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alteration of oxygenation or nutrition related to Kattan MW. A nomogram for individualized estimation of survival
vascularization, rather than a tumor‑intrinsic among patients with brain metastasis. Neuro Oncol 2012;14:
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phenomenon. Since we could not define the factors 10. Galicich JH, Sundaresan N, Thaler HT. Surgical treatment of single
which are responsible for TNFRSF9 upregulation in brain metastasis. Evaluation of results by computerized tomography
melanoma brain metastasis, we can only speculate scanning. J Neurosurg 1980;53:63-7.
about the underlying reasons. Previous studies have 11. Noji S, Hosoi A, Takeda K, Matsushita H, Morishita Y, Seto Y,
shown that activating protein‑1 (AP‑1) and NF‑kappaB Kakimi K. Targeting spatiotemporal expression of CD137 on
tumor-infiltrating cytotoxic T lymphocytes as a novel strategy for
in particular are involved in regulating TNFRSF9. [26] In agonistic antibody therapy. J Immunother 2012;35:460-72.
contrast to AP‑1, NF‑kappaB DNA‑binding is strongly 12. Blank AE, Baumgarten P, Zeiner P, Zachskorn C, Löffler C,
upregulated in melanomas, indicating that NF‑kappaB, Schittenhelm J, Czupalla CJ, Capper D, Plate KH, Harter PN,
but not AP‑1, might be one candidate that could drive Mittelbronn M. Tumor necrosis factor receptor superfamily
member 9 (TNFRSF9) is up-regulated in reactive astrocytes in human
TNFRSF9 expression in melanomas. [27] However, gliomas. Neuropathol Appl Neurobiol 2014; Epub ahead of print.
the relevance of the NF‑κB pathway in stimulating 13. Yun CH, Lee HM, Lee SC, Kim BS, Park JW, Lee BJ. Involvement
TNFRSF9 expressing in human melanoma brain of CD137 ligand signaling in neural stem cell death. Mol Cells
2013;36:245-51.
metastasis definitely needs further investigation. 14. Harter PN, Bunz B, Dietz K, Hoffmann K, Meyermann R,
Mittelbronn M. Spatio-temporal deleted in colorectal cancer (DCC)
In summary, our results show that TNFRSF9 is frequently and netrin-1 expression in human foetal brain development.
upregulated on both tumor and endothelial cells in Neuropathol Appl Neurobiol 2010;36:623-35.
melanoma brain metastasis, without being associated 15. Harter PN, Zinke J, Scholz A, Tichy J, Zachskorn C, Kvasnicka HM,
Goeppert B, Delloye-Bourgeois C, Hattingen E, Senft C,
with patient survival or any of the clinicopathological Steinbach JP, Plate KH, Mehlen P, Schulte D, Mittelbronn M. Netrin-1
parameters assessed in our study. In conclusion, further expression is an independent prognostic factor for poor patient
studies are needed to decipher the exact role of the survival in brain metastases. PLoS One 2014;9:e92311.
TNFSF9‑TNFRSF9 axis in tumor cells, as well as cells 16. Hernandez-Chacon JA, Li Y, Wu RC, Bernatchez C, Wang Y,
Weber JS, Hwu P, Radvanyi LG. Costimulation through
of the tumor micromilieu, in order to understand its the CD137/4-1BB pathway protects human melanoma
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