estão associados com a presença de HPV e com o comportamento biológico do câncer de pênis, uma neoplasia rara com subtipos HPV-positivos e HPV-negativos. Métodos-Foram analisados os prontuários médicos, bem como amostras congeladas de tecidos tumorais e peritumorais de pacientes de câncer de pênis. As amostras tumorais foram usadas para detectar DNA de HPV usando PCR neste. Os níveis de expressão de RANK, RANKL e do seu receptor decoy osteoprotegerina (OPG) foram estudados nas amostras tumorais e peritumorais por PCR em tempo real. Resultados- Oitenta e seis por cento dos casos apresentaram DNA de HPV. Os casos HPV-positivos e HPV-negativos tiveram níveis semelhantes de RANK, RANKL e OPG. A expressão de RANK esteve aumentada em casos com invasão linfovascular (p=0,027) e, pelo contrário, esteve diminuída em casos com invasão perineural (p=0,006). Conclusões- Estes resultados indicam que o HPV não é um fator regulador do eixo RANK/RANKL/OPG no câncer de pênis. Os níveis de expressão de RANK podem permitir definir subgrupos de pacientes nos quais a invasão tumoral ocorre preferencialmente por invasão linfovascular e que podem beneficiar de terapias anti-RANKL. Estudos adicionais são necessários para esclarecer o papel desta via de sinalização no câncer de pênis e as suas implicações prognósticas e terapêuticas.
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1 Wong BR, Josien R, Lee SY, Sauter B, Li HL, Steinman RM, Choi Y. TRANCE (tumor necrosis factor [TNF]-related activation-induced cytokine), a new TNF family member predominantly expressed in T cells, is a dendritic cell-specific survival factor. J Exp Med. 1997 Dec 15;186(12):2075-80. doi: 10.1084/jem.186.12.2075.
2 Ikeda T, Kasai M, Utsuyama M, Hirokawa K. Determination of three isoforms of the receptor activator of nuclear factor-kappaB ligand and their differential expression in bone and thymus. Endocrinology. 2001 Apr;142(4):1419-26. doi: 10.1210/endo.142.4.8070.
3 González-Suárez E, Sanz-Moreno A. RANK as a therapeutic target in cancer. FEBS J. 2016 Jun;283(11):2018-33. doi: 10.1111/febs.13645.
4 Schneeweis LA, Willard D, Milla ME. Functional dissection of osteoprotegerin and its interaction with receptor activator of NF-kappaB ligand. J Biol Chem. 2005 Dec 16;280(50):41155-64. doi: 10.1074/jbc.M506366200.
5 Luo J, Yang Z, Ma Y, Yue Z, Lin H, Qu G, Huang J, Dai W, Li C, Zheng C, Xu L, Chen H, Wang J, Li D, Siwko S, Penninger JM, Ning G, Xiao J, Liu M. LGR4 is a receptor for RANKL and negatively regulates osteoclast differentiation and bone resorption. Nat Med. 2016 May;22(5):539-46. doi: 10.1038/nm.4076.
6 Yue Z, Niu X, Yuan Z, Qin Q, Jiang W, He L, Gao J, Ding Y, Liu Y, Xu Z, Li Z, Yang Z, Li R, Xue X, Gao Y, Yue F, Zhang XH, Hu G, Wang Y, Li Y, Chen G, Siwko S, Gartland A, Wang N, Xiao J, Liu M, Luo J. RSPO2 and RANKL signal through LGR4 to regulate osteoclastic premetastatic niche formation and bone metastasis. J Clin Invest. 2022 Jan 18;132(2):e144579. doi: 10.1172/JCI144579.
7 Gonzalez-Suarez E, Jacob AP, Jones J, Miller R, Roudier-Meyer MP, Erwert R, Pinkas J, Branstetter D, Dougall WC. RANK ligand mediates progestin-induced mammary epithelial proliferation and carcinogenesis. Nature. 2010 Nov 4;468(7320):103-7. doi: 10.1038/nature09495.
8 Park M, Cho YJ, Kim B, Ko YJ, Jang Y, Moon YH, Hyun H, Lim W. RANKL immunisation inhibits prostate cancer metastasis by modulating EMT through a RANKL-dependent pathway. Sci Rep. 2021 Jun 9;11(1):12186. doi: 10.1038/s41598-021-91721-2.
