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Nivi-Dissertation 2nd Submission.pdf (10.9 MB)

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NF-kB Regulates GDF-15 to Suppress Macrophage Surveillance During Early Tumor Development

Ratnam, Nivedita Mohan
http://rave.ohiolink.edu/etdc/view?acc_num=osu1505306161707059

Abstract Details

2017, Doctor of Philosophy, Ohio State University, Molecular, Cellular and Developmental Biology.
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.
Denis Guttridge, Dr. (Advisor)
Michael Ostrowski, Dr. (Committee Member)
Thomas Ludwig, Dr. (Committee Member)
Susheela Tridandapani, Dr. (Committee Member)
169 p.
Biology; Cellular Biology; Genetics; Immunology; Molecular Biology; Oncology

Recommended Citations

Citations

  • Ratnam, N. M. (2017). NF-kB Regulates GDF-15 to Suppress Macrophage Surveillance During Early Tumor Development [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1505306161707059

    APA Style (7th edition)

  • Ratnam, Nivedita. NF-kB Regulates GDF-15 to Suppress Macrophage Surveillance During Early Tumor Development. 2017. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1505306161707059.

    MLA Style (8th edition)

  • Ratnam, Nivedita. "NF-kB Regulates GDF-15 to Suppress Macrophage Surveillance During Early Tumor Development." Doctoral dissertation, Ohio State University, 2017. http://rave.ohiolink.edu/etdc/view?acc_num=osu1505306161707059

    Chicago Manual of Style (17th edition)

osu1505306161707059
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© 2017, all rights reserved.
This open access ETD is published by The Ohio State University and OhioLINK.