Skip to main content

Advertisement

SpringerLink
Log in

Circulating Biomarkers in Advanced Renal Cell Carcinoma: Clinical Applications

  • Genitourinary Cancers (E Jonasch, Section Editor)
  • Published:
Current Oncology Reports Aims and scope Submit manuscript

Abstract

Advances in understanding the biology of renal cell carcinoma (RCC) have resulted in treatment strategies based on molecularly targeted agents that have substantially improved the outcomes of patients with metastatic RCC. Agents targeting the vascular endothelial growth factor pathway and the mammalian target of rapamycin have shown efficacy in randomized clinical trials and received international approval for treating RCC. Multiple candidate biomarkers of the biologic activity of such targeted therapies as well as markers of treatment response and patients’ prognosis are being evaluated to improve drug development and to identify patients who may obtain the greatest benefit from the various treatment options. This review summarizes recent developments in identifying circulating biomarkers of targeted therapies for metastatic RCC, including soluble proteins and circulating cells.

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

Similar content being viewed by others

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Eble JN, Sauter G, Epstein JI, Sesterhenn IA. Pathology and genetics of tumours of the urinary system and male genital organs. Lyon: IARC; 2004.

    Google Scholar 

  2. Furge KA, Lucas KA, Takahashi M, Sugimura J, Kort EJ, Kanayama HO, et al. Robust classification of renal cell carcinoma based on gene expression data and predicted cytogenetic profiles. Cancer Res. 2004;64(12):4117–21. doi:10.1158/0008-5472.CAN-04-0534.

    Article  PubMed  CAS  Google Scholar 

  3. Tan MH, Wong CF, Tan HL, Yang XJ, Ditlev J, Matsuda D, et al. Genomic expression and single-nucleotide polymorphism profiling discriminates chromophobe renal cell carcinoma and oncocytoma. BMC Cancer. 2010;10:196. doi:10.1186/1471-2407-10-196.

    Article  PubMed  Google Scholar 

  4. Yang XJ, Sugimura J, Schafernak KT, Tretiakova MS, Han M, Vogelzang NJ, et al. Classification of renal neoplasms based on molecular signatures. J Urol. 2006;175(6):2302–6. doi:10.1016/S0022-5347(06)00255-2.

    Article  PubMed  CAS  Google Scholar 

  5. Cheville JC, Lohse CM, Zincke H, Weaver AL, Blute ML. Comparisons of outcome and prognostic features among histologic subtypes of renal cell carcinoma. Am J Surg Pathol. 2003;27(5):612–24.

    Article  PubMed  Google Scholar 

  6. Patard JJ, Leray E, Rioux-Leclercq N, Cindolo L, Ficarra V, Zisman A, et al. Prognostic value of histologic subtypes in renal cell carcinoma: a multicenter experience. J Clin Oncol. 2005;23(12):2763–71. doi:10.1200/JCO.2005.07.055.

    Article  PubMed  Google Scholar 

  7. Chowdhury S, Matrana MR, Tsang C, Atkinson B, Choueiri TK, Tannir NM. Systemic therapy for metastatic non-clear-cell renal cell carcinoma: recent progress and future directions. Hematol Oncol Clin North Am. 2011;25(4):853–69. doi:10.1016/j.hoc.2011.05.003.

    Article  PubMed  Google Scholar 

  8. Gnarra JR, Tory K, Weng Y, Schmidt L, Wei MH, Li H, et al. Mutations of the VHL tumour suppressor gene in renal carcinoma. Nat Genet. 1994;7(1):85–90. doi:10.1038/ng0594-85.

    Article  PubMed  CAS  Google Scholar 

  9. Nickerson ML, Jaeger E, Shi Y, Durocher JA, Mahurkar S, Zaridze D, et al. Improved identification of von Hippel-Lindau gene alterations in clear cell renal tumors. Clin Cancer Res. 2008;14(15):4726–34. doi:10.1158/1078-0432.CCR-07-4921.

    Article  PubMed  CAS  Google Scholar 

  10. Semenza GL. Targeting HIF-1 for cancer therapy. Nat Rev Cancer. 2003;3(10):721–32.

    Article  PubMed  CAS  Google Scholar 

  11. Gordan JD, Simon MC. Hypoxia-inducible factors: central regulators of the tumor phenotype. Curr Opin Genet Dev. 2007;17(1):71–7. doi:10.1016/j.gde.2006.12.006.

    Article  PubMed  CAS  Google Scholar 

  12. Rini BI, Campbell SC, Escudier B. Renal cell carcinoma. Lancet. 2009;373(9669):1119–32. doi:10.1016/S0140-6736(09)60229-4.

