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High Expression of Colony-Stimulating Factor 1 Receptor Associates with Unfavorable Cancer-Specific Survival of Patients with Clear Cell Renal Cell Carcinoma

  • Urologic Oncology
  • Published:
Annals of Surgical Oncology Aims and scope Submit manuscript

Abstract

Background

Colony-stimulating factor 1 receptor (CSF-1R), a single-pass type III transmembrane tyrosine–protein kinase, is mainly involved in inflammation and immune regulation to facilitate the progression of solid tumors. This study aimed to evaluate the impact of CSF-1R expression on clinical outcome of patients with clear cell renal cell carcinoma (ccRCC) after surgery.

Methods

We retrospectively enrolled 268 patients with ccRCC undergoing nephrectomy between 2001 and 2004. Clinicopathologic features and cancer-specific survival (CSS) were collected. Western blot analysis was performed in the pairwise comparisons of CSF-1R expression in peritumor and tumor tissues of patients with ccRCC. Immunohistochemistry was conducted to determine CSF-1R expression level in tumor specimens. Survival analysis was performed by the Kaplan–Meier method. Cox regression models were used to evaluate the impact of prognostic factors on CSS. A concordance index was calculated to measure prognostic accuracy. A prognostic nomogram was constructed on the basis of the identified independent prognostic factors.

Results

CSF-1R expression in tumor tissues was higher than in peritumor tissues in 71.4 % (5 of 7) patients. CSF-1R expression of tumor tissues was positively associated with metastasis, tumor, node, metastasis classification system (TNM) stage, Eastern Cooperative Oncology Group performance status score and poor CSS. CSF-1R expression was determined as an independent prognostic factor for CSS in patients with ccRCC. Furthermore, extension of the well-established prognostic models with CSF-1R expression presented significantly improved prognostic accuracy. An efficient prognostic nomogram was constructed on the basis of the independent prognostic factors.

Conclusions

High CSF-1R expression is a potential independent adverse prognostic factor for CSS in patients with ccRCC.

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References

  1. Siegel R, Naishadham D, Jemal A. Cancer statistics, 2013. CA Cancer J Clin. 2013;63:11–30.

    Article  PubMed  Google Scholar 

  2. Cohen HT, McGovern FJ. Renal-cell carcinoma. N Engl J Med. 2005;353:2477–90.

    Article  CAS  PubMed  Google Scholar 

  3. MacLennan S, Imamura M, Lapitan MC, et al. Systematic review of oncological outcomes following surgical management of localised renal cancer. Eur Urol. 2012;61:972–93.

    Article  PubMed  Google Scholar 

  4. Parker AS, Eckel-Passow JE, Serie D, et al. Higher expression of topoisomerase II alpha is an independent marker of increased risk of cancer-specific death in patients with clear cell renal cell carcinoma. Eur Urol. 2013;66:929–35.

    Article  PubMed Central  PubMed  Google Scholar 

  5. Joseph RW, Kapur P, Serie DJ, et al. Loss of BAP1 protein expression is an independent marker of poor prognosis in patients with low-risk clear cell renal cell carcinoma. Cancer. 2014;120:1059–67.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  6. Yang L, Wu Q, Xu L, et al. Increased expression of colony stimulating factor-1 is a predictor of poor prognosis in patients with clear-cell renal cell carcinoma. BMC Cancer. 2015;15:67.

    Article  PubMed Central  PubMed  Google Scholar 

  7. Patsialou A, Wyckoff J, Wang Y, Goswami S, Stanley ER, Condeelis JS. Invasion of human breast cancer cells in vivo requires both paracrine and autocrine loops involving the colony-stimulating factor-1 receptor. Cancer Res. 2009;69:9498–506.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  8. Mouchemore KA, Pixley FJ. CSF-1 signaling in macrophages: pleiotrophy through phosphotyrosine-based signaling pathways. Crit Rev Clin Lab Sci. 2012;49:49–61.

