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Paraneoplastic hormones: parathyroid hormone-related protein (PTHrP) and erythropoietin (EPO) are related to vascular endothelial growth factor (VEGF) expression in clear cell renal cell carcinoma

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Tumor Biology

Abstract

To investigate the correlation between parathyroid hormone-related protein (PTHrP), erythropoietin (EPO), and vascular endothelial growth factor (VEGF) expression in clear cell renal cell carcinoma (ccRCC). Immunohistochemical studies on PTHrP, EPO and VEGF were performed in 249 patients with ccRCC. Serum calcium level and haematocrit were analyzed. The expression of the factors and clinicopathological parameters were studied statistically for possible correlations. The incidence for hypercalcaemia and polycythaemia were 15.3 % and 2.0 % respectively. Expression of PTHrP, EPO, and VEGF were respectively related to advanced stage (P < 0.0001 respectively). PTHrP was not related to tumour grade. Expressions of EPO and VEGF were correlated to tumour grade significantly. All factors were expressed higher in hypercalcaemic patients. PTHrP, EPO, and VEGF were positively correlated with each other in non-hypercalcaemic patients yet not in hypercalcaemic ones. PTHrP and EPO are related to VEGF expression and to the progression of ccRCC. This finding offers us new insight on the behaviour of ccRCC and offers possible targets in RCC treatment.

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References

  1. Motzer RJ et al. Renal cell carcinoma. Curr Probl Cancer. 1997;21:185–232.

    Article  PubMed  CAS  Google Scholar 

  2. Sourbier C et al. Parathyroid hormone-related protein in human renal cell carcinoma. Cancer Lett. 2006;240:170–82.

    Article  PubMed  CAS  Google Scholar 

  3. Ding GX, Song NH, Feng CC, Xia GW, Jiang HW, Hua LX, et al. Is there an association between advanced stage of renal cell carcinoma and paraneoplastic syndrome? Med Princ Pract. 2012;21:370–4.

    Article  PubMed  Google Scholar 

  4. Minardi D, Lucarini G, Filosa A, et al. Prognostic role of tumor necrosis, microvessel density, vascular endothelial growth factor and hypoxia inducible factor-1alpha in patients with clear cell renal carcinoma after radical nephrectomy in a long term follow-up. Int J Immunopathol Pharmacol. 2008;21:447–55.

    PubMed  CAS  Google Scholar 

  5. Ding GX, Feng CC, Song NH, Fang ZJ, Xia GW, Jiang HW, et al. Paraneoplastic symptoms: cachexia, polycythemia, and hypercalcemia are, respectively, related to vascular endothelial growth factor (VEGF) expression in renal clear cell carcinoma. Urol Oncol. 2012. doi:10.1016/j.urolonc.2012.03.021.

    Google Scholar 

  6. Wiesener MS, Seyfarth M, Warecke C, et al. Paraneoplastic erythrocytosis associated with an inactivating point mutation of the von Hippel-Lindau gene in a renal cell carcinoma. Blood. 2002;99:3562–5.

    Article  PubMed  CAS  Google Scholar 

  7. Fandrey J. Oxygen-dependent and tissue-specific regulation of erythropoietin gene expression. Am J Physiol Regul Integr Comp Physiol. 2004;286:R977–88.

    Article  PubMed  CAS  Google Scholar 

  8. Farrell F, Lee A. The erythropoietin receptor and its expression in tumor cells and other tissues. Oncologist. 2004;9:18–30.

    Article  PubMed  CAS  Google Scholar 

  9. Esbrit P, Egido J. The emerging role of parathyroid hormone-related protein as a renal regulating factor. Nephrol Dial Transplant. 2000;15:1109–11.

    Article  PubMed  CAS  Google Scholar 

  10. Philbrick WM, Galbraith S, Wysolmerski JJ, Holt E, Orloff JJ, Yang KH, et al. Defining the roles of parathyroid hormone-related protein in normal physiology. Physiol Rev. 1996;76:127–73.

