Skip to main content

Advertisement

SpringerLink
Log in

PDGF-BB/PDGFRβ induces tumour angiogenesis via enhancing PKM2 mediated by the PI3K/AKT pathway in Wilms’ tumour

  • Original Paper
  • Published:
Medical Oncology Aims and scope Submit manuscript

Abstract

Platelet-derived growth factor receptor-β (PDGFRβ) is a critical type III receptor tyrosine kinase family member, which is involved in Wilms’ tumour (WT) metastasis and aerobic glycolysis. The role of PDGFRβ in tumour angiogenesis has not been fully elucidated. Here, we examined the effect of PDGFRβ on angiogenesis in WT. First, the NCBI database integrated three datasets, GSE2712, GSE11151, and GSE73209, to screen differentially expressed genes. The R language was used to analyse the correlation between PDGFRB and vascular endothelial growth factor (VEGF). The results showed that PDGFRB, encoding PDGFRβ, was upregulated in WT, and its level was correlated with VEGFA expression. Next, PDGFRβ expression was inhibited by small interfering RNA (siRNA) or activated with the exogenous ligand PDGF-BB. The expression and secretion of the angiogenesis elated factor VEGFA in WT G401 cells were detected using Western blotting and ELISA, respectively. The effects of conditioned medium from G401 cells on endothelial cell viability, migration, invasion, the total length of the tube, and the number of fulcrums were investigated. To further explore the mechanism of PDGFRβ in the angiogenesis of WT, the expression of VEGFA was detected after blocking the phosphatidylinositol-3-kinase (PI3K) pathway and inhibiting the expression of PKM2, a key enzyme of glycolysis. The results indicated that PDGFRβ regulated the process of tumour angiogenesis through the PI3K/AKT/PKM2 pathway. Therefore, this study provides a novel therapeutic strategy to target PDGFRβ and PKM2 to inhibit glycolysis and anti-angiogenesis, thus, developing a new anti-vascular therapy.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

Data availability

The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.

References

  1. Nakata K, Colombet M, Stiller CA, Pritchard-Jones K, Steliarova-Foucher E. Incidence of childhood renal tumours: an international population-based study. Int J Cancer. 2020;147(12):3313–27.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Spreafico F, Fernandez CV, Brok J, Nakata K, Vujanic G, Geller JI, Gessler M, Maschietto M, Behjati S, Polanco A, Paintsil V, Luna-Fineman S, Pritchard-Jones K. Wilms tumour. Nat Rev Dis Primers. 2021;7(1):75.

    Article  PubMed  Google Scholar 

  3. Brok J, Treger TD, Gooskens SL, van den Heuvel-Eibrink MM, Pritchard-Jones K. Biology and treatment of renal tumours in childhood. Eur J Cancer (Oxford). 2016;68:179–95.

    Article  CAS  Google Scholar 

  4. Dome JS, Mullen EA, Dix DB, Gratias EJ, Ehrlich PF, Daw NC, Geller JI, Chintagumpala M, Khanna G, Kalapurakal JA, Renfro LA, Perlman EJ, Grundy PE, Fernandez CV. Impact of the first generation of Children’s Oncology Group Clinical trials on clinical practice for Wilms tumor. J Natl Compr Cancer Netw. 2021;19(8):978–85.

    Article  CAS  Google Scholar 

  5. Mullen EA, Chi Y-Y, Hibbitts E, Anderson JR, Steacy KJ, Geller JI, Green DM, Khanna G, Malogolowkin MH, Grundy PE, Fernandez CV, Dome JS. Impact of surveillance imaging modality on survival after recurrence in patients with favorable-histology wilms tumor: a report from the Children’s Oncology Group. J Clin Oncol. 2018;36:3396.

    Article  PubMed Central  Google Scholar 

  6. Suh E, Stratton KL, Leisenring WM, Nathan PC, Ford JS, Freyer DR, McNeer JL, Stock W, Stovall M, Krull KR, Sklar CA, Neglia JP, Armstrong GT, Oeffinger KC, Robison LL, Henderson TO. Late mortality and chronic health conditions in long-term survivors of early-adolescent and young adult cancers: a retrospective cohort analysis from the Childhood Cancer Survivor Study. Lancet Oncol. 2020;21(3):421–35.

    Article  PubMed  PubMed Central  Google Scholar 

  7. van den Heuvel-Eibrink MM, Hol JA, Pritchard-Jones K, van Tinteren H, Furtwängler R, Verschuur AC, Vujanic GM, Leuschner I, Brok J, Rübe C, Smets AM, Janssens GO, Godzinski J, Ramírez-Villar GL, de Camargo B, Segers H, Collini P, Gessler M, Bergeron C, Spreafico F, Graf N. Position paper: rationale for the treatment of Wilms tumour in the UMBRELLA SIOP-RTSG 2016 protocol. Nat Rev Urol. 2017;14(12):743–52.