    Article  PubMed  CAS  Google Scholar 

  13. • Klatte T, Pantuck AJ, Said JW, Seligson DB, Rao NP, LaRochelle JC, et al. Cytogenetic and molecular tumor profiling for type 1 and type 2 papillary renal cell carcinoma. Clin Cancer Res. 2009;15(4):1162–9. doi:10.1158/1078-0432.CCR-08-1229. Evaluation of the prognostic significance of clinicopathological and cytogenetic features in papillary renal cell carcinoma subtypes.

    Article  PubMed  CAS  Google Scholar 

  14. Antonelli A, Tardanico R, Balzarini P, Arrighi N, Perucchini L, Zanotelli T, et al. Cytogenetic features, clinical significance and prognostic impact of type 1 and type 2 papillary renal cell carcinoma. Canc Genet Cytogenet. 2010;199(2):128–33. doi:10.1016/j.cancergencyto.2010.02.013.

    Article  CAS  Google Scholar 

  15. Schmidt L, Duh FM, Chen F, Kishida T, Glenn G, Choyke P, et al. Germline and somatic mutations in the tyrosine kinase domain of the MET proto-oncogene in papillary renal carcinomas. Nat Genet. 1997;16(1):68–73. doi:10.1038/ng0597-68.

    Article  PubMed  CAS  Google Scholar 

  16. Toro JR, Nickerson ML, Wei MH, Warren MB, Glenn GM, Turner ML, et al. Mutations in the fumarate hydratase gene cause hereditary leiomyomatosis and renal cell cancer in families in North America. Am J Hum Genet. 2003;73(1):95–106. doi:10.1086/376435.

    Article  PubMed  CAS  Google Scholar 

  17. Nickerson ML, Warren MB, Toro JR, Matrosova V, Glenn G, Turner ML, et al. Mutations in a novel gene lead to kidney tumors, lung wall defects, and benign tumors of the hair follicle in patients with the Birt-Hogg-Dube syndrome. Canc Cell. 2002;2(2):157–64.

    Article  CAS  Google Scholar 

  18. Lam JS, Shvarts O, Leppert JT, Figlin RA, Belldegrun AS. Renal cell carcinoma 2005: new frontiers in staging, prognostication and targeted molecular therapy. J Urol. 2005;173(6):1853–62. doi:10.1097/01.ju.0000165693.68449.c3.

    Article  PubMed  Google Scholar 

  19. Motzer RJ, Russo P. Systemic therapy for renal cell carcinoma. J Urol. 2000;163(2):408–17.

    Article  PubMed  CAS  Google Scholar 

  20. Gore ME, Griffin CL, Hancock B, Patel PM, Pyle L, Aitchison M, et al. Interferon alfa-2a versus combination therapy with interferon alfa-2a, interleukin-2, and fluorouracil in patients with untreated metastatic renal cell carcinoma (MRC RE04/EORTC GU 30012): an open-label randomised trial. Lancet. 2010;375(9715):641–8. doi:10.1016/S0140-6736(09)61921-8.

    Article  PubMed  CAS  Google Scholar 

  21. McDermott DF, Rini BI. Immunotherapy for metastatic renal cell carcinoma. BJU Int. 2007;99(5 Pt B):1282–8. doi:10.1111/j.1464-410X.2007.06818.x.

    Article  PubMed  CAS  Google Scholar 

  22. McDermott DF, Regan MM, Clark JI, Flaherty LE, Weiss GR, Logan TF, et al. Randomized phase III trial of high-dose interleukin-2 versus subcutaneous interleukin-2 and interferon in patients with metastatic renal cell carcinoma. J Clin Oncol. 2005;23(1):133–41. doi:10.1200/JCO.2005.03.206.

    Article  PubMed  CAS  Google Scholar 

  23. Clement JM, McDermott DF. The high-dose aldesleukin (IL-2) “select” trial: a trial designed to prospectively validate predictive models of response to high-dose IL-2 treatment in patients with metastatic renal cell carcinoma. Clin Genitourin Canc. 2009;7(2):E7–9. doi:10.3816/CGC.2009.n.014.

    Article  CAS  Google Scholar 

  24. Motzer RJ, Hutson TE, Tomczak P, Michaelson MD, Bukowski RM, Oudard S, et al. Overall survival and updated results for sunitinib compared with interferon alfa in patients with metastatic renal cell carcinoma. J Clin Oncol. 2009;27(22):3584–90. doi:10.1200/JCO.2008.20.1293.

    Article  PubMed  CAS  Google Scholar 

  25. Escudier B, Eisen T, Stadler WM, Szczylik C, Oudard S, Staehler M, et al. Sorafenib for treatment of renal cell carcinoma: final efficacy and safety results of the phase III treatment approaches in renal cancer global evaluation trial. J Clin Oncol. 2009;27(20):3312–8. doi:10.1200/JCO.2008.19.5511.

    Article  PubMed  CAS  Google Scholar 

  26. Sternberg CN, Davis ID, Mardiak J, Szczylik C, Lee E, Wagstaff J, et al. Pazopanib in locally advanced or metastatic renal cell carcinoma: results of a randomized phase III trial. J Clin Oncol. 2010;28(6):1061–8. doi:10.1200/JCO.2009.23.9764.

