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The role of toll-like receptors (TLRs) and their therapeutic applications in endometrial cancer

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Abstract

Endometrial cancer (EC) is developed nations' most prevalent form of gynecologic cancer. Patients are frequently diagnosed with EC when the tumor is still limited to the uterus. Patients without tumor metastasis have a 5-year survival rate ranging from 80 to 90%; however, almost 16.8% of EC patients develop a metastatic form of the tumor. In the early stages of tumorigenesis, the immune system is able to identify aberrant cells as non-self, therefore providing the optimal pro-inflammatory microenvironment for the elimination of cancer cells. Although, chronic inflammation can be a crucial aspect of tumor development. Toll-like receptors (TLRs), as the main pattern recognition receptors (PRRs) in innate immunity, may stimulate an inflammatory response and provide cell survival in the tumor microenvironment (TME). TLRs are vital immunomodulators that may significantly impact the development of gynecologic malignancies. Therefore, TLR inhibitors are being researched for their possible benefits in treating gynecologic cancers. The aim of this study is to review the current knowledge in this field and provide some insight into the therapeutic potential of TLR inhibitors in EC.

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References

  1. Scott OW, Tin ST, Bigby SM, Elwood JM. Rapid increase in endometrial cancer incidence and ethnic differences in New Zealand. Cancer Causes Control. 2019;30(2):121–7.

    Article  PubMed  Google Scholar 

  2. McDonald ME, Bender DP. Endometrial cancer: obesity, genetics, and targeted agents. Obstet Gynecol Clin. 2019;46(1):89–105.

    Article  Google Scholar 

  3. Amant F, Moerman P, Neven P, Timmerman D, Van Limbergen E, Vergote I. Endometrial cancer. The Lancet. 2005;366(9484):491–505.

    Article  Google Scholar 

  4. Amant F, Mirza MR, Koskas M, Creutzberg CL. Cancer of the corpus uteri. Int J Gynecol Obstet. 2018;143:37–50.

    Article  Google Scholar 

  5. Vanderstraeten A, Tuyaerts S, Amant F. The immune system in the normal endometrium and implications for endometrial cancer development. J Reprod Immunol. 2015;109:7–16.

    Article  CAS  PubMed  Google Scholar 

  6. Guzman-Genuino RM, Diener KR. Regulatory B cells in pregnancy: lessons from autoimmunity, graft tolerance, and cancer. Front Immunol. 2017;8:172.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Pasare C, Medzhitov R. Toll-like receptors: linking innate and adaptive immunity. In: Min H, editor. Mechanisms of lymphocyte activation and immune regulation X. Springer; 2005. p. 11–8.

    Chapter  Google Scholar 

  8. Aluri J, Cooper MA, Schuettpelz LG. Toll-like receptor signaling in the establishment and function of the immune system. Cells. 2021;10(6):1374.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Mokhtari Y, Pourbagheri-Sigaroodi A, Zafari P, Bagheri N, Ghaffari SH, Bashash D. Toll-like receptors (TLRs): an old family of immune receptors with a new face in cancer pathogenesis. J Cell Mol Med. 2021;25(2):639–51.

    Article  CAS  PubMed  Google Scholar 

  10. Angrini M, Varthaman A, Cremer I. Toll-like receptors (TLRs) in the tumor microenvironment (TME): a dragon-like weapon in a non-fantasy game of thrones. In: Tumor microenvironment. Springer; 2020. p. 145–73.

    Chapter  Google Scholar 

  11. Pahlavanneshan S, Sayadmanesh A, Ebrahimiyan H, Basiri M. Toll-Like receptor-based strategies for cancer immunotherapy. J Immunol Res. 2021;2021:1–14.

    Article  Google Scholar 

  12. Ferdeghini M, Gadducci A, Prontera C, Marrai R, Malagnino G, Annicchiarico C, et al. Serum soluble interleukin-2 receptor (sIL-2R) assay in cervical and endometrial cancer. Preliminary data. Anticancer Res. 1993;13(3):709–13.

    CAS  PubMed  Google Scholar 

  13. Siegel RL, Miller KD, Goding Sauer A, Fedewa SA, Butterly LF, Anderson JC, et al. Colorectal cancer statistics, 2020. CA: Cancer J Clin. 2020;70(3):145–64.

    PubMed  Google Scholar 

  14. Morice P, Leary A, Creutzberg C, Abu-Rustum N, Darai E. Endometrial cancer. The Lancet. 2016;387(10023):1094–108.

    Article  Google Scholar 

  15. Obstetricians ACo, Gynecologists. ACOG practice bulletin, clinical management guidelines for obstetrician-gynecologists, number 65, August 2005: management of endometrial cancer. Obstet Gynecol. 2005;106(2):413–25.

