Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

The pancancer landscape of Wnt family expression reveals potential biomarkers in urinary system tumors

Cancer Gene Therapy volume 28, pages 1035–1045 (2021)Cite this article

Subjects

Abstract

Immunotherapy and targeted therapy have been particularly effective in treating tumors of the urinary system; however, the mechanisms of the Wnt family of proteins in the tumorigenesis, development, and immune response of urinary system tumors are not fully understood. Here, we show that the Wnt family was extensively upregulated in and impacted the prognosis of patients with prostate adenocarcinoma (PRAD) and bladder urothelial carcinoma (BLCA). Moreover, the Wnt family correlated with the levels of infiltrating immune cells, including B cells, CD4 + T cells, CD8 + T cells, neutrophils, macrophages, and dendritic cells. The expression levels of Wnt family members were closely related to neoantigens, the mismatch repair system (MMRS) and DNA methyltransferases, and the mutation rate was generally low. Wnt family members are potential biomarkers for precision immunotherapy of urinary system tumors.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Wnt family expression levels (log2(TPM + 1)) in the urinary system based on GTEx normal tissues, CCLE cancer cells, TCGA normal tissues, and TCGA cancer tissues.
Fig. 2: Forest plots and Kaplan–Meier survival curves of the Wnt family in BLCA and PRAD.
Fig. 3: The expression of Wnt family correlated with TME in BLCA and PRAD.
Fig. 4: The expression of Wnt family correlated with neoantigen numbers, TMB and MSI in BLCA and PRAD.
Fig. 5: The expression of Wnt family correlated with MMRS and DNA methyltransferase in BLCA and PRAD.

Similar content being viewed by others

References

  1. McKenney JK. Mesenchymal tumors of the prostate. Mod Pathol. 2018;31:S133–42.

    Article  PubMed  Google Scholar 

  2. Solomon JP, Hansel DE. Prognostic factors in urothelial carcinoma of the bladder: histologic and molecular correlates. Adv Anat Pathol. 2015;22:102–12.

    Article  CAS  PubMed  Google Scholar 

  3. Lee JK, Bangayan NJ, Chai T, Smith BA, Pariva TE, Yun S, et al. Systemic surfaceome profiling identifies target antigens for immune-based therapy in subtypes of advanced prostate cancer. Proc Natl Acad Sci USA. 2018;115:E4473–e82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Zhang C, Shen L, Qi F, Wang J, Luo J. Multi-omics analysis of tumor mutation burden combined with immune infiltrates in bladder urothelial carcinoma. J Cell Physiol. 2020;235:3849–63.

    Article  CAS  PubMed  Google Scholar 

  5. Nusse R, Varmus HE. Many tumors induced by the mouse mammary tumor virus contain a provirus integrated in the same region of the host genome. Cell. 1982;31:99–109.

    Article  CAS  PubMed  Google Scholar 

  6. Cruciat CM, Niehrs C. Secreted and transmembrane wnt inhibitors and activators. Cold Spring Harb Perspect Biol. 2013;5:a015081.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  7. Krausova M, Korinek V. Wnt signaling in adult intestinal stem cells and cancer. Cell Signal. 2014;26:570–9.

    Article  CAS  PubMed  Google Scholar 

  8. Patel S, Alam A, Pant R, Chattopadhyay S. Wnt signaling and its significance within the tumor microenvironment: novel therapeutic insights. Front Immunol. 2019;10:2872.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Niehrs C. The complex world of WNT receptor signalling. Nat Rev Mol Cell Biol. 2012;13:767–79.

    Article  CAS  PubMed  Google Scholar 

  10. Dale TC. Signal transduction by the Wnt family of ligands. Biochem J. 1998;329:209–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Neth P, Ciccarella M, Egea V, Hoelters J, Jochum M, Ries C. Wnt signaling regulates the invasion capacity of human mesenchymal stem cells. Stem Cells. 2006;24:1892–903.

    Article  CAS  PubMed  Google Scholar 

  12. Zhang X, Gaspard JP, Chung DC. Regulation of vascular endothelial growth factor by the Wnt and K-ras pathways in colonic neoplasia. Cancer Res. 2001;61:6050–4.

    CAS  PubMed  Google Scholar 

  13. Yong X, Tang B, Xiao YF, Xie R, Qin Y, Luo G, et al. Helicobacter pylori upregulates Nanog and Oct4 via Wnt/β-catenin signaling pathway to promote cancer stem cell-like properties in human gastric cancer. Cancer Lett. 2016;374:292–303.

