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Relationship Between Increased Expression of the Axl/Gas6 Signal Cascade and Prognosis of Patients with Upper Tract Urothelial Carcinoma

  • Translational Research and Biomarkers
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Annals of Surgical Oncology Aims and scope Submit manuscript

Abstract

Purpose

Axl, which is in the TAM family of receptor tyrosine kinases, and its ligand, growth arrest-specific gene 6 (Gas6), have been associated with worse prognoses after the surgical treatment of some types of cancers. We herein investigated the biological significance of the protein expression of Axl and Gas6 on the outcomes of patients with upper tract urothelial carcinoma (UTUC).

Methods

The protein expression of Axl and Gas6 was evaluated by immunohistochemistry, and their relationships with clinicopathological features were investigated in surgical specimens obtained from 161 patients who had been surgically treated for UTUC.

Results

Axl labeling was strong in 67 of 161 (42 %) cases, while Gas6 labeling was strong in 72 of 161 (45 %) cases. The strong expression of Axl correlated with that of Gas6. A high pathological stage (p = 0.009), strong expression of Gas6 (p = 0.038), and strong expression of Axl (p = 0.016) were independent factors for predicting worse cancer-specific survival (CSS). In a subgroup analysis of patients with pT < 2 (N = 53), no significant difference in CSS was observed between patients weakly and strongly expressing Axl/Gas6. In contrast, a subgroup analysis of patients with pT ≥ 2 (N = 108) revealed that the expression levels of Axl and Gas6 correlated with CSS.

Conclusion

The protein expression of Axl and its ligand Gas6 may be a useful indicator for a worse clinical outcome in UTUC patients, especially patients with pT ≥ 2, who underwent radical nephroureterectomy.

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References

  1. Oosterlinck W. Ureteral tumour: a specific upper urinary tract transitional cell carcinoma. Eur Urol. 2007;51(5):1164–5.

    Article  PubMed  Google Scholar 

  2. Oya M, Kikuchi E, Committee for Establishment of Clinical Practice Guideline for Management of Upper Tract Urothelial Carcinoma, Japanese Urological Association. Evidenced-based clinical practice guideline for upper tract urothelial carcinoma (summary–Japanese Urological Association, 2014 edition). Int J Urol. 2015;22(1):3–13.

    Article  PubMed  Google Scholar 

  3. Verma A, Warner SL, Vankayalapati H, Bearss DJ, Sharma S. Targeting Axl and Mer kinases in cancer. Mol Cancer Ther. 2011;10(10):1763–73.

    Article  PubMed  CAS  Google Scholar 

  4. Angelillo-Scherrer A, Burnier L, Flores N, et al. Role of Gas6 receptors in platelet signaling during thrombus stabilization and implications for antithrombotic therapy. J Clin Invest. 2005;115(2):237–46.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  5. Angelillo-Scherrer A, Burnier L, Lambrechts D, et al. Role of Gas6 in erythropoiesis and anemia in mice. J Clin Invest. 2008;118(2):583–96.

    PubMed  CAS  PubMed Central  Google Scholar 

  6. Tjwa M, Bellido-Martin L, Lin Y, et al. Gas6 promotes inflammation by enhancing interactions between endothelial cells, platelets, and leukocytes. Blood. 2008;111(8):4096–105.

    Article  PubMed  CAS  Google Scholar 

  7. Bellosta P, Zhang Q, Goff SP, Basilico C. Signaling through the ARK tyrosine kinase receptor protects from apoptosis in the absence of growth stimulation. Oncogene. 1997;15(20):2387–97.

    Article  PubMed  CAS  Google Scholar 

  8. Loges S, Schmidt T, Tjwa M, et al. Malignant cells fuel tumor growth by educating infiltrating leukocytes to produce the mitogen Gas6. Blood. 2010;115(11):2264–73.

    Article  PubMed  CAS  Google Scholar 

  9. Sun W, Fujimoto J, Tamaya T. Coexpression of Gas6/Axl in human ovarian cancers. Oncology. 2004;66(6):450–57.

    Article  PubMed  CAS  Google Scholar 

  10. Green J, Ikram M, Vyas J, et al. Overexpression of the Axl tyrosine kinase receptor in cutaneous SCC-derived cell lines and tumours. Br J Cancer. 2006;94(10):1446–51.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  11. Ou WB, Corson JM, Flynn DL, et al. AXL regulates mesothelioma proliferation and invasiveness. Oncogene. 2011;30(14):1643–52.

    Article  PubMed  CAS  Google Scholar 

  12. Gustafsson A, Martuszewska D, Johansson M, et al. Differential expression of Axl and Gas6 in renal cell carcinoma reflecting tumor advancement and survival. Clin Cancer Res. 2009;15(14):4742–9.

    Article  PubMed  CAS  Google Scholar 

  13. Hutterer M, Knyazev P, Abate A, et al. Axl and growth arrest-specific gene 6 are frequently overexpressed in human gliomas and predict poor prognosis in patients with glioblastoma multiforme. Clin Cancer Res. 2008;14(1):130–38.

    Article  PubMed  CAS  Google Scholar 

  14. Epstein JI, Amin MB, Reuter VR, Mostofi FK. The World Health Organization/International Society of Urological Pathology consensus classification of urothelial (transitional cell) neoplasms of the urinary bladder. Bladder Consensus Conference Committee. Am J Surg Pathol. 1998;22(12):1435–48.