    Google Scholar 

  16. Reid-Nicholson M, Iyengar P, Hummer AJ, Linkov I, Asher M, Soslow RA. Immunophenotypic diversity of endometrial adenocarcinomas: implications for differential diagnosis. Mod Pathol. 2006;19(8):1091–100.

    Article  CAS  PubMed  Google Scholar 

  17. Colombo N, Creutzberg C, Amant F, Bosse T, González-Martín A, Ledermann J, et al. ESMO-ESGO-ESTRO consensus conference on endometrial cancer: diagnosis, treatment and follow-up. Int J Gynecol Cancer. 2016;26(1):2–30.

    Article  PubMed  Google Scholar 

  18. Sahin Ekici A, Sahin S, Demir B, Elboga G, Altindag A. A case of catatonia related to infective endocarditis during pregnancy. Psychiatr Danub. 2021;33(4):569–70.

    Article  PubMed  Google Scholar 

  19. Škegro B, Bjedov S, Mikuš M, Mustač F, Lešin J, Matijević V, et al. Endometriosis, pain and mental health. Psychiatr Danub. 2021;33(suppl 4):632–6.

    PubMed  Google Scholar 

  20. Sahoo BR. Structure of fish Toll-like receptors (TLR) and NOD-like receptors (NLR). Int J Biol Macromol. 2020;161:1602–17.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Gao Y, Chen S, Vafaei S, Zhong X. Tumor-infiltrating immune cell signature predicts the prognosis and chemosensitivity of patients with pancreatic ductal adenocarcinoma. Front Oncol. 2020;10: 557638.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Muzio M, Polentarutti N, Bosisio D, Kumar PM, Mantovani A. Toll-like receptor family and signalling pathway. Biochem Soc Trans. 2000;28(5):563–6.

    Article  CAS  PubMed  Google Scholar 

  23. Takeda K, Akira S. Toll-like receptors. Curr Protocols Immunol. 2015. https://doi.org/10.1002/0471142735.im1412s109.

    Article  Google Scholar 

  24. Foster SL, Hargreaves DC, Medzhitov R. Gene-specific control of inflammation by TLR-induced chromatin modifications. Nature. 2007;447(7147):972–8.

    Article  CAS  PubMed  Google Scholar 

  25. Rajabinejad M, Asadi G, Ranjbar S, Varmaziar FR, Karimi M, Salari F, et al. The MALAT1-H19/miR-19b-3p axis can be a fingerprint for diabetic neuropathy. Immunol Lett. 2022;245:69–78.

    Article  CAS  PubMed  Google Scholar 

  26. Jang G-Y, Kim YS, Lee SE, Han HD, Hong K-J, Kang TH, et al. Interactions between tumor-derived proteins and Toll-like receptors. Exp Mol Med. 2020;52(12):1926–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Vafaei S, Mirnejad R, Amirmozafari N. Determining the patterns of antimicrobial susceptibility and the distribution of blaCTX-M genes in strains of Acinetobacter Baumannii isolated from clinical samples. J Isfahan Med School. 2013;31(252):1443–51.

    Google Scholar 

  28. Kawasaki T, Kawai T. Toll-like receptor signaling pathways. Front Immunol. 2014;5:461.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Akira S, Takeda K. Toll-like receptor signalling. Nat Rev Immunol. 2004;4(7):499–511.

    Article  CAS  PubMed  Google Scholar 

  30. Qu Y-Y, Zhao R, Zhang H-L, Zhou Q, Xu F-J, Zhang X, et al. Inactivation of the AMPK–GATA3–ECHS1 pathway induces fatty acid synthesis that promotes clear cell renal cell carcinoma growth. Can Res. 2020;80(2):319–33.

    Article  CAS  Google Scholar 

  31. Kawai T, Akira S. Signaling to NF-κB by Toll-like receptors. Trends Mol Med. 2007;13(11):460–9.

    Article  CAS  PubMed  Google Scholar 

  32. Zafari P, Yari K, Mostafaei S, Iranshahi N, Assar S, Fekri A, et al. Analysis of Helios gene expression and Foxp3 TSDR methylation in the newly diagnosed Rheumatoid Arthritis patients. Immunol Invest. 2018;47(6):632–42.

    Article  CAS  PubMed  Google Scholar 

  33. Samimi Z, Kardideh B, Zafari P, Bahrehmand F, Roghani SA, Taghadosi M. The impaired gene expression of adenosine monophosphate-activated kinase (AMPK), a key metabolic enzyme in leukocytes of newly diagnosed rheumatoid arthritis patients. Mol Biol Rep. 2019;46(6):6353–60.

