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Targeted Therapeutics against Biliary Cancer Elicit Concurrent Tumor Extrinsic Effects on Immune Suppression and Cancer Cachexia

Yang, Jennifer
http://rave.ohiolink.edu/etdc/view?acc_num=osu1461777433

Abstract Details

2016, Doctor of Philosophy, Ohio State University, Molecular, Cellular and Developmental Biology.
Biliary tract cancer (BTC) represents a rare but deadly disease due to difficulties in diagnosis and identifying effective treatment regimens. Even with continual improvement in patient care and therapeutic agents, the survival rate has remained relatively unchanged in the last 30 years. Compounding with the ever increasing rate of incidence worldwide, it is crucial to find an effective way to target this disease. BTC, like many human cancers, is multifaceted and affects the host in multitude of ways. The cancer is marked by dysregulated Ras/Raf/MEK/ERK, PI3K/Akt, and Jak/STAT pathways that contribute to the survival, proliferation, angiogenesis, and resistance of BTC to targeted therapy. These signaling pathways also lead to upregulated secretion of soluble mediators, such as interleukin-6 (IL-6), to create an immunosuppressive tumor microenvironment, which in turn feeds back to the tumor by providing an inflammatory setting as well as an infrastructure for proliferation and metastasis. IL-6 is also an important mediator of cancer cachexia, which is a wasting of skeletal muscle observed in BTC patients. In order to address the different components of a very complex disease, we systematically looked at the effect that specific pathway inhibitors have intrinsically on the cancer cells, as well as extrinsically on the immune cells and the skeletal muscle. First, looking at the tumor compartment using human BTC cell lines (HuCCT1, HuH28, WITT, Mz-ChA-1, SNU-245, SNU-478), we observed upregulation of pERK and pSTAT3 in 5 out of 6 cell lines, while 2 had high pAkt expression. Treatment with single agent MEK inhibitor and the combination of MEK and PI3K inhibitors had differential effects in vitro. BTC patients have previously been shown to have upregulated IL-6 levels that could contribute to immune suppression. Analysis of BTC supernatants found to have a variety of soluble chemokines and cytokines. These supernatants were co-cultured with peripheral blood mononuclear cells (PBMCs) isolated from healthy donor blood, which led to increase the expansion of functional immunosuppressive myeloid derived suppressor cells (MDSCs). BTC supernatants also induced STAT3 and STAT5 protein expression when incubated with PBMCs. Neutralization of IL-6 and GM-CSF in these supernatants lead to inhibition of STAT3 and STAT5 phosphorylation, respectively. Neutralization of IL-6, not GM-CSF, from the supernatants reduced the expansion of MDSCs, suggesting that IL-6 is the primary cytokine involved in this process. In a previous phase II multicenter trial using MEK inhibitor selumetinib, BTC patients had significantly higher skeletal muscle mass compared to those on standard therapy, leading us to hypothesize that MEK inhibitor could have muscle protective effects. Using a model of cancer cachexia, MEK inhibition lead to preservation of weight in these mice, and the addition of PI3K inhibitor did not negate this muscle protective activity. Depletion of CD4+ and CD8+ T cells from these mice did not affect the anti-tumor activity of MEK and PI3K inhibitors. Together, this work demonstrated that targeted inhibition can have tumor intrinsic and tumor extrinsic activities that can be leveraged to benefit patients with BTC cancer.
Gregory Lesinski (Advisor)
Jia-Yuh Lin (Committee Member