    Article  PubMed  CAS  Google Scholar 

  27. Rini BI, Escudier B, Tomczak P, Kaprin A, Szczylik C, Hutson TE, et al. Comparative effectiveness of axitinib versus sorafenib in advanced renal cell carcinoma (AXIS): a randomised phase 3 trial. Lancet. 2011;378(9807):1931–9. doi:10.1016/S0140-6736(11)61613-9.

    Article  PubMed  CAS  Google Scholar 

  28. Escudier B, Bellmunt J, Negrier S, Bajetta E, Melichar B, Bracarda S, et al. Phase III trial of bevacizumab plus interferon alfa-2a in patients with metastatic renal cell carcinoma (AVOREN): final analysis of overall survival. J Clin Oncol. 2010;28(13):2144–50. doi:10.1200/JCO.2009.26.7849.

    Article  PubMed  CAS  Google Scholar 

  29. Hudes G, Carducci M, Tomczak P, Dutcher J, Figlin R, Kapoor A, et al. Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med. 2007;356(22):2271–81. doi:10.1056/NEJMoa066838.

    Article  PubMed  CAS  Google Scholar 

  30. Motzer RJ, Escudier B, Oudard S, Hutson TE, Porta C, Bracarda S, et al. Phase 3 trial of everolimus for metastatic renal cell carcinoma: final results and analysis of prognostic factors. Cancer. 2010;116(18):4256–65. doi:10.1002/cncr.25219.

    Article  PubMed  CAS  Google Scholar 

  31. Sturgeon CM, Hoffman BR, Chan DW, Ch'ng SL, Hammond E, Hayes DF, et al. National Academy of Clinical Biochemistry Laboratory Medicine Practice Guidelines for use of tumor markers in clinical practice: quality requirements. Clin Chem. 2008;54(8):e1–e10. doi:10.1373/clinchem.2007.094144.

    Article  PubMed  CAS  Google Scholar 

  32. •• Heng DY, Xie W, Regan MM, Warren MA, Golshayan AR, Sahi C, et al. Prognostic factors for overall survival in patients with metastatic renal cell carcinoma treated with vascular endothelial growth factor-targeted agents: results from a large, multicenter study. J Clin Oncol. 2009;27(34):5794–9. doi:10.1200/JCO.2008.21.4809. Updated clinical prognostic model for VEGF-targeted agents.

    Article  PubMed  CAS  Google Scholar 

  33. Motzer RJ, Bacik J, Murphy BA, Russo P, Mazumdar M. Interferon-alfa as a comparative treatment for clinical trials of new therapies against advanced renal cell carcinoma. J Clin Oncol. 2002;20(1):289–96.

    Article  PubMed  CAS  Google Scholar 

  34. • Manola J, Royston P, Elson P, McCormack JB, Mazumdar M, Negrier S, et al. Prognostic model for survival in patients with metastatic renal cell carcinoma: results from the international kidney cancer working group. Clin Cancer Res. 2011;17(16):5443–50. doi:10.1158/1078-0432.CCR-11-0553. Recent evaluation of clinical prognostic factors.

    Article  PubMed  Google Scholar 

  35. • Rini BI, Cohen DP, Lu DR, Chen I, Hariharan S, Gore ME, et al. Hypertension as a biomarker of efficacy in patients with metastatic renal cell carcinoma treated with sunitinib. J Natl Cancer Inst. 2011;103(9):763–73. doi:10.1093/jnci/djr128. The largest available study confirming the prognostic value of hypertension developing during treatment with VEGF receptor inhibitors.

    Article  CAS  Google Scholar 

  36. Rini BI, Schiller JH, Fruehauf JP, Cohen EE, Tarazi JC, Rosbrook B, et al. Diastolic blood pressure as a biomarker of axitinib efficacy in solid tumors. Clin Cancer Res. 2011;17(11):3841–9. doi:10.1158/1078-0432.CCR-10-2806.

    Article  PubMed  CAS  Google Scholar 

  37. • Gossage L, Eisen T. Alterations in VHL as potential biomarkers in renal-cell carcinoma. Nat Rev Clin Oncol. 2010;7(5):277–88. doi:10.1038/nrclinonc.2010.42. Recent detailed review on the significance of VHL as a biomarker in renal cell carcinoma.

    Article  PubMed  CAS  Google Scholar 

  38. Gordan JD, Lal P, Dondeti VR, Letrero R, Parekh KN, Oquendo CE, et al. HIF-alpha effects on c-Myc distinguish two subtypes of sporadic VHL-deficient clear cell renal carcinoma. Canc Cell. 2008;14(6):435–46. doi:10.1016/j.ccr.2008.10.016.