    Article  CAS  PubMed  Google Scholar 

  34. Zhang G, Ghosh S. Toll-like receptor–mediated NF-κB activation: a phylogenetically conserved paradigm in innate immunity. J Clin Investig. 2001;107(1):13–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Yan J, Yao Y, Yan S, Gao R, Lu W, He W. Chiral protein supraparticles for tumor suppression and synergistic immunotherapy: an enabling strategy for bioactive supramolecular chirality construction. Nano Lett. 2020;20(8):5844–52.

    Article  CAS  PubMed  Google Scholar 

  36. Liu C, Wang Y, Li L, He D, Chi J, Li Q, et al. Engineered extracellular vesicles and their mimetics for cancer immunotherapy. J Control Release. 2022;349:679–98.

    Article  CAS  PubMed  Google Scholar 

  37. Kondo T, Kawai T, Akira S. Dissecting negative regulation of Toll-like receptor signaling. Trends Immunol. 2012;33(9):449–58.

    Article  CAS  PubMed  Google Scholar 

  38. Iranshahi N, Assar S, Amiri SM, Zafari P, Fekri A, Taghadosi M. Decreased gene expression of Epstein-Barr Virus-Induced Gene 3 (EBI-3) may contribute to the pathogenesis of rheumatoid arthritis. Immunol Invest. 2019;48(4):367–77.

    Article  CAS  PubMed  Google Scholar 

  39. Schaefer TM, Desouza K, Fahey JV, Beagley KW, Wira CR. Toll-like receptor (TLR) expression and TLR-mediated cytokine/chemokine production by human uterine epithelial cells. Immunology. 2004;112(3):428–36.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Zhou M, McFarland-Mancini MM, Funk HM, Husseinzadeh N, Mounajjed T, Drew AF. Toll-like receptor expression in normal ovary and ovarian tumors. Cancer Immunol Immunother. 2009;58(9):1375–85.

    Article  CAS  PubMed  Google Scholar 

  41. Cheng JQ, Jiang X, Fraser M, Li M, Dan HC, Sun M, et al. Role of X-linked inhibitor of apoptosis protein in chemoresistance in ovarian cancer: possible involvement of the phosphoinositide-3 kinase/Akt pathway. Drug Resist Updat. 2002;5(3–4):131–46.

    Article  CAS  PubMed  Google Scholar 

  42. Kim WY, Lee JW, Choi JJ, Choi CH, Kim TJ, Kim BG, et al. Increased expression of Toll-like receptor 5 during progression of cervical neoplasia. Int J Gynecol Cancer. 2008;18(2):300–5.

    Article  CAS  PubMed  Google Scholar 

  43. Lee JW, Choi JJ, Seo ES, Kim MJ, Kim WY, Choi CH, et al. Increased toll-like receptor 9 expression in cervical neoplasia. Mol Carcinog. 2007;46(11):941–7.

    Article  CAS  PubMed  Google Scholar 

  44. Wojcik-Krowiranda KM, Forma E, Bienkiewicz A, Cwonda L, Wronska-Stefaniak J, Brys M. TLR family gene expression in relation to the HIF1α and the VEGFR pathway activation in endometrial cancer. Ginekol Pol. 2020;91(8):439–46.

    Article  PubMed  Google Scholar 

  45. Wang X-H, Xu S, Zhou X-Y, Zhao R, Lin Y, Cao J, et al. Low chorionic villous succinate accumulation associates with recurrent spontaneous abortion risk. Nat Commun. 2021;12(1):1–14.

    Google Scholar 

  46. Lotze MT, Zeh HJ, Rubartelli A, Sparvero LJ, Amoscato AA, Washburn NR, et al. The grateful dead: damage-associated molecular pattern molecules and reduction/oxidation regulate immunity. Immunol Rev. 2007;220:60–81.

    Article  CAS  PubMed  Google Scholar 

  47. Allhorn S, Böing C, Koch AA, Kimmig R, Gashaw I. TLR3 and TLR4 expression in healthy and diseased human endometrium. Reprod Biol Endocrinol. 2008;6:40.

    Article  PubMed  PubMed Central  Google Scholar 

  48. Ashton KA, Proietto A, Otton G, Symonds I, McEvoy M, Attia J, et al. Toll-like receptor (TLR) and nucleosome-binding oligomerization domain (NOD) gene polymorphisms and endometrial cancer risk. BMC Cancer. 2010;10:382.

    Article  PubMed  PubMed Central  Google Scholar 

  49. Gençoğlu Bakbak BB, Ilhan TT, Pekin A, Kerimoğlu ÖS, Yılmaz SA, Kebapçılar A, et al. Evaluation of toll-like receptor expression with clinicopathologic variables in endometrium cancer. Sisli Etfal Hastan Tip Bul. 2018;52(3):196–200.