    Article  CAS  PubMed  Google Scholar 

  14. Bengochea A, de Souza MM, Lefrançois L, Le Roux E, Galy O, Chemin I, et al. Common dysregulation of Wnt/Frizzled receptor elements in human hepatocellular carcinoma. Br J Cancer. 2008;99:143–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Dong JJ, Ying L, Shi KQ. Expression of the Wnt ligands gene family and its relationship to prognosis in hepatocellular carcinoma. Cancer Cell Int. 2019;19:34.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Ramos-Solano M, Meza-Canales ID, Torres-Reyes LA, Alvarez-Zavala M, Alvarado-Ruíz L, Rincon-Orozco B, et al. Expression of WNT genes in cervical cancer-derived cells: implication of WNT7A in cell proliferation and migration. Exp Cell Res. 2015;335:39–50.

    Article  CAS  PubMed  Google Scholar 

  17. Cai Y, Mohseny AB, Karperien M, Hogendoorn PC, Zhou G, Cleton-Jansen AM. Inactive Wnt/beta-catenin pathway in conventional high-grade osteosarcoma. J Pathol. 2010;220:24–33.

    Article  CAS  PubMed  Google Scholar 

  18. Zhan T, Rindtorff N, Boutros M. Wnt signaling in cancer. Oncogene. 2017;36:1461–73.

    Article  CAS  PubMed  Google Scholar 

  19. Wu T, Dai Y. Tumor microenvironment and therapeutic response. Cancer Lett. 2017;387:61–8.

    Article  CAS  PubMed  Google Scholar 

  20. Staal FJ, Luis TC, Tiemessen MM. WNT signalling in the immune system: WNT is spreading its wings. Nat Rev Immunol. 2008;8:581–93.

    Article  CAS  PubMed  Google Scholar 

  21. Klemm F, Joyce JA. Microenvironmental regulation of therapeutic response in cancer. Trends cell Biol. 2015;25:198–213.

    Article  PubMed  Google Scholar 

  22. El-Sahli S, Xie Y, Wang L, Liu S. Wnt signaling in cancer metabolism and immunity. Cancers. 2019;11:904.

  23. Yoshihara K, Shahmoradgoli M, Martínez E, Vegesna R, Kim H, Torres-Garcia W, et al. Inferring tumour purity and stromal and immune cell admixture from expression data. Nat Commun. 2013;4:2612.

    Article  PubMed  CAS  Google Scholar 

  24. Darvin P, Toor SM, Sasidharan Nair V, Elkord E. Immune checkpoint inhibitors: recent progress and potential biomarkers. Exp Mol Med. 2018;50:1–11.

    Article  PubMed  CAS  Google Scholar 

  25. Desrichard A, Snyder A, Chan TA. Cancer neoantigens and applications for immunotherapy. Clin Cancer Res. 2016;22:807–12.

    Article  CAS  PubMed  Google Scholar 

  26. Samstein RM, Lee CH, Shoushtari AN, Hellmann MD, Shen R, Janjigian YY, et al. Tumor mutational load predicts survival after immunotherapy across multiple cancer types. Nat Genet. 2019;51:202–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Hause RJ, Pritchard CC, Shendure J, Salipante SJ. Classification and characterization of microsatellite instability across 18 cancer types. Nat Med. 2016;22:1342–50.

    Article  CAS  PubMed  Google Scholar 

  28. Subudhi SK, Vence L, Zhao H, Blando J, Yadav SS, Xiong Q, et al. Neoantigen responses, immune correlates, and favorable outcomes after ipilimumab treatment of patients with prostate cancer. Sci Transl Med. 2020;12:eaaz3577.

  29. Bui TD, O’Brien T, Crew J, Cranston D, Harris AL. High expression of Wnt7b in human superficial bladder cancer vs invasive bladder cancer. Br J Cancer 1998;77:319–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Das M, Zhu C, Kuchroo VK. Tim-3 and its role in regulating anti-tumor immunity. Immunological Rev. 2017;276:97–111.

    Article  CAS  Google Scholar 

  31. Sadreddini S, Baradaran B, Aghebati-Maleki A, Sadreddini S, Shanehbandi D, Fotouhi A, et al. Immune checkpoint blockade opens a new way to cancer immunotherapy. J Cell Physiol. 2019;234:8541–9.

