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NF-kappaB Regulates GDF-15 to Suppress Macrophage Surveillance During Early Tumor Development
Başlık:
NF-kappaB Regulates GDF-15 to Suppress Macrophage Surveillance During Early Tumor Development
Yazar:
Ratnam, Nivedita Mohan, author.
ISBN:
9780438071513
Yazar Ek Girişi:
Fiziksel Tanımlama:
1 electronic resource (169 pages)
Genel Not:
Source: Dissertation Abstracts International, Volume: 79-10(E), Section: B.
Advisors: Denis Guttridge Committee members: Thomas Ludwig; Michael Ostrowski; Susheela Tridandapani.
Özet:
Macrophages are attracted to developing tumors and can participate in immune surveillance to eliminate neoplastic cells. In response, neoplastic cells utilize NF-kB to suppress this killing activity, but the mechanisms underlying their self-protection remain unclear. Here, we report that this dynamic interaction between tumor cells and macrophages is integrally linked by a soluble factor identified as growth and differentiation factor 15 (GDF-15). In vitro, tumor-derived GDF-15 signals in macrophages to suppress their proapoptotic activity by inhibiting TNF and nitric oxide (NO) production. In vivo, depletion of GDF-15 in Ras-driven tumor xenografts and in an orthotopic model of pancreatic cancer delayed tumor development. This delay correlated with increased infiltrating antitumor macrophages. Further, production of GDF-15 is directly regulated by NF-kB, and the colocalization of activated NF-kB and GDF-15 in epithelial ducts of human pancreatic adenocarcinoma supports the importance of this observation. Mechanistically, we found that GDF-15 suppresses macrophage activity by inhibiting TGF-b activated kinase (TAK1) signaling to NF-kB, thereby blocking synthesis of TNF and NO. Based on these results, we propose that the NF-kB/GDF-15 regulatory axis is important for tumor cells in evading macrophage immune surveillance during the early stages of tumorigenesis.
Notlar:
School code: 0168
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Yer Numarası | Demirbaş Numarası | Shelf Location | Lokasyon / Statüsü / İade Tarihi |
---|---|---|---|
XX(684892.1) | 684892-1001 | Proquest E-Tez Koleksiyonu | Arıyor... |
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