    PubMed  PubMed Central  Google Scholar 

  50. Wolchok JD, Chiarion-Sileni V, Gonzalez R, Rutkowski P, Grob J-J, Cowey CL, et al. Overall survival with combined nivolumab and ipilimumab in advanced melanoma. N Engl J Med. 2017;377(14):1345–56.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Motzer RJ, Tannir NM, McDermott DF, Frontera OA, Melichar B, Choueiri TK, et al. Nivolumab plus ipilimumab versus sunitinib in advanced renal-cell carcinoma. New Engl J Med. 2018;378(14):1277–90.

    Article  CAS  PubMed  Google Scholar 

  52. Azadeh H, Alizadeh-Navaei R, Rezaiemanesh A, Rajabinejad M. Immune-related adverse events (irAEs) in ankylosing spondylitis (AS) patients treated with interleukin (IL)-17 inhibitors: a systematic review and meta-analysis. Inflammopharmacology. 2022;30(2):435–51.

    Article  CAS  PubMed  Google Scholar 

  53. Di Tucci C, Capone C, Galati G, Iacobelli V, Schiavi MC, Di Donato V, et al. Immunotherapy in endometrial cancer: new scenarios on the horizon. J Gynecol Oncol. 2019. https://doi.org/10.3802/jgo.2019.30.e46.

    Article  PubMed  PubMed Central  Google Scholar 

  54. Getz G, Gabriel SB, Cibulskis K, Lander E, Sivachenko A, Sougnez C, et al. Integrated genomic characterization of endometrial carcinoma. Nature. 2013;497(7447):67–73.

    Article  CAS  Google Scholar 

  55. Nishio H, Iwata T, Aoki D. Current status of cancer immunotherapy for gynecologic malignancies. Jpn J Clin Oncol. 2021;51(2):167–72.

    Article  PubMed  Google Scholar 

  56. Di Tucci C, Schiavi MC, Faiano P, D’Oria O, Prata G, Sciuga V, et al. Therapeutic vaccines and immune checkpoints inhibition options for gynecological cancers. Crit Rev Oncol Hematol. 2018;128:30–42.

    Article  PubMed  Google Scholar 

  57. Khan KN, Fujishita A, Hiraki K, Kitajima M, Nakashima M, Fushiki S, et al. Bacterial contamination hypothesis: a new concept in endometriosis. Reprod Med Biol. 2018;17(2):125–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Zhang H, Wu ZM, Yang YP, Shaukat A, Yang J, Guo YF, et al. Catalpol ameliorates LPS-induced endometritis by inhibiting inflammation and TLR4/NF-κB signaling. J Zhejiang Univ Sci B. 2019;20(10):816–27.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Lin Y, Li Y, Li X, Liu X, Wang X, Yu M, et al. SCM-198 ameliorates endometrial inflammation via suppressing the LPS-JNK-cJUN/cFOS-TLR4-NF-κB pathway. Acta Biochim Biophys Sin (Shanghai). 2021;53(9):1207–15.

    Article  CAS  PubMed  Google Scholar 

  60. Ghanavatinejad A, Rashidi N, Mirahmadian M, Rezania S, Mosalaei M, Ghasemi J, et al. Vitamin D3 controls TLR4- and TLR2-mediated inflammatory responses of endometrial cells. Gynecol Obstet Invest. 2021;86(1–2):139–48.

    Article  CAS  PubMed  Google Scholar 

  61. Buathong N, Poonyachoti S, Deachapunya C. Isoflavone genistein modulates the protein expression of toll-like receptors in cancerous human endometrial cells. J Med Assoc Thai. 2015;98(Suppl 9):S31–8.

    PubMed  Google Scholar 

  62. Zhou M, Yi Y, Hong L. Oridonin ameliorates lipopolysaccharide-induced endometritis in mice via inhibition of the TLR-4/NF-κBpathway. Inflammation. 2019;42(1):81–90.

    Article  PubMed  Google Scholar 

  63. Jiang K, Yang J, Yang C, Zhang T, Shaukat A, Yang X, et al. miR-148a suppresses inflammation in lipopolysaccharide-induced endometritis. J Cell Mol Med. 2020;24(1):405–17.

    Article  CAS  PubMed  Google Scholar 

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  1. Abnormal Uterine Bleeding Research Center, Semnan University of Medical Sciences, Semnan, Iran

    Sahereh Arabian, Aynaz Boostan & Satinik Darzi

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  1. Sahereh Arabian
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SA and SD contributed to the idea design, literature search, writing the manuscript. AB drafted the work.

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Correspondence to Satinik Darzi.

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Arabian, S., Boostan, A. & Darzi, S. The role of toll-like receptors (TLRs) and their therapeutic applications in endometrial cancer. Clin Transl Oncol 25, 859–865 (2023). https://doi.org/10.1007/s12094-022-02999-1

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