    Article  CAS  PubMed  Google Scholar 

  9. Yu WF, Chen J, Xiong Y, Pixley FJ, Yeung YG, Stanley ER. Macrophage proliferation is regulated through CSF-1 receptor tyrosines 544, 559, and 807. J Biol Chem. 2012;287:13694–704.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  10. Stanley ER, Chitu V. CSF-1 receptor signaling in myeloid cells. Cold Spring Harb Perspect Biol. 2014;6(6):a021857. doi:10.1101/cshperspect.a021857.

  11. Jones CV, Ricardo SD. Macrophages and CSF-1: implications for development and beyond. Organogenesis. 2013;9:249–60.

    Article  PubMed Central  PubMed  Google Scholar 

  12. Pyonteck SM, Akkari L, Schuhmacher AJ, et al. CSF-1R inhibition alters macrophage polarization and blocks glioma progression. Nat Med. 2013;19:1264–72.

    Article  CAS  PubMed  Google Scholar 

  13. Toy EP, Azodi M, Folk NL, Zito CM, Zeiss CJ, Chambers SK. Enhanced ovarian cancer tumorigenesis and metastasis by the macrophage colony-stimulating factor. Neoplasia. 2009;11:136–44.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  14. Jia JB, Wang WQ, Sun HC, et al. High expression of macrophage colony-stimulating factor-1 receptor in peritumoral liver tissue is associated with poor outcome in hepatocellular carcinoma after curative resection. Oncologist. 2010;15:732–43.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  15. Wei SW, Dai XM, Stanley ER. Transgenic expression of CSF-1 in CSF-1 receptor-expressing cells leads to macrophage activation, osteoporosis, and early death. J Leukoc Biol. 2006;80:1445–53.

    Article  CAS  PubMed  Google Scholar 

  16. Menke J, Kriegsmann J, Schimanski CC, Schwartz MM, Schwarting A, Kelley VR. Autocrine CSF-1 and CSF-1 receptor coexpression promotes renal cell carcinoma growth. Cancer Res. 2012;72:187–200.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  17. Richardsen E, Uglehus RD, Due J, Busch C, Busund LT. The prognostic impact of M-CSF, CSF-1 receptor, CD68 and CD3 in prostatic carcinoma. Histopathology. 2008;53:30–8.

    Article  CAS  PubMed  Google Scholar 

  18. Koh YW, Park C, Yoon DH, Suh C, Huh J. CSF-1R expression in tumor-associated macrophages is associated with worse prognosis in classical Hodgkin lymphoma. Am J Clin Pathol. 2014;141:573–83.

    Article  CAS  PubMed  Google Scholar 

  19. Xu J, Yun X, Jiang J, et al. Hepatitis B virus X protein blunts senescence-like growth arrest of human hepatocellular carcinoma by reducing Notch1 cleavage. Hepatology. 2010;52:142–54.

    Article  CAS  PubMed  Google Scholar 

  20. Detre S, Saclani Jotti G, Dowsett M. A “quickscore” method for immunohistochemical semiquantitation: validation for oestrogen receptor in breast carcinomas. J Clin Pathol. 1995;48:876–8.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  21. Caescu CI, Guo X, Tesfa L, et al. Colony stimulating factor-1 receptor signaling networks inhibit mouse macrophage inflammatory responses by induction of microRNA-21. Blood. 2015;125:e1–13.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  22. Digiacomo G, Ziche M, Dello Sbarba P, Donnini S, Rovida E. Prostaglandin E2 transactivates the colony-stimulating factor-1 receptor and synergizes with colony-stimulating factor-1 in the induction of macrophage migration via the mitogen-activated protein kinase ERK1/2. FASEB J. 2015;29(6):2545–54.

    Article  CAS  PubMed  Google Scholar 

  23. Jensen TO, Schmidt H, Moller HJ, et al. Macrophage markers in serum and tumor have prognostic impact in American Joint Committee on Cancer stage I/II melanoma. J Clin Oncol. 2009;27:3330–7.

    Article  PubMed  Google Scholar 

  24. Xu L, Zhu Y, Chen L, et al. Prognostic value of diametrically polarized tumor-associated macrophages in renal cell carcinoma. Ann Surg Oncol. 2014;21:3142–50.