    PubMed  CAS  Google Scholar 

  11. Clemens TL, Cormier S, Eichinger A, Endlich K, Fiaschi-Taesch N, Fischer E, et al. Parathyroid hormone-related protein and its receptors: nuclear functions and roles in the renal and cardiovascular systems, the placental trophoblasts and the pancreatic islets. Br J Pharmacol. 2001;134:1113–36.

    Article  PubMed  CAS  Google Scholar 

  12. Sobin LH, Wittekind CH, editors. International Union Against Cancer (UICC). TNM classification of malignant tumours, 6th ed. New York: Wiley-Liss; 2002; p. 193–195.

  13. Fuhrman SA, Lasky LC, Limas C. Prognostic significance of morphologic parameters in renal cell carcinoma. Am J Surg Pathol. 1982;6:655–63.

    Article  PubMed  CAS  Google Scholar 

  14. Kim HL, Belldegrun AS, Freitas DG, Bui MH, Han KR, Dorey FJ, et al. Paraneoplastic signs and symptoms of renal cell carcinoma: implications for prognosis. J Urol. 2003;170:1742–6.

    Article  PubMed  Google Scholar 

  15. Palapattu GS, Kristo B, Rajfer J. Paraneoplastic syndromes in urologic malignancy: the many faces of renal cell carcinoma. Rev Urol. 2002;4:163–70.

    PubMed  Google Scholar 

  16. Papac RJ, Poo-Hwu WJ. Renal cell carcinoma: a paradigm of lanthanic disease. Am J Clin Oncol. 1999;22:223–31.

    Article  PubMed  CAS  Google Scholar 

  17. Koo AS, Armstrong C, Bochner B, Shimabukuro T, Tso CL. deKernion JB, et al. Interleukin-6 and renal cell cancer: production, regulation and growth effects. Cancer Immunol Immunother. 1992;35:97–105.

    Article  PubMed  CAS  Google Scholar 

  18. Blay JY, Rossi JF, Wijdenes J, Menetrier-Caux C, Schemann S, Négrier S, et al. Role of interleukin-6 in the paraneoplastic inflammatory syndrome associated with renal-cell carcinoma. Int J Cancer. 1997;72:424–30.

    Article  PubMed  CAS  Google Scholar 

  19. Rini BI, Small EJ. Biology and clinical development of vascular endothelial growth factor-targeted therapy in renal cell carcinoma. J Clin Oncol. 2005;23:1028–43.

    Article  PubMed  CAS  Google Scholar 

  20. Amato RJ. Renal cell carcinoma: review of novel single-agent therapeutics and combination regimens. Ann Oncol. 2005;16:7–15.

    Article  PubMed  CAS  Google Scholar 

  21. Carmeliet P. Angiogenesis in health and disease. Nat Med. 2003;9:653–60.

    Article  PubMed  CAS  Google Scholar 

  22. Escudier B, Eisen T, Stadler WM, Szczylik C, Oudard S, Siebels M, et al. TARGET Study Group. Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med. 2007;356:125–34.

    Article  PubMed  CAS  Google Scholar 

  23. Motzer RJ, Michaelson MD, Redman BG, Hudes GR, Wilding G, Figlin RA, et al. Activity of SU11248, a multitargeted inhibitor of vascular endothelial growth factor receptor and platelet-derived growth factor receptor, in patients with metastatic renal cell carcinoma. J Clin Oncol. 2006;24:16–24.

    Article  PubMed  CAS  Google Scholar 

  24. Kazal LA, Erslev AJ. Erythropoietin production in renal tumors. Ann Clin Sci. 1975;5:98–109.

    CAS  Google Scholar 

  25. Noguchi Y, Goto T, Yufu Y, Uike N, Hasegawa Y, Fukuda T, et al. Gene expression of erythropoietin in renal cell carcinoma. Intern Med. 1999;38:991–4.