    Article  CAS  Google Scholar 

  39. Ferrara N, Gerber HP, LeCouter J. The biology of VEGF and its receptors. Nat Med. 2003;9(6):669–76. doi:10.1038/nm0603-669.

    Article  PubMed  CAS  Google Scholar 

  40. Kendall RL, Thomas KA. Inhibition of vascular endothelial cell growth factor activity by an endogenously encoded soluble receptor. Proc Natl Acad Sci U S A. 1993;90(22):10705–9.

    Article  PubMed  CAS  Google Scholar 

  41. Ebos JM, Bocci G, Man S, Thorpe PE, Hicklin DJ, Zhou D, et al. A naturally occurring soluble form of vascular endothelial growth factor receptor 2 detected in mouse and human plasma. Mol Canc Res. 2004;2(6):315–26.

    CAS  Google Scholar 

  42. Deprimo SE, Bello CL, Smeraglia J, Baum CM, Spinella D, Rini BI, et al. Circulating protein biomarkers of pharmacodynamic activity of sunitinib in patients with metastatic renal cell carcinoma: modulation of VEGF and VEGF-related proteins. J Transl Med. 2007;5:32. doi:10.1186/1479-5876-5-32.

    Article  PubMed  Google Scholar 

  43. Negrier S, Perol D, Menetrier-Caux C, Escudier B, Pallardy M, Ravaud A, et al. Interleukin-6, interleukin-10, and vascular endothelial growth factor in metastatic renal cell carcinoma: prognostic value of interleukin-6–from the Groupe Francais d’Immunotherapie. J Clin Oncol. 2004;22(12):2371–8. doi:10.1200/JCO.2004.06.121.

    Article  PubMed  CAS  Google Scholar 

  44. • Pena C, Lathia C, Shan M, Escudier B, Bukowski RM. Biomarkers predicting outcome in patients with advanced renal cell carcinoma: results from sorafenib phase III Treatment Approaches in Renal Cancer Global Evaluation Trial. Clin Cancer Res. 2010;16(19):4853–63. doi:10.1158/1078-0432.CCR-09-3343. Prognostic evaluation of candidate soluble biomarkers in a randomized, placebo-controlled clinical trial.

    Article  PubMed  CAS  Google Scholar 

  45. Negrier S, Chabaud S, Escudier B, Ravaud A, Chevreau C, Blay JY, et al. Serum level of vascular endothelial growth factor (VEGF) as an independent prognostic factor in metastatic renal cell carcinoma (MRCC). J Clin Oncol. 2007;25:abstr 5044.

    Google Scholar 

  46. Escudier B, Ravaud A, Negrier S, Szczylik C, Bellmunt J, Bracarda S, et al. Update on AVOREN trial in metastatic renal cell carcinoma (mRCC): efficacy and safety in subgroups of patients (pts) and pharmacokinetic (PK) analysis. J Clin Oncol. 2008;26:abstr 5025.

    Google Scholar 

  47. Montero AJ, Diaz-Montero CM, Millikan RE, Liu J, Do KA, Hodges S, et al. Cytokines and angiogenic factors in patients with metastatic renal cell carcinoma treated with interferon-alpha: association of pretreatment serum levels with survival. Ann Oncol. 2009;20(10):1682–7. doi:10.1093/annonc/mdp054.

    Article  PubMed  CAS  Google Scholar 

  48. Guida M, Casamassima A, Monticelli G, Quaranta M, Colucci G. Basal cytokines profile in metastatic renal cell carcinoma patients treated with subcutaneous IL-2-based therapy compared with that of healthy donors. J Transl Med. 2007;5:51. doi:10.1186/1479-5876-5-51.

    Article  PubMed  Google Scholar 

  49. Blay JY, Rossi JF, Wijdenes J, Menetrier-Caux C, Schemann S, Negrier S, et al. Role of interleukin-6 in the paraneoplastic inflammatory syndrome associated with renal-cell carcinoma. Int J Cancer. 1997;72(3):424–30.

    Article  PubMed  CAS  Google Scholar 

  50. Walther MM, Johnson B, Culley D, Shah R, Weber J, Venzon D, et al. Serum interleukin-6 levels in metastatic renal cell carcinoma before treatment with interleukin-2 correlates with paraneoplastic syndromes but not patient survival. J Urol. 1998;159(3):718–22.

    Article  PubMed  CAS  Google Scholar 

  51. Ramankulov A, Lein M, Kristiansen G, Meyer HA, Loening SA, Jung K. Elevated plasma osteopontin as marker for distant metastases and poor survival in patients with renal cell carcinoma. J Cancer Res Clin Oncol. 2007;133(9):643–52. doi:10.1007/s00432-007-0215-z.