    Article  PubMed  CAS  Google Scholar 

  15. Ishikawa M, Sonobe M, Nakayama E, et al. Higher expression of receptor tyrosine kinase Axl, and differential expression of its ligand, Gas6, predict poor survival in lung adenocarcinoma patients. Ann Surg Oncol. 2013;20(Suppl 3):S467–76.

    Article  PubMed  Google Scholar 

  16. Ye X, Li Y, Stawicki S, et al. An anti-Axl monoclonal antibody attenuates xenograft tumor growth and enhances the effect of multiple anticancer therapies. Oncogene. 2010;29(38):5254–64.

    Article  PubMed  CAS  Google Scholar 

  17. Linger RM, Keating AK, Earp HS, Graham DK. TAM receptor tyrosine kinases: biologic functions, signaling, and potential therapeutic targeting in human cancer. Adv Cancer Res. 2008;100:35–83.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  18. Vajkoczy P, Knyazev P, Kunkel A, et al. Dominant-negative inhibition of the Axl receptor tyrosine kinase suppresses brain tumor cell growth and invasion and prolongs survival. Proc Natl Acad Sci USA. 2006;103(15):5799–804.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  19. Wu CW, Li AF, Chi CW, et al. Clinical significance of AXL kinase family in gastric cancer. Anticancer Res. 2002;22(2B):1071–8.

    PubMed  CAS  Google Scholar 

  20. Koorstra JB, Karikari CA, Feldmann G, et al. The Axl receptor tyrosine kinase confers an adverse prognostic influence in pancreatic cancer and represents a new therapeutic target. Cancer Biol Ther. 2009;8(7):618–26.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  21. Yauch RL, Januario T, Eberhard DA, et al. Epithelial versus mesenchymal phenotype determines in vitro sensitivity and predicts clinical activity of erlotinib in lung cancer patients. Clin Cancer Res. 2005;11(24 Pt 1):8686–98.

    Article  PubMed  CAS  Google Scholar 

  22. Ben-Batalla I, Schultze A, Wroblewski M, et al. Axl, a prognostic and therapeutic target in acute myeloid leukemia mediates paracrine crosstalk of leukemia cells with bone marrow stroma. Blood. 2013;122(14):2443–52.

    Article  PubMed  CAS  Google Scholar 

  23. Yeh CY, Shin SM, Yeh HH, et al. Transcriptional activation of the Axl and PDGFR-alpha by c-Met through a ras- and Src-independent mechanism in human bladder cancer. BMC Cancer. 2011;11:139.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  24. Holland SJ, Pan A, Franci C, et al. R428, a selective small molecule inhibitor of Axl kinase, blocks tumor spread and prolongs survival in models of metastatic breast cancer. Cancer Res. 2010;70(4):1544–54.

    Article  PubMed  CAS  Google Scholar 

  25. Wang X, Saso H, Iwamoto T, et al. TIG1 promotes the development and progression of inflammatory breast cancer through activation of Axl kinase. Cancer Res. 2013;73(21):6516–25.

    Article  PubMed  CAS  Google Scholar 

  26. Kurzrock R, Sherman SI, Ball DW, et al. Activity of XL184 (Cabozantinib), an oral tyrosine kinase inhibitor, in patients with medullary thyroid cancer. J Clin Oncol. 2011;29(19):2660–66.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  27. Mayer EL, Krop IE. Advances in targeting SRC in the treatment of breast cancer and other solid malignancies. Clin Cancer Res. 2010;16(14):3526–32.

    Article  PubMed  CAS  Google Scholar 

  28. Mosse YP, Lim MS, Voss SD, et al. Safety and activity of crizotinib for paediatric patients with refractory solid tumours or anaplastic large-cell lymphoma: a Children’s Oncology Group phase 1 consortium study. Lancet Oncol. 2013;14(6):472–80.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  29. Tibes R, Fine G, Choy G, et al. A phase I, first-in-human dose-escalation study of amuvatinib, a multi-targeted tyrosine kinase inhibitor, in patients with advanced solid tumors. Cancer Chemother Pharmacol. 2013;71(2):463–71.

    Article  PubMed  CAS  Google Scholar 

  30. Sayan AE, Stanford R, Vickery R, et al. Fra-1 controls motility of bladder cancer cells via transcriptional upregulation of the receptor tyrosine kinase AXL. Oncogene. 2012;31(12):1493–503.

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Urology, Keio University School of Medicine, Tokyo, Japan

    Seiya Hattori MD, Eiji Kikuchi MD, PhD, Takeo Kosaka MD, PhD, Yasumasa Miyazaki MD, Nobuyuki Tanaka MD, PhD, Akira Miyajima MD, PhD & Mototsugu Oya MD, PhD

  2. Department of Pathology, Keio University School of Medicine, Tokyo, Japan

    Shuji Mikami MD, PhD

Authors
  1. Seiya Hattori MD
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  2. Eiji Kikuchi MD, PhD
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  3. Takeo Kosaka MD, PhD
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  4. Yasumasa Miyazaki MD
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  5. Nobuyuki Tanaka MD, PhD
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  6. Akira Miyajima MD, PhD
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  7. Shuji Mikami MD, PhD
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  8. Mototsugu Oya MD, PhD
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Corresponding author

Correspondence to Eiji Kikuchi MD, PhD.

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Hattori, S., Kikuchi, E., Kosaka, T. et al. Relationship Between Increased Expression of the Axl/Gas6 Signal Cascade and Prognosis of Patients with Upper Tract Urothelial Carcinoma. Ann Surg Oncol 23, 663–670 (2016). https://doi.org/10.1245/s10434-015-4848-x

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  • DOI: https://doi.org/10.1245/s10434-015-4848-x

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