    Article  CAS  PubMed  Google Scholar 

  32. Jin J, Wang Y, Ma Q, Wang N, Guo W, Jin B, et al. LAIR-1 activation inhibits inflammatory macrophage phenotype in vitro. Cell Immunol. 2018;331:78–84.

    Article  CAS  PubMed  Google Scholar 

  33. Peng DH, Rodriguez BL, Diao L, Chen L, Wang J, Byers LA, et al. Collagen promotes anti-PD-1/PD-L1 resistance in cancer through LAIR1-dependent CD8(+) T cell exhaustion. Nat Commun. 2020;11:4520.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Jochems C, Schlom J. Tumor-infiltrating immune cells and prognosis: the potential link between conventional cancer therapy and immunity. Exp Biol Med (Maywood, NJ). 2011;236:567–79.

    Article  CAS  Google Scholar 

  35. Polakis P. Wnt signaling in cancer. Cold Spring Harb Perspect Biol. 2012;4:a008052.

  36. Anastas JN, Moon RT. WNT signalling pathways as therapeutic targets in cancer. Nat Rev Cancer. 2013;13:11–26.

    Article  CAS  PubMed  Google Scholar 

  37. van der Bruggen P, Traversari C, Chomez P, Lurquin C, De Plaen E, Van, et al. A gene encoding an antigen recognized by cytolytic T lymphocytes on a human melanoma. Science. 1991;254:1643–7.

    Article  PubMed  Google Scholar 

  38. Salgado R, Denkert C, Demaria S, Sirtaine N, Klauschen F, Pruneri G, et al. The evaluation of tumor-infiltrating lymphocytes (TILs) in breast cancer: recommendations by an International TILs Working Group 2014. Ann Oncol: Off J Eur Soc Med Oncol. 2015;26:259–71.

    Article  CAS  Google Scholar 

  39. Hwang WT, Adams SF, Tahirovic E, Hagemann IS, Coukos G. Prognostic significance of tumor-infiltrating T cells in ovarian cancer: a meta-analysis. Gynecologic Oncol. 2012;124:192–8.

    Article  Google Scholar 

  40. Waisman A, Lukas D, Clausen BE, Yogev N. Dendritic cells as gatekeepers of tolerance. Semin Immunopathol. 2017;39:153–63.

    Article  CAS  PubMed  Google Scholar 

  41. den Haan JM, Lehar SM, Bevan MJ. CD8(+) but not CD8(−) dendritic cells cross-prime cytotoxic T cells in vivo. J Exp Med. 2000;192:1685–96.

    Article  Google Scholar 

  42. Kushwah R, Hu J. Role of dendritic cells in the induction of regulatory T cells. Cell Biosci. 2011;1:20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Luke JJ, Bao R, Sweis RF, Spranger S, Gajewski TF. WNT/β-catenin pathway activation correlates with immune exclusion across human cancers. Clin Cancer Res. 2019;25:3074–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Veeman MT, Axelrod JD, Moon RT. A second canon. Functions and mechanisms of beta-catenin-independent Wnt signaling. Dev Cell. 2003;5:367–77.

    Article  CAS  PubMed  Google Scholar 

  45. Fu C, Liang X, Cui W, Ober-Blöbaum JL, Vazzana J, Shrikant PA, et al. β-Catenin in dendritic cells exerts opposite functions in cross-priming and maintenance of CD8+ T cells through regulation of IL-10. Proc Natl Acad Sci USA. 2015;112:2823–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Spranger S, Gajewski TF. A new paradigm for tumor immune escape: β-catenin-driven immune exclusion. J Immunother Cancer. 2015;3:43.

    Article  PubMed  PubMed Central  Google Scholar 

  47. Katoh M. WNT/PCP signaling pathway and human cancer (review). Oncol Rep. 2005;14:1583–8.

    Article  CAS  PubMed  Google Scholar 

  48. Egeblad M, Nakasone ES, Werb Z. Tumors as organs: complex tissues that interface with the entire organism. Dev Cell. 2010;18:884–901.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Austin TW, Solar GP, Ziegler FC, Liem L, Matthews W. A role for the Wnt gene family in hematopoiesis: expansion of multilineage progenitor cells. Blood. 1997;89:3624–35.