    Article  PubMed  CAS  Google Scholar 

  26. Sakamoto S, Igarashi T, Osumi N, Imamoto T, Tobe T, Kamiya M, et al. Erythropoietin producing renal cell carcinoma in chronic hemodialysis patients: a report of two cases. Int J Urol. 2003;10:49–51.

    Article  PubMed  Google Scholar 

  27. Wiesener MS, Münchenhagen P, Gläser M, Sobottka BA, Kanup KX, Jozefowski K, et al. Erythropoietin gene expression in renal carcinoma is considerably more frequent than paraneoplastic polycythemia. Int J Cancer. 2007;121:2434–42.

    Article  PubMed  CAS  Google Scholar 

  28. Westenfelder C, Baranowski RL. Erythropoietin stimulates proliferation of human renal carcinoma cells. Kidney Int. 2000;58:647–57.

    Article  PubMed  CAS  Google Scholar 

  29. Arcasoy MO, Amin K, Chou SC, Haroon ZA, Varia M, Raleigh JA. Erythropoietin and erythropoietin receptor expression in head and neck cancer: relationship to tumor hypoxia. Clin Cancer Res. 2005;11:20–7.

    PubMed  CAS  Google Scholar 

  30. Gong K, Zhang N, Zhang Z, Na Y. Coexpression of erythopoietin and erythopoietin receptor in sporadic clear cell renal cell carcinoma. Cancer Biol Ther. 2006;5:582–5.

    Article  PubMed  CAS  Google Scholar 

  31. Scortegagna M, Ding K, Zhang Q, Oktay Y, Bennett MJ, Bennett M, et al. HIF-2a regulates murine hematopoietic development in an erythropoietin-dependent manner. Blood. 2005;105:3133–40.

    Article  PubMed  CAS  Google Scholar 

  32. Scortegagna M, Morris MA, Oktay Y, Bennett M, Garcia JA. The HIF family member EPAS1/HIF-2a is required for normal hematopoiesis in mice. Blood. 2003;102:1634–40.

    Article  PubMed  CAS  Google Scholar 

  33. Carroll VA, Ashcroft M. Role of hypoxia-inducible factor (HIF)-1alpha versus HIF-2alpha in the regulation of HIF target genes in response to hypoxia, insulin-like growth factor-I, or loss of Hippel-Lindau function: implications for targeting the HIF pathway. Cancer Res. 2006;15:6264–70.

    Article  Google Scholar 

  34. Burton PB, Moniz C, Knight DE. Parathyroid hormone related peptide can function as an autocrine growth factor in human renal cell carcinoma. Biochem Biophys Res Commun. 1990;167:1134–8.

    Article  PubMed  CAS  Google Scholar 

  35. Gotoh A, Kitazawa S, Mizuno Y, Takenaka A, Arakawa S, Matsumoto O, et al. Common expression of parathyroid hormone-related protein and no correlation of calcium level in renal cell carcinomas. Cancer. 1993;71:2803–6.

    Article  PubMed  CAS  Google Scholar 

  36. Massfelder T, Lang H, Schordan E, Lindner V, Rothhut S, Welsch S, et al. Parathyroid hormone-related protein is an essential growth factor for human clear cell renal carcinoma and a target for the von Hippel-Lindau tumor suppressor gene. Cancer Res. 2004;64:180–8.

    Article  PubMed  CAS  Google Scholar 

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Correspondence to Qiang Ding.

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Feng, Cc., Ding, Gx., Song, Nh. et al. Paraneoplastic hormones: parathyroid hormone-related protein (PTHrP) and erythropoietin (EPO) are related to vascular endothelial growth factor (VEGF) expression in clear cell renal cell carcinoma. Tumor Biol. 34, 3471–3476 (2013). https://doi.org/10.1007/s13277-013-0924-7

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  • DOI: https://doi.org/10.1007/s13277-013-0924-7

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