    Article  PubMed  Google Scholar 

  8. Majidpoor J, Mortezaee K. Angiogenesis as a hallmark of solid tumors—clinical perspectives. Cell Oncol (Dordr). 2021;44(4):715–37.

    Article  CAS  PubMed  Google Scholar 

  9. Li X, Zhou J, Wang X, Li C, Ma Z, Wan Q, Peng F. New advances in the research of clinical treatment and novel anticancer agents in tumor angiogenesis. Biomed Pharmacother. 2023;163:114806.

    Article  CAS  PubMed  Google Scholar 

  10. Abramson LP, Grundy PE, Rademaker AW, Helenowski I, Cornwell M, Katzenstein HM, Reynolds M, Arensman RM, Crawford SE. Increased microvascular density predicts relapse in Wilms’ tumor. J Pediatr Surg. 2003;38(3):325.

    Article  PubMed  Google Scholar 

  11. Ozluk Y, Kilicaslan I, Gulluoglu MG, Ayan I, Uysal V. The prognostic significance of angiogenesis and the effect of vascular endothelial growth factor on angiogenic process in Wilms’ tumour. Pathology. 2006;38(5):408–14.

    CAS  PubMed  Google Scholar 

  12. Li W, Kessler P, Yeger H, Alami J, Reeve AE, Heathcott R, Skeen J, Williams BRG. A gene expression signature for relapse of primary Wilms tumors. Can Res. 2005;65(7):2592–601.

    Article  CAS  Google Scholar 

  13. Frischer JS, Huang J, Serur A, Kadenhe-Chiweshe A, McCrudden KW, O’Toole K, Holash J, Yancopoulos GD, Yamashiro DJ, Kandel JJ. Effects of potent VEGF blockade on experimental Wilms tumor and its persisting vasculature. Int J Oncol. 2004;25(3):549–53.

    CAS  PubMed  Google Scholar 

  14. Ferrara N, Hillan KJ, Gerber H-P, Novotny W. Discovery and development of bevacizumab, an anti-VEGF antibody for treating cancer. Nat Rev Drug Discov. 2004;3(5):391–400.

    Article  CAS  PubMed  Google Scholar 

  15. Kumar S, Burney IA, Al-Moundhri MS. Near complete resolution of refractory, relapsed, metastatic Wilms’ tumour in an adolescent with bevacizumab. J Coll Phys Surg-Pak. 2014;24(Suppl 1):S71–2.

    Google Scholar 

  16. Schiavetti A, Varrasso G, Collini P, Clerico A. Vincristine, irinotecan, and bevacizumab in relapsed Wilms tumor with diffuse anaplasia. J Pediatr Hematol Oncol. 2018;40(4):331–3.

    Article  PubMed  Google Scholar 

  17. Interiano RB, McCarville MB, Wu J, Davidoff AM, Sandoval J, Navid F. Pneumothorax as a complication of combination antiangiogenic therapy in children and young adults with refractory/recurrent solid tumors. J Pediatr Surg. 2015;50(9):1484–9.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Ostman A. PDGF receptors-mediators of autocrine tumor growth and regulators of tumor vasculature and stroma. Cytokine Growth Factor Rev. 2004;15(4):275–86.

    Article  PubMed  Google Scholar 

  19. Apte SM, Fan D, Killion JJ, Fidler IJ. Targeting the platelet-derived growth factor receptor in antivascular therapy for human ovarian carcinoma. Clin Cancer Res. 2004;10(3):897–908.

    Article  CAS  PubMed  Google Scholar 

  20. ManzatSaplacan RM, Balacescu L, Gherman C, Chira RI, Craiu A, Mircea PA, Lisencu C, Balacescu O. The role of PDGFs and PDGFRs in colorectal cancer. Mediat Inflamm. 2017;2017:4708076.

    Google Scholar 

  21. Corvigno S, Frödin M, Wisman GBA, Nijman HW, Van der Zee AG, Jirström K, Nodin B, Hrynchyk I, Edler D, Ragnhammar P, Johansson M, Dahlstrand H, Mezheyeuski A, Östman A. Multi-parametric profiling of renal cell, colorectal, and ovarian cancer identifies tumour-type-specific stroma phenotypes and a novel vascular biomarker. J Pathol Clin Res. 2017;3(3):214–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Huang J, Soffer SZ, Kim ES, McCrudden KW, Huang J, New T, Manley CA, Middlesworth W, O’Toole K, Yamashiro DJ, Kandel JJ. Vascular remodeling marks tumors that recur during chronic suppression of angiogenesis. Mol Cancer Res. 2004;2(1):36–42.