    Article  PubMed  CAS  Google Scholar 

  52. • Liu Y, Tran HT, Lin Y, Martin AM, Zurita AJ, Sternberg CN, et al. Plasma cytokine and angiogenic factors (CAFs) predictive of clinical benefit and prognosis in patients (Pts) with advanced or metastatic renal cell cancer (mRCC) treated in phase III trials of pazopanib (PAZO). J Clin Oncol. 2011;29:abstr 334. Validation of plasma IL-6, IL-8, and osteopontin as markers prognostic for progression-free survival in metastatic renal cell carcinoma.

    Article  Google Scholar 

  53. Hutson TE, Davis ID, Machiels JP, De Souza PL, Rottey S, Hong BF, et al. Efficacy and safety of pazopanib in patients with metastatic renal cell carcinoma. J Clin Oncol. 2010;28(3):475–80. doi:10.1200/JCO.2008.21.6994.

    Article  PubMed  CAS  Google Scholar 

  54. • Zurita AJ, Jonasch E, Wang X, Khajavi M, Yan S, Du DZ, et al. A cytokine and angiogenic factor (CAF) analysis in plasma for selection of sorafenib therapy in patients with metastatic renal cell carcinoma. Ann Oncol. 2012;23(1):46–52. doi:10.1093/annonc/mdr047. Identification of a candidate predictive angiogenic signature based on soluble factors for VEGF receptor kinase inhibitors.

    Article  PubMed  CAS  Google Scholar 

  55. • Nikolinakos PG, Altorki N, Yankelevitz D, Tran HT, Yan S, Rajagopalan D, et al. Plasma cytokine and angiogenic factor profiling identifies markers associated with tumor shrinkage in early-stage non-small cell lung cancer patients treated with pazopanib. Cancer Res. 2010;70(6):2171–9. doi:10.1158/0008-5472.CAN-09-2533. VEGF receptor kinase inhibitors induce multiple host-derived cytokines and other biologically active mediators.

    Article  PubMed  CAS  Google Scholar 

  56. Heymach JV, Shackleford TJ, Tran HT, Yoo SY, Do KA, Wergin M, et al. Effect of low-fat diets on plasma levels of NF-kappaB-regulated inflammatory cytokines and angiogenic factors in men with prostate cancer. Canc Prev Res (Phila). 2011;4(10):1590–8. doi:10.1158/1940-6207.CAPR-10-0136.

    Article  CAS  Google Scholar 

  57. Liu Y, Tran HT, Lin Y, Martin AM, Zurita AJ, Sternberg CN, et al. Baseline (BL) IL-6, IL-8, and VEGF as predictive and prognostic markers for Overall Survival (OS) in Metastatic Renal Cell Carcinoma (mRCC) Patients (pts) treated in a Phase III Trial of Pazopanib (PAZO) versus Placebo (PL). Eur J Cancer. 2011;47 suppl 1:S170.

    Article  Google Scholar 

  58. Hutson TE, Davis ID, Machiels JH, de Souza PL, Baker KL, McCann L, et al. Biomarker analysis and final efficacy and safety results of a phase II renal cell carcinoma trial with pazopanib (GW786034), a multi-kinase angiogenesis inhibitor. J Clin Oncol. 2008;26:abstr 5046.

    Google Scholar 

  59. Rixe O, Meric J, Bloch J, Gentile A, Mouawad R, Adam V, et al. Surrogate markers of activity of AG-013736, a multi-target tyrosine kinase receptor inhibitor, in metastatic renal cell cancer (RCC). J Clin Oncol. 2005;23(16S):abstr 3003.

    Google Scholar 

  60. • Xu CF, Bing NX, Ball HA, Rajagopalan D, Sternberg CN, Hutson TE, et al. Pazopanib efficacy in renal cell carcinoma: evidence for predictive genetic markers in angiogenesis-related and exposure-related genes. J Clin Oncol. 2011;29(18):2557–64. doi:10.1200/JCO.2010.32.9110. Evaluation of single nucleotide polymorphisms associated with response and tolerability to VEGF receptor kinase inhibitors in advanced renal cell carcinoma.

    Article  PubMed  CAS  Google Scholar 

  61. • Garcia-Donas J, Esteban E, Leandro-Garcia LJ, Castellano DE, del Alba AG, Climent MA, et al. Single nucleotide polymorphism associations with response and toxic effects in patients with advanced renal-cell carcinoma treated with first-line sunitinib: a multicentre, observational, prospective study. Lancet Oncol. 2011;12(12):1143–50. doi:10.1016/S1470-2045(11)70266-2. Evaluation of single nucleotide polymorphisms associated with response and tolerability to VEGF receptor kinase inhibitors in advanced renal cell carcinoma.

    Article  PubMed  CAS  Google Scholar 

  62. Hanrahan EO, Lin HY, Kim ES, Yan S, Du DZ, McKee KS, et al. Distinct patterns of cytokine and angiogenic factor modulation and markers of benefit for vandetanib and/or chemotherapy in patients with non-small-cell lung cancer. J Clin Oncol. 2010;28(2):193–201. doi:10.1200/JCO.2009.22.4279.

    Article  PubMed  CAS  Google Scholar 

  63. Paez-Ribes M, Allen E, Hudock J, Takeda T, Okuyama H, Vinals F, et al. Antiangiogenic therapy elicits malignant progression of tumors to increased local invasion and distant metastasis. Canc Cell. 2009;15(3):220–31. doi:10.1016/j.ccr.2009.01.027.

    Article  CAS  Google Scholar 

  64. Ebos JM, Lee CR, Cruz-Munoz W, Bjarnason GA, Christensen JG, Kerbel RS. Accelerated metastasis after short-term treatment with a potent inhibitor of tumor angiogenesis. Canc Cell. 2009;15(3):232–9. doi:10.1016/j.ccr.2009.01.021.

    Article  CAS  Google Scholar 

  65. Ebos JM, Lee CR, Christensen JG, Mutsaers AJ, Kerbel RS. Multiple circulating proangiogenic factors induced by sunitinib malate are tumor-independent and correlate with antitumor efficacy. Proc Natl Acad Sci U S A. 2007;104(43):17069–74. doi:10.1073/pnas.0708148104.

    Article  PubMed  CAS  Google Scholar 

  66. • Lindauer A, Di Gion P, Kanefendt F, Tomalik-Scharte D, Kinzig M, Rodamer M, et al. Pharmacokinetic/pharmacodynamic modeling of biomarker response to sunitinib in healthy volunteers. Clin Pharmacol Ther. 2010;87(5):601–8. doi:10.1038/clpt.2010.20. VEGF receptor kinase inhibitors induce multiple host-derived cytokines and other biologically active mediators.

    Article  PubMed  CAS  Google Scholar 

  67. • Huang D, Ding Y, Zhou M, Rini BI, Petillo D, Qian CN, et al. Interleukin-8 mediates resistance to antiangiogenic agent sunitinib in renal cell carcinoma. Cancer Res. 2010;70(3):1063–71. doi:10.1158/0008-5472.CAN-09-3965. Identification of candidate mediators of resistance to sunitinib.

    Article  PubMed  CAS  Google Scholar 

  68. • Shojaei F, Lee JH, Simmons BH, Wong A, Esparza CO, Plumlee PA, et al. HGF/c-Met acts as an alternative angiogenic pathway in sunitinib-resistant tumors. Cancer Res. 2010;70(24):10090–100. doi:10.1158/0008-5472.CAN-10-0489. Identification of candidate mediators of resistance to sunitinib.

    Article  PubMed  CAS  Google Scholar 

  69. Beerepoot LV, Mehra N, Vermaat JS, Zonnenberg BA, Gebbink MF, Voest EE. Increased levels of viable circulating endothelial cells are an indicator of progressive disease in cancer patients. Ann Oncol. 2004;15(1):139–45.

    Article  PubMed  CAS  Google Scholar 

  70. Mancuso P, Burlini A, Pruneri G, Goldhirsch A, Martinelli G, Bertolini F. Resting and activated endothelial cells are increased in the peripheral blood of cancer patients. Blood. 2001;97(11):3658–61.

    Article  PubMed  CAS  Google Scholar 

  71. Solovey A, Lin Y, Browne P, Choong S, Wayner E, Hebbel RP. Circulating activated endothelial cells in sickle cell anemia. N Engl J Med. 1997;337(22):1584–90. doi:10.1056/NEJM199711273372203.

    Article  PubMed  CAS  Google Scholar 

  72. George F, Brouqui P, Boffa MC, Mutin M, Drancourt M, Brisson C, et al. Demonstration of Rickettsia conorii-induced endothelial injury in vivo by measuring circulating endothelial cells, thrombomodulin, and von Willebrand factor in patients with Mediterranean spotted fever. Blood. 1993;82(7):2109–16.

    PubMed  CAS  Google Scholar 

  73. Gao D, Nolan DJ, Mellick AS, Bambino K, McDonnell K, Mittal V. Endothelial progenitor cells control the angiogenic switch in mouse lung metastasis. Science. 2008;319(5860):195–8. doi:10.1126/science.1150224.

    Article  PubMed  CAS  Google Scholar 

  74. Shaked Y, Ciarrocchi A, Franco M, Lee CR, Man S, Cheung AM, et al. Therapy-induced acute recruitment of circulating endothelial progenitor cells to tumors. Science. 2006;313(5794):1785–7. doi:10.1126/science.1127592.

    Article  PubMed  CAS  Google Scholar 

  75. Shaked Y, Henke E, Roodhart JM, Mancuso P, Langenberg MH, Colleoni M, et al. Rapid chemotherapy-induced acute endothelial progenitor cell mobilization: implications for antiangiogenic drugs as chemosensitizing agents. Canc Cell. 2008;14(3):263–73. doi:10.1016/j.ccr.2008.08.001.

