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Urol Oncol. 2018 Nov;36(11):502.e15-502.e24. doi: 10.1016/j.urolonc.2018.07.013. Epub 2018 Aug 28.

Receptor activator of NF-κB (RANK)-mediated induction of metastatic spread and association with poor prognosis in renal cell carcinoma.

Author information

1
Institute of Medical Immunology at the Martin Luther University Halle/Wittenberg, Halle, Germany.
2
Department of Urology, University Medicine at the Ernst-Moritz-Arndt University Greifswald, Greifswald, Germany.
3
Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at the University of California, Los Angeles, CA.
4
Department of Hematology and Oncology Research, Amgen Inc., Seattle, WA.
5
Institute of Urologic Oncology, Department of Urology, David Geffen School of Medicine at the University of California, Los Angeles, CA.
6
Department of Urology, University Medicine at the Ernst-Moritz-Arndt University Greifswald, Greifswald, Germany; Institute of Urologic Oncology, Department of Urology, David Geffen School of Medicine at the University of California, Los Angeles, CA; Institute of Medical Biochemistry and Molecular Medicine, University Medicine at the Ernst-Moritz-Arndt University Greifswald, Greifswald, Germany. Electronic address: md.nkroeger@gmail.com.

Abstract

BACKGROUND:

Inhibition of the receptor activator of NF-κB ligand (RANKL) has become a standard of care supportive treatment to prevent skeletal related events in cancer patients. Moreover, RANKL inhibition has been implicated with better survival outcome in lung cancer, while RANKL expression induces tumor progression and metastatic spread in vivo in breast cancer. Whether RANK/RANKL may have an impact on the pathogenesis of clear cell renal cell carcinoma (ccRCC) is currently unknown.

PATIENTS AND METHODS:

A retrospective tissue micro array (TMA)-study was carried out determining the expression of RANK/RANKL in primary tumors of 306 ccRCC patients. Additionally, 24 ccRCC cell lines were employed for in vitro analyses of the RANK/RANKL axis including cell proliferation, migration and anchorage independent growth.

RESULTS:

RANK (+) vs. RANK (-) tumors had both worse cancer specific survival (CSS) (6.3 vs. 1.3 years; p < 0.001) and recurrence free survival (RFS) (9.9 vs. 5.8 years; p < 0.001). RANK (+) (HR 2.21; p < 0.001) was an independent prognostic factor for CSS and RFS (HR 4.98; p < 0.001). RANKL treatment resulted in increased proliferation, soft agar growth, and colony formation of RANK (+) RCC cell lines, which could be reversed by treatment with an NF-κB inhibitor and with a combination of osteoprotegrin and RANKL in vitro.

CONCLUSIONS:

RANK is expressed in ccRCC tissue, correlates with clinicopathological features, survival outcome, and when stimulated with RANKL can induce ccRCC progression in vitro. Consequently, RANKL inhibition combined with standard of care treatment may be a promising approach to improve ccRCC patient's survival.

KEYWORDS:

Biomarker; Cancer therapy; RANK; RANKL inhibition; Renal cell carcinoma

PMID:
30170981
DOI:
10.1016/j.urolonc.2018.07.013
[Indexed for MEDLINE]

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