    Article  CAS  PubMed  Google Scholar 

  23. Aye JM, Stafman LL, Williams AP, Garner EF, Stewart JE, Anderson JC, Mruthyunjayappa S, Waldrop MG, Goolsby CD, Markert HR, Quinn C, Marayati R, Mroczek-Musulman E, Willey CD, Yoon KJ, Whelan KF, Beierle EA. The effects of focal adhesion kinase and platelet-derived growth factor receptor beta inhibition in a patient-derived xenograft model of primary and metastatic Wilms tumor. Oncotarget. 2019;10(53):5534–48.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Huang XL, Khan MI, Wang J, Ali R, Ali SW, Zahra Q-U-A, Kazmi A, Lolai A, Huang YL, Hussain A, Bilal M, Li F, Qiu B. Role of receptor tyrosine kinases mediated signal transduction pathways in tumor growth and angiogenesis—new insight and futuristic vision. Int J Biol Macromol. 2021;180:739–52.

    Article  CAS  PubMed  Google Scholar 

  25. Wang H, Yin Y, Li W, Zhao X, Yu Y, Zhu J, Qin Z, Wang Q, Wang K, Lu W, Liu J, Huang L. Over-expression of PDGFR-β promotes PDGF-induced proliferation, migration, and angiogenesis of EPCs through PI3K/Akt signaling pathway. PLoS ONE. 2012;7(2):e30503.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Xia L, Oyang L, Lin J, Tan S, Han Y, Wu N, Yi P, Tang L, Pan Q, Rao S, Liang J, Tang Y, Su M, Luo X, Yang Y, Shi Y, Wang H, Zhou Y, Liao Q. The cancer metabolic reprogramming and immune response. Mol Cancer. 2021;20(1):28.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Guo J-Q, Wang C-D, Tang H-Y, Sang B-T, Liu X, Yi F-P, Wu X-M. PDGF-BB/PDGFRβ promotes epithelial-mesenchymal transition by affecting PI3K/AKT/mTOR-driven aerobic glycolysis in Wilms’ tumor G401 cells. Cell Biol Int. 2022;46(6):907–21.

    Article  CAS  PubMed  Google Scholar 

  28. Itatani Y, Kawada K, Yamamoto T, Sakai Y. Resistance to anti-angiogenic therapy in cancer-alterations to anti-VEGF pathway. Int J Mol Sci. 2018;19(4):1232.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Huang M, Lin Y, Wang C, Deng L, Chen M, Assaraf YG, Chen Z-S, Ye W, Zhang D. New insights into antiangiogenic therapy resistance in cancer: mechanisms and therapeutic aspects. Drug Resist Updates. 2022;64:100849.

    Article  CAS  Google Scholar 

  30. Groenendijk A, Spreafico F, de Krijger RR, Drost J, Brok J, Perotti D, van Tinteren H, Venkatramani R, Godziński J, Rübe C, Geller JI, Graf N, van den Heuvel-Eibrink MM, Mavinkurve-Groothuis AMC. Prognostic factors for wilms tumor recurrence: A review of the literature. Cancers. 2021;13(13):3142.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Spini A, Ciccone V, Rosellini P, Ziche M, Lucenteforte E, Salvo F, Donnini S. Safety of anti-angiogenic drugs in pediatric patients with solid tumors: A systematic review and meta-analysis. Cancers. 2022;14(21):5315.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Rowe DH, Kayton ML, O’Toole KM, Ingram M, Stolar CJ, Kandel JJ. Pathological angiogenesis in a murine model of human Wilms’ tumor. J Pediatr Surg. 1999;34(5):676–9.

    Article  CAS  PubMed  Google Scholar 

  33. Sköldenberg EG, Christiansson J, Sandstedt B, Larsson A, Läckgren G, Christofferson R. Angiogenesis and angiogenic growth factors in Wilms tumor. J Urol. 2001;165(6 Pt 2):2274–9.

    Article  PubMed  Google Scholar 

  34. Wang J, Fan S, Feng Y, Zhang H, Zou W, Hu C. Antiangiogenic therapy for Wilms tumor in an adult and literature review. Anticancer Drugs. 2019;30(6):640–5.

    Article  CAS  PubMed  Google Scholar 

  35. Huang J, Moore J, Soffer S, Kim E, Rowe D, Manley CA, O’Toole K, Middlesworth W, Stolar C, Yamashiro D, Kandel J. Highly specific antiangiogenic therapy is effective in suppressing growth of experimental Wilms tumors. J Pediatr Surg. 2001;36(2):357–61.

    Article  CAS  PubMed  Google Scholar 

  36. Ghanem MA, van der Kwast TH, Molenaar WM, Safan MA, Nijman RJ, van Steenbrugge GJ. The predictive value of immunohistochemical markers in untreated Wilms’ tumour: are they useful? World J Urol. 2013;31(4):811–6.

    Article  CAS  PubMed  Google Scholar 

  37. Ghanem M, Nijman R, Safan M, van der Kwast T, Vansteenbrugge G. Expression and prognostic value of platelet-derived growth factor-AA and its receptor α in nephroblastoma. BJU Int. 2010;106(9):1389–93.

    Article  CAS  PubMed  Google Scholar 

  38. Thies KA, Hammer AM, Hildreth BE, Steck SA, Spehar JM, Kladney RD, Geisler JA, Das M, Russell LO, Bey JF, Bolyard CM, Pilarski R, Trimboli AJ, Cuitiño MC, Koivisto CS, Stover DG, Schoenfield L, Otero J, Godbout JP, Chakravarti A, Ringel MD, Ramaswamy B, Li Z, Kaur B, Leone G, Ostrowski MC, Sizemore ST, Sizemore GM. Stromal platelet-derived growth factor receptor-β signaling promotes breast cancer metastasis in the brain. Can Res. 2021;81(3):606–18.

    Article  CAS  Google Scholar 

  39. Guérit E, Arts F, Dachy G, Boulouadnine B, Demoulin J-B. PDGF receptor mutations in human diseases. Cell Mol Life Sci. 2021;78(8):3867–81.

    Article  PubMed  Google Scholar 

  40. Gatenby RA, Gillies RJ. Why do cancers have high aerobic glycolysis? Nat Rev Cancer. 2004;4(11):891–9.

    Article  CAS  PubMed  Google Scholar 

  41. de la Cruz-López KG, Castro-Muñoz LJ, Reyes-Hernández DO, García-Carrancá A, Manzo-Merino J. Lactate in the regulation of tumor microenvironment and therapeutic approaches. Front Oncol. 2019;9:1143.

    Article  PubMed  PubMed Central  Google Scholar 

  42. Azoitei N, Becher A, Steinestel K, Rouhi A, Diepold K, Genze F, Simmet T, Seufferlein T. PKM2 promotes tumor angiogenesis by regulating HIF-1α through NF-κB activation. Mol Cancer. 2016;15:3.

    Article  PubMed  PubMed Central  Google Scholar 

  43. Wright SCE, Vasilevski N, Serra V, Rodon J, Eichhorn PJA. Mechanisms of resistance to PI3K inhibitors in cancer: Adaptive responses, drug tolerance and cellular plasticity. Cancers. 2021;13(7):1538.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Park JH, Pyun WY, Park HW. Cancer metabolism: phenotype, signaling and therapeutic targets. Cells. 2020;9(10):2308.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Courtnay R, Ngo DC, Malik N, Ververis K, Tortorella SM, Karagiannis TC. Cancer metabolism and the Warburg effect: the role of HIF-1 and PI3K. Mol Biol Rep. 2015;42(4):841–51.

    Article  CAS  PubMed  Google Scholar 

Download references

Funding

Program for Youth Innovation in Future Medicine, Chongqing Medical University.

Author information

Authors and Affiliations

  1. Molecular Medicine and Cancer Research Center, Basic Medical College, Chongqing Medical University, Chongqing, China

    Bo-tao Sang, Chang-dong Wang, Jia-qi Guo, Jia-yi Lai & Xiang-mei Wu

  2. Department of Physiology, Basic Medical College, Chongqing Medical University, Chongqing, China

    Bo-tao Sang, Jia-qi Guo & Xiang-mei Wu

  3. Department of Biochemistry and Molecular Biology, Basic Medical College, Chongqing Medical University, Chongqing, China

    Chang-dong Wang & Jia-yi Lai

  4. Department of Pediatric Urology, Chongqing Children’s Hospital, Chongqing Medical University, Chongqing, China

    Xing Liu

Authors
  1. Bo-tao Sang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Chang-dong Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Xing Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jia-qi Guo
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jia-yi Lai
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Xiang-mei Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

BS was responsible for the experimental design of the study; Experimental operation; Results analysis and paper writing. CW and XL were responsible for the experimental design of the study. JG was responsible for the results analysis. JL was responsible for the bioinformatics analysis. XW was responsible for the experimental design and results analysis of the study.

Corresponding author

Correspondence to Xiang-mei Wu.

Ethics declarations

Competing interests

The authors have no relevant financial or non-financial interests to disclose.

Additional information

Publisher's Note

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

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (XLSX 326 KB)

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Sang, Bt., Wang, Cd., Liu, X. et al. PDGF-BB/PDGFRβ induces tumour angiogenesis via enhancing PKM2 mediated by the PI3K/AKT pathway in Wilms’ tumour. Med Oncol 40, 240 (2023). https://doi.org/10.1007/s12032-023-02115-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s12032-023-02115-5

Keywords

Search

Navigation