    Article  CAS  Google Scholar 

  76. Bhatt RS, Zurita AJ, O'Neill A, Norden-Zfoni A, Zhang L, Wu HK, et al. Increased mobilisation of circulating endothelial progenitors in von Hippel-Lindau disease and renal cell carcinoma. Br J Cancer. 2011;105(1):112–7. doi:10.1038/bjc.2011.186.

    Article  PubMed  CAS  Google Scholar 

  77. Gruenwald V, Beutel G, Schuch-Jantsch S, Reuter C, Ivanyi P, Ganser A, et al. Circulating endothelial cells are an early predictor in renal cell carcinoma for tumor response to sunitinib. BMC Cancer. 2010;10:695. doi:10.1186/1471-2407-10-695.

    Article  PubMed  Google Scholar 

  78. Mancuso A, Di Paola ED, Leone A, Catalano A, Calabro F, Cerbone L, et al. Phase II escalation study of sorafenib in patients with metastatic renal cell carcinoma who have been previously treated with anti-angiogenic treatment. BJU Int. 2012;109(2):200–6. doi:10.1111/j.1464-410X.2011.10421.x.

    Article  PubMed  CAS  Google Scholar 

  79. Wu HK, Jonasch E, Wood C, Tannir NM, Matin S, McKee KS, et al., editors. Circulating endothelial cells (CEC) and progenitors (CEP) and VEGFR-1-expressing monocytes as biomarkers for patients (pts) with renal cell carcinoma (RCC). Proceedings of the 100th Annual Meeting of the American Association for Cancer Research; 2009 Apr 18–22; Denver, CO: LB-268.

  80. Farace F, Gross-Goupil M, Tournay E, Taylor M, Vimond N, Jacques N, et al. Levels of circulating CD45(dim)CD34(+)VEGFR2(+) progenitor cells correlate with outcome in metastatic renal cell carcinoma patients treated with tyrosine kinase inhibitors. Br J Cancer. 2011;104(7):1144–50. doi:10.1038/bjc.2011.72.

    Article  PubMed  CAS  Google Scholar 

  81. Beaudry P, Force J, Naumov GN, Wang A, Baker CH, Ryan A, et al. Differential effects of vascular endothelial growth factor receptor-2 inhibitor ZD6474 on circulating endothelial progenitors and mature circulating endothelial cells: implications for use as a surrogate marker of antiangiogenic activity. Clin Cancer Res. 2005;11(9):3514–22. doi:10.1158/1078-0432.CCR-04-2271.

    Article  PubMed  CAS  Google Scholar 

  82. Vroling L, van der Veldt AA, de Haas RR, Haanen JB, Schuurhuis GJ, Kuik DJ, et al. Increased numbers of small circulating endothelial cells in renal cell cancer patients treated with sunitinib. Angiogenesis. 2009;12(1):69–79. doi:10.1007/s10456-009-9133-9.

    Article  PubMed  CAS  Google Scholar 

  83. Qian BZ, Pollard JW. Macrophage diversity enhances tumor progression and metastasis. Cell. 2010;141(1):39–51. doi:10.1016/j.cell.2010.03.014.

    Article  PubMed  CAS  Google Scholar 

  84. Coffelt SB, Lewis CE, Naldini L, Brown JM, Ferrara N, De Palma M. Elusive identities and overlapping phenotypes of proangiogenic myeloid cells in tumors. Am J Pathol. 2010;176(4):1564–76. doi:10.2353/ajpath.2010.090786.

    Article  PubMed  Google Scholar 

  85. Shojaei F, Wu X, Malik AK, Zhong C, Baldwin ME, Schanz S, et al. Tumor refractoriness to anti-VEGF treatment is mediated by CD11b + Gr1+ myeloid cells. Nat Biotechnol. 2007;25(8):911–20. doi:10.1038/nbt1323.

    Article  PubMed  CAS  Google Scholar 

  86. Finke J, Ko J, Rini B, Rayman P, Ireland J, Cohen P. MDSC as a mechanism of tumor escape from sunitinib mediated anti-angiogenic therapy. Int Immunopharmacol. 2011;11(7):856–61. doi:10.1016/j.intimp.2011.01.030.

    Article  PubMed  CAS  Google Scholar 

  87. • Rodriguez PC, Ernstoff MS, Hernandez C, Atkins M, Zabaleta J, Sierra R, et al. Arginase I-producing myeloid-derived suppressor cells in renal cell carcinoma are a subpopulation of activated granulocytes. Cancer Res. 2009;69(4):1553–60. doi:10.1158/0008-5472.CAN-08-1921. Description of the phenotypic characteristics of a subset of circulating myeloid-derived suppressor cells in renal cell carcinoma patients.

    Article  PubMed  CAS  Google Scholar 

  88. Ko JS, Zea AH, Rini BI, Ireland JL, Elson P, Cohen P, et al. Sunitinib mediates reversal of myeloid-derived suppressor cell accumulation in renal cell carcinoma patients. Clin Cancer Res. 2009;15(6):2148–57. doi:10.1158/1078-0432.CCR-08-1332.

    Article  PubMed  CAS  Google Scholar 

  89. Kusmartsev S, Su Z, Heiser A, Dannull J, Eruslanov E, Kubler H, et al. Reversal of myeloid cell-mediated immunosuppression in patients with metastatic renal cell carcinoma. Clin Cancer Res. 2008;14(24):8270–8. doi:10.1158/1078-0432.CCR-08-0165.

    Article  PubMed  CAS  Google Scholar 

  90. Kusmartsev S, Eruslanov E, Kubler H, Tseng T, Sakai Y, Su Z, et al. Oxidative stress regulates expression of VEGFR1 in myeloid cells: link to tumor-induced immune suppression in renal cell carcinoma. J Immunol. 2008;181(1):346–53.

    PubMed  CAS  Google Scholar 

  91. Ko JS, Rayman P, Ireland J, Swaidani S, Li G, Bunting KD, et al. Direct and differential suppression of myeloid-derived suppressor cell subsets by sunitinib is compartmentally constrained. Cancer Res. 2010;70(9):3526–36. doi:10.1158/0008-5472.CAN-09-3278.

    Article  PubMed  CAS  Google Scholar 

  92. Ozao-Choy J, Ma G, Kao J, Wang GX, Meseck M, Sung M, et al. The novel role of tyrosine kinase inhibitor in the reversal of immune suppression and modulation of tumor microenvironment for immune-based cancer therapies. Cancer Res. 2009;69(6):2514–22. doi:10.1158/0008-5472.CAN-08-4709.

    Article  PubMed  CAS  Google Scholar 

  93. Hipp MM, Hilf N, Walter S, Werth D, Brauer KM, Radsak MP, et al. Sorafenib, but not sunitinib, affects function of dendritic cells and induction of primary immune responses. Blood. 2008;111(12):5610–20. doi:10.1182/blood-2007-02-075945.

    Article  PubMed  CAS  Google Scholar 

  94. van Cruijsen H, van der Veldt AA, Vroling L, Oosterhoff D, Broxterman HJ, Scheper RJ, et al. Sunitinib-induced myeloid lineage redistribution in renal cell cancer patients: CD1c + dendritic cell frequency predicts progression-free survival. Clin Cancer Res. 2008;14(18):5884–92. doi:10.1158/1078-0432.CCR-08-0656.

    Article  PubMed  Google Scholar 

  95. Adotevi O, Pere H, Ravel P, Haicheur N, Badoual C, Merillon N, et al. A decrease of regulatory T cells correlates with overall survival after sunitinib-based antiangiogenic therapy in metastatic renal cancer patients. J Immunother. 2010;33(9):991–8. doi:10.1097/CJI.0b013e3181f4c208.

    Article  PubMed  CAS  Google Scholar 

  96. Bluemke K, Bilkenroth U, Meye A, Fuessel S, Lautenschlaeger C, Goebel S, et al. Detection of circulating tumor cells in peripheral blood of patients with renal cell carcinoma correlates with prognosis. Canc Epidemiol Biomarkers Prev. 2009;18(8):2190–4. doi:10.1158/1055-9965.EPI-08-1178.

    Article  CAS  Google Scholar 

  97. Gradilone A, Iacovelli R, Cortesi E, Raimondi C, Gianni W, Nicolazzo C, et al. Circulating tumor cells and “suspicious objects” evaluated through Cell Search(R) in metastatic renal cell carcinoma. Anticancer Res. 2011;31(12):4219–21.

    PubMed  CAS  Google Scholar 

Download references

Acknowledgments

Supported in part by the National Institutes of Health through MD Anderson’s Cancer Center Support Grant, CA016672. AJZ received support from the MD Anderson-AstraZeneca Alliance.

Disclosure

No potential conflicts of interest relevant to this article were reported.

Author information

Authors and Affiliations

  1. Department of Genitourinary Medical Oncology, Unit 1374, The University of Texas MD Anderson Cancer Center, 1155 Pressler Street, Houston, TX, 77030, USA

    Maria Hernandez-Yanez & Amado J. Zurita

  2. Department of Thoracic/Head & Neck Medical Oncology, Unit 432, The University of Texas MD Anderson Cancer Center, 1400 Pressler Street, Houston, TX, 77030, USA

    John V. Heymach

Authors
  1. Maria Hernandez-Yanez
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. John V. Heymach
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Amado J. Zurita
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Amado J. Zurita.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Hernandez-Yanez, M., Heymach, J.V. & Zurita, A.J. Circulating Biomarkers in Advanced Renal Cell Carcinoma: Clinical Applications. Curr Oncol Rep 14, 221–229 (2012). https://doi.org/10.1007/s11912-012-0231-2

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11912-012-0231-2

Keywords

Search

Navigation