    Article  PubMed  Google Scholar 

  25. Medrek C, Ponten F, Jirstrom K, Leandersson K. The presence of tumor associated macrophages in tumor stroma as a prognostic marker for breast cancer patients. BMC Cancer. 2012;12:306. doi:10.1186/1471-2407-12-306.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  26. Komohara Y, Hasita H, Ohnishi K, et al. Macrophage infiltration and its prognostic relevance in clear cell renal cell carcinoma. Cancer Sci. 2011;102:1424–31.

    Article  CAS  PubMed  Google Scholar 

  27. Patsialou A, Wang Y, Pignatelli J, et al. Autocrine CSF1R signaling mediates switching between invasion and proliferation downstream of TGFbeta in claudin-low breast tumor cells. Oncogene. 2015;34(21):2721–31.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  28. Xu J, Escamilla J, Mok S, et al. CSF1R signaling blockade stanches tumor-infiltrating myeloid cells and improves the efficacy of radiotherapy in prostate cancer. Cancer Res. 2013;73:2782–94.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  29. Escamilla J, Schokrpur S, Liu C, et al. CSF1 receptor targeting in prostate cancer reverses macrophage-mediated resistance to androgen blockade therapy. Cancer Res. 2015;75:950–62.

    Article  CAS  PubMed  Google Scholar 

  30. Ries CH, Cannarile MA, Hoves S, et al. Targeting tumor-associated macrophages with anti-CSF-1R antibody reveals a strategy for cancer therapy. Cancer Cell. 2014;25:846–59.

    Article  CAS  PubMed  Google Scholar 

  31. Sui X, Ma J, Han W, et al. The anticancer immune response of anti-PD-1/PD-L1 and the genetic determinants of response to anti-PD-1/PD-L1 antibodies in cancer patients. Oncotarget. 2015;6:19393–404.

    Article  PubMed Central  PubMed  Google Scholar 

  32. Massari F, Santoni M, Ciccarese C, et al. PD-1 blockade therapy in renal cell carcinoma: current studies and future promises. Cancer Treat Rev. 2015;41:114–21.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

Supported in part by grants from National Basic Research Program of China (2012CB822104), National Natural Science Foundation of China (31100629, 31270863, 31300671, 81372755, 31470794, 81401988, 81402082, 81402085, 81471621, 81472227, 81472376, 31570803, and 81572352), Program for New Century Excellent Talents in University (NCET-13-0146), and Shanghai Rising-Star Program (13QA1400300). All these study sponsors played no role in the study design or in the collection, analysis, and interpretation of data

Disclosure

The authors declare no conflict of interest.

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Authors

Corresponding authors

Correspondence to Weijuan Zhang MD, PhD or Jiejie Xu MD, PhD.

Additional information

Liu Yang and Yidong Liu contributed equally to this article, and both should be considered first author.

Electronic supplementary material

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10434_2015_4911_MOESM1_ESM.tif

Supplementary material 1 (TIFF 10014 kb). The results of “minimum P value” approach showed the score of 135 had the best discriminatory power.

10434_2015_4911_MOESM2_ESM.tif

Supplementary material 2 (TIFF 20623 kb). Kaplan-Meier analysis for CSS of patients with ccRCC in each risk group of TNM stage and UISS. Kaplan-Meier analysis for CSS of patients in TNM I+II (n = 194), TNM III+IV (n = 74), UISS low risk (LR) group (n = 100), UISS intermediate risk (IR) group (n = 142) and UISS high risk (HR) group (n = 26), respectively. P value was calculated by log-rank test.

Supplementary material 3 (DOC 60 kb)

Supplementary material 4 (DOC 32 kb)

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Yang, L., Liu, Y., An, H. et al. High Expression of Colony-Stimulating Factor 1 Receptor Associates with Unfavorable Cancer-Specific Survival of Patients with Clear Cell Renal Cell Carcinoma. Ann Surg Oncol 23, 1044–1052 (2016). https://doi.org/10.1245/s10434-015-4911-7

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  • DOI: https://doi.org/10.1245/s10434-015-4911-7

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