    Article  CAS  PubMed  Google Scholar 

  50. Cheng X, Huber TL, Chen VC, Gadue P, Keller GM. Numb mediates the interaction between Wnt and Notch to modulate primitive erythropoietic specification from the hemangioblast. Development. 2008;135:3447–58.

    Article  CAS  PubMed  Google Scholar 

  51. Clements WK, Kim AD, Ong KG, Moore JC, Lawson ND, Traver D. A somitic Wnt16/Notch pathway specifies haematopoietic stem cells. Nature. 2011;474:220–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Rothenberg EV, Moore JE, Yui MA. Launching the T-cell-lineage developmental programme. Nat Rev Immunol. 2008;8:9–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Osugui L, de Roo JJ, de Oliveira VC, Sodré ACP, Staal FJT, Popi AF. B-1 cells and B-1 cell precursors prompt different responses to Wnt signaling. PloS ONE. 2018;13:e0199332.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  54. Capietto AH, Kim S, Sanford DE, Linehan DC, Hikida M, Kumosaki T, et al. Down-regulation of PLCγ2-β-catenin pathway promotes activation and expansion of myeloid-derived suppressor cells in cancer. J Exp Med. 2013;210:2257–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Valencia J, Hernández-López C, Martínez VG, Hidalgo L, Zapata AG, Vicente Á, et al. Wnt5a skews dendritic cell differentiation to an unconventional phenotype with tolerogenic features. J Immunol. 2011;187:4129–39.

    Article  CAS  PubMed  Google Scholar 

  56. Oderup C, LaJevic M, Butcher EC. Canonical and noncanonical Wnt proteins program dendritic cell responses for tolerance. J Immunol. 2013;190:6126–34.

    Article  CAS  PubMed  Google Scholar 

  57. Mao Y, Feng Q, Zheng P, Yang L, Liu T, Xu Y, et al. Low tumor purity is associated with poor prognosis, heavy mutation burden, and intense immune phenotype in colon cancer. Cancer Manag Res. 2018;10:3569–77.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Lee V, Murphy A, Le DT, Diaz LA Jr. Mismatch repair deficiency and response to immune checkpoint blockade. Oncologist. 2016;21:1200–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Kim H, Jen J, Vogelstein B, Hamilton SR. Clinical and pathological characteristics of sporadic colorectal carcinomas with DNA replication errors in microsatellite sequences. Am J Pathol. 1994;145:148–56.

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Alexander J, Watanabe T, Wu TT, Rashid A, Li S, Hamilton SR. Histopathological identification of colon cancer with microsatellite instability. Am J Pathol. 2001;158:527–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Dunn GP, Bruce AT, Ikeda H, Old LJ, Schreiber RD. Cancer immunoediting: from immunosurveillance to tumor escape. Nat Immunol. 2002;3:991–8.

    Article  CAS  PubMed  Google Scholar 

  62. Topalian SL, Drake CG, Pardoll DM. Immune checkpoint blockade: a common denominator approach to cancer therapy. Cancer Cell. 2015;27:450–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Saghafinia S, Mina M, Riggi N, Hanahan D, Ciriello G. Pan-Cancer landscape of aberrant DNA methylation across human tumors. Cell Rep. 2018;25:1066–80.e8.

    Article  CAS  PubMed  Google Scholar 

  64. Das PM, Singal R. DNA methylation and cancer. J Clin Oncol. 2004;22:4632–42.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Author notes

  1. These authors contributed equally: Jialiang Hui, Chengxinqiao Wang, Yun Miao

Authors and Affiliations

  1. Department of Organ Transplant, Nanfang Hospital, Southern Medical University, 510515, Guangzhou, China

    Jialiang Hui, Yun Miao & Jian Xu

  2. Nanfang Hospital, Southern Medical University, 510515, Guangzhou, China

    Chengxinqiao Wang

  3. Department of Urology, Nanfang Hospital, Southern Medical University, 510515, Guangzhou, China

    Ruiyu Liu

Authors
  1. Jialiang Hui
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Chengxinqiao Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yun Miao
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ruiyu Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jian Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Ruiyu Liu or Jian Xu.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Hui, J., Wang, C., Miao, Y. et al. The pancancer landscape of Wnt family expression reveals potential biomarkers in urinary system tumors. Cancer Gene Ther 28, 1035–1045 (2021). https://doi.org/10.1038/s41417-020-00273-6

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41417-020-00273-6

Search

Advanced search

Quick links