9 Shang WQ, Li H, Liu LB, Chang KK, Yu JJ, Xie F, Li MQ, Yu JJ. RANKL/RANK interaction promotes the growth of cervical cancer cells by strengthening the dialogue between cervical cancer cells and regulation of IL-8 secretion. Oncol Rep. 2015 Dec;34(6):3007-16. doi: 10.3892/or.2015.4303.
10 Demoulin SA, Somja J, Duray A, Guénin S, Roncarati P, Delvenne PO, Herfs MF, Hubert PM. Cervical (pre)neoplastic microenvironment promotes the emergence of tolerogenic dendritic cells via RANKL secretion. Oncoimmunology. 2015 Mar 19;4(6):e1008334. doi: 10.1080/2162402X.2015.1008334.
11 Ma D, Chang LY, Zhao S, Zhao JJ, Xiong YJ, Cao FY, Yuan L, Zhang Q, Wang XY, Geng ML, Zheng HY, Li O. KLF5 promotes cervical cancer proliferation, migration and invasion in a manner partly dependent on TNFRSF11a expression. Sci Rep. 2017 Nov 16;7(1):15683. doi: 10.1038/s41598-017-15979-1.
12 van Dam PA, Verhoeven Y, Jacobs J, Wouters A, Tjalma W, Lardon F, Van den Wyngaert T, Dewulf J, Smits E, Colpaert C, Prenen H, Peeters M, Lammens M, Trinh XB. RANK-RANKL Signaling in Cancer of the Uterine Cervix: A Review. Int J Mol Sci. 2019 May 2;20(9):2183. doi: 10.3390/ijms20092183.
13 Moch H, Cubilla AL, Humphrey PA, Reuter VE, Ulbright TM. The 2016 WHO Classification of Tumours of the Urinary System and Male Genital Organs-Part A: Renal, Penile, and Testicular Tumours. Eur Urol. 2016 Jul;70(1):93-105. doi: 10.1016/j.eururo.2016.02.029.
14 Pow-Sang MR, Ferreira U, Pow-Sang JM, Nardi AC, Destefano V. Epidemiology and natural history of penile cancer. Urology. 2010 Aug;76(2 Suppl 1):S2-6. doi: 10.1016/j.urology.2010.03.003.
15 Medeiros-Fonseca B, Mestre VF, Estêvão D, Sánchez DF, Cañete-Portillo S, Fernández-Nestosa MJ, Casaca F, Silva S, Brito H, Félix A, Medeiros R, Colaço B, Oliveira PA, Bastos MM, Nelson PS, Vakar-Lopez F, Gaivão I, Brito L, Lopes C, Cubilla AL, Gil da Costa RM. HPV16 induces penile intraepithelial neoplasia and squamous cell carcinoma in transgenic mice: first mouse model for HPV-related penile cancer. J Pathol. 2020 Aug;251(4):411-419. doi: 10.1002/path.5475.
16 Alemany L, Cubilla A, Halec G, Kasamatsu E, Quirós B, Masferrer E, Tous S, Lloveras B, Hernández-Suarez G, Lonsdale R, Tinoco L, Alejo M, Alvarado-Cabrero I, Laco J, Guimerà N, Poblet E, Lombardi LE, Bergeron C, Clavero O, Shin HR, Ferrera A, Felix A, Germar J, Mandys V, Clavel C, Tzardi M, Pons LE, Wain V, Cruz E, Molina C, Mota JD, Jach R, Velasco J, Carrilho C, López-Revilla R, Goodman MT, Quint WG, Castellsagué X, Bravo I, Pawlita M, Muñoz N, Bosch FX, de Sanjosé S; HPV VVAP study group. Role of Human Papillomavirus in Penile Carcinomas Worldwide. Eur Urol. 2016 May;69(5):953-61. doi: 10.1016/j.eururo.2015.12.007.
17 Olesen TB, Sand FL, Rasmussen CL, Albieri V, Toft BG, Norrild B, Munk C, Kjær SK. Prevalence of human papillomavirus DNA and p16INK4a in penile cancer and penile intraepithelial neoplasia: a systematic review and meta-analysis. Lancet Oncol. 2019 Jan;20(1):145-158. doi: 10.1016/S1470-2045(18)30682-X.
18 Labrecque MP, Coleman IM, Brown LG, True LD, Kollath L, Lakely B, Nguyen HM, Yang YC, da Costa RMG, Kaipainen A, Coleman R, Higano CS, Yu EY, Cheng HH, Mostaghel EA, Montgomery B, Schweizer MT, Hsieh AC, Lin DW, Corey E, Nelson PS, Morrissey C. Molecular profiling stratifies diverse phenotypes of treatment-refractory metastatic castration-resistant prostate cancer. J Clin Invest. 2019 Jul 30;129(10):4492-4505. doi: 10.1172/JCI128212.
19 Alifrangis C, McGovern U, Freeman A, Powles T, Linch M. Molecular and histopathology directed therapy for advanced bladder cancer. Nat Rev Urol. 2019 Aug;16(8):465-483. doi: 10.1038/s41585-019-0208-0.
20 DeLucia DC, Cardillo TM, Ang L, Labrecque MP, Zhang A, Hopkins JE, De Sarkar N, Coleman I, da Costa RMG, Corey E, True LD, Haffner MC, Schweizer MT, Morrissey C, Nelson PS, Lee JK. Regulation of CEACAM5 and Therapeutic Efficacy of an Anti-CEACAM5-SN38 Antibody-drug Conjugate in Neuroendocrine Prostate Cancer. Clin Cancer Res. 2021 Feb 1;27(3):759-774. doi: 10.1158/1078-0432.CCR-20-3396.
21 Necchi A, de Jong JJ, Raggi D, Briganti A, Marandino L, Gallina A, Bandini M, Dabbas B, Davicioni E, Capitanio U, Montorsi F, Seiler R, Wright JL, Lotan Y, Black PC, Gibb EA. Molecular Characterization of Residual Bladder Cancer after Neoadjuvant Pembrolizumab. Eur Urol. 2021 Aug;80(2):149-159. doi: 10.1016/j.eururo.2021.03.014.
22 Wang K, Gu Y, Liao Y, Bang S, Donnelly CR, Chen O, Tao X, Mirando AJ, Hilton MJ, Ji RR. PD-1 blockade inhibits osteoclast formation and murine bone cancer pain. J Clin Invest. 2020 Jul 1;130(7):3603-3620. doi: 10.1172/JCI133334.
23 Song X, Wei C, Li X. The Signaling Pathways Associated With Breast Cancer Bone Metastasis. Front Oncol. 2022 Mar 10;12:855609. doi: 10.3389/fonc.2022.855609.
24 Tang ZN, Bi XF, Chen WL, Zhang CL. RANKL Promotes Chemotherapy Resistance in Breast Cancer Cells Through STAT3 Mediated Autophagy Induction. Clin Breast Cancer. 2023 Jun;23(4):388-396. doi: 10.1016/j.clbc.2023.01.014.
25 Simatou A, Sarantis P, Koustas E, Papavassiliou AG, Karamouzis MV. The Role of the RANKL/RANK Axis in the Prevention and Treatment of Breast Cancer with Immune Checkpoint Inhibitors and Anti-RANKL. Int J Mol Sci. 2020 Oct 14;21(20):7570. doi: 10.3390/ijms21207570.
26 Armando F, Mecocci S, Orlandi V, Porcellato I, Cappelli K, Mechelli L, Brachelente C, Pepe M, Gialletti R, Ghelardi A, Passeri B, Razzuoli E. Investigation of the Epithelial to Mesenchymal Transition (EMT) Process in Equine Papillomavirus-2 (EcPV-2)-Positive Penile Squamous Cell Carcinomas. Int J Mol Sci. 2021 Sep 30;22(19):10588. doi: 10.3390/ijms221910588.
27 Aydin AM, Chahoud J, Adashek JJ, Azizi M, Magliocco A, Ross JS, Necchi A, Spiess PE. Understanding genomics and the immune environment of penile cancer to improve therapy. Nat Rev Urol. 2020 Oct;17(10):555-570. doi: 10.1038/s41585-020-0359-z.
28 de Sousa ID, Vidal FC, Branco Vidal JP, de Mello GC, do Desterro Soares Brandão Nascimento M, Brito LM. Prevalence of human papillomavirus in penile malignant tumors: viral genotyping and clinical aspects. BMC Urol. 2015 Feb 24;15(1):13. doi: 10.1186/s12894-015-0007-8.
29 Gil da Costa RM, Medeiros R. Bovine papillomavirus: opening new trends for comparative pathology. Arch Virol. 2014 Feb;159(2):191-8. doi: 10.1007/s00705-013-1801-9.
30 Arbeit JM, Howley PM, Hanahan D. Chronic estrogen-induced cervical and vaginal squamous carcinogenesis in human papillomavirus type 16 transgenic mice. Proc Natl Acad Sci U S A. 1996 Apr 2;93(7):2930-5. doi: 10.1073/pnas.93.7.2930.
31 Stelzer MK, Pitot HC, Liem A, Schweizer J, Mahoney C, Lambert PF. A mouse model for human anal cancer. Cancer Prev Res (Phila). 2010 Dec;3(12):1534-41. doi: 10.1158/1940-6207.CAPR-10-0086.
32 Medeiros-Fonseca B, Cubilla A, Brito H, Martins T, Medeiros R, Oliveira P, Gil da Costa RM. Experimental Models for Studying HPV-Positive and HPV-Negative Penile Cancer: New Tools for An Old Disease. Cancers (Basel). 2021 Jan 26;13(3):460. doi: 10.3390/cancers13030460.
33 de Martel C, Plummer M, Vignat J, Franceschi S. Worldwide burden of cancer attributable to HPV by site, country and HPV type. Int J Cancer. 2017 Aug 15;141(4):664-670. doi: 10.1002/ijc.30716.
34 Estêvão D, Costa NR, Gil da Costa RM, Medeiros R. Hallmarks of HPV carcinogenesis: The role of E6, E7 and E5 oncoproteins in cellular malignancy. Biochim Biophys Acta Gene Regul Mech. 2019 Feb;1862(2):153-162. doi: 10.1016/j.bbagrm.2019.01.001.
35 Brouwer AF, Campredon LP, Walline HM, Marinelli BM, Goudsmit CM, Thomas TB, Delinger RL, Lau YK, Andrus EC, Nair T, Carey TE, Eisenberg MC, Meza R. Incidence and clearance of oral and cervicogenital HPV infection: longitudinal analysis of the MHOC cohort study. BMJ Open. 2022 Jan 3;12(1):e056502. doi: 10.1136/bmjopen-2021-056502.
36 Santos C, Neto T, Ferreirinha P, Sousa H, Ribeiro J, Bastos MMSM, Faustino-Rocha AI, Oliveira PA, Medeiros R, Vilanova M, da Costa RMG. Celecoxib promotes degranulation of CD8(+) T cells in HPV-induced lesions of K14-HPV16 transgenic mice. Life Sci. 2016 Jul 15;157:67-73. doi: 10.1016/j.lfs.2016.05.040.
37 Moch H, Amin MB, Berney DM, Compérat EM, Gill AJ, Hartmann A, Menon S, Raspollini MR, Rubin MA, Srigley JR, Hoon Tan P, Tickoo SK, Tsuzuki T, Turajlic S, Cree I, Netto GJ. The 2022 World Health Organization Classification of Tumours of the Urinary System and Male Genital Organs-Part A: Renal, Penile, and Testicular Tumours. Eur Urol. 2022 Nov;82(5):458-468. doi: 10.1016/j.eururo.2022.06.016.
38 Sanchez DF, Fernandez-Nestosa MJ, Canete-Portillo S, Rodriguez I, Cubilla AL. What Is New in the Pathologic Staging of Penile Carcinoma in the 8th Edition of AJCC TNM Model: Rationale for Changes With Practical Stage-by-stage Category Diagnostic Considerations. Adv Anat Pathol. 2021 Jul 1;28(4):209-227. doi: 10.1097/PAP.0000000000000297.
39 Pecoraro A, Elst L, Roussel E, Miletić M, Vanthoor J, De Ridder D, Van Rompuy AS, De Cuyper E, Dumez H, De Meerleer G, de Wever L, Goffin K, Van Poppel H, Joniau S, Albersen M. Impact of the Standardization of Penile Cancer Care on the Quality of Care, Outcomes, and Academic-driven Centralization in a Single eUROGEN Referral Center. Eur Urol Focus. 2023 Aug 1:S2405-4569(23)00175-X. doi: 10.1016/j.euf.2023.07.003.
40 Silva LLD, Teles AM, Santos JMO, Souza de Andrade M, Medeiros R, Faustino-Rocha AI, Oliveira PA, Dos Santos APA, Ferreira Lopes F, Braz G, Brito HO, Costa RMGD. Malignancy Associated with Low-Risk HPV6 and HPV11: A Systematic Review and Implications for Cancer Prevention. Cancers (Basel). 2023 Aug 11;15(16):4068. doi: 10.3390/cancers15164068.
41 Zhang Q, Guo R, Lu Y, Zhao L, Zhou Q, Schwarz EM, Huang J, Chen D, Jin ZG, Boyce BF, Xing L. VEGF-C, a lymphatic growth factor, is a RANKL target gene in osteoclasts that enhances osteoclastic bone resorption through an autocrine mechanism. J Biol Chem. 2008 May 9;283(19):13491-9. doi: 10.1074/jbc.M708055200.
42 Hatano Y, Nakahama K, Isobe M, Morita I. Tumor associated osteoclast-like giant cells promote tumor growth and lymphangiogenesis by secreting vascular endothelial growth factor-C. Biochem Biophys Res Commun. 2014 Mar 28;446(1):149-54. doi: 10.1016/j.bbrc.2014.02.113.
43 Yoneda T, Hiasa M, Okui T, Hata K. Sensory nerves: A driver of the vicious cycle in bone metastasis? J Bone Oncol. 2021 Aug 25;30:100387. doi: 10.1016/j.jbo.2021.100387.
44 Coleman RE, Croucher PI, Padhani AR, Clézardin P, Chow E, Fallon M, Guise T, Colangeli S, Capanna R, Costa L. Bone metastases. Nat Rev Dis Primers. 2020 Oct 15;6(1):83. doi: 10.1038/s41572-020-00216-3.
45 Stopeck AT, Lipton A, Body JJ, Steger GG, Tonkin K, de Boer RH, Lichinitser M, Fujiwara Y, Yardley DA, Viniegra M, Fan M, Jiang Q, Dansey R, Jun S, Braun A. Denosumab compared with zoledronic acid for the treatment of bone metastases in patients with advanced breast cancer: a randomized, double-blind study. J Clin Oncol. 2010 Dec 10;28(35):5132-9. doi: 10.1200/JCO.2010.29.7101.
46 Fizazi K, Carducci M, Smith M, Damião R, Brown J, Karsh L, Milecki P, Shore N, Rader M, Wang H, Jiang Q, Tadros S, Dansey R, Goessl C. Denosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer: a randomised, double-blind study. Lancet. 2011 Mar 5;377(9768):813-22. doi: 10.1016/S0140-6736(10)62344-6.
47 Raje N, Terpos E, Willenbacher W, Shimizu K, García-Sanz R, Durie B, Legieć W, Krejčí M, Laribi K, Zhu L, Cheng P, Warner D, Roodman GD. Denosumab versus zoledronic acid in bone disease treatment of newly diagnosed multiple myeloma: an international, double-blind, double-dummy, randomised, controlled, phase 3 study. Lancet Oncol. 2018 Mar;19(3):370-381. doi: 10.1016/S1470-2045(18)30072-X.
48 Vanthoor J, Vos G, Albersen M. Penile cancer: potential target for immunotherapy? World J Urol. 2011 May;39(1):1-7. doi: 10.1007/s00345-020-03510-7.
49 de Vries HM, Ottenhof SR, Horenblas S, van der Heijden MS, Jordanova ES. Defining the Tumor Microenvironment of Penile Cancer by Means of the Cancer Immunogram. Eur Urol Focus. 2019 Sep;5(5):718-721. doi: 10.1016/j.euf.2019.02.019.
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Direitos autorais (c) 2026 Jhessica Ivanilde Silva Gomes, Ana Paula de Araújo Abreu, Jucileide Mota Costa, Ana Paula Almeida Cunha, Daniel Ruan Alves Reis, Fabrício Viana Sousa, Elda Pereira Noronha Ávila, Rita da Graça Carvalhal Frazão Correa, José de Ribamar Rodrigues Calixto, Flávia Castello Branco Vidal Cabral, Melaine Mont Alverne Lawall Silva, Rui Gil da Costa, Haissa Oliveira Brito, Luciane Maria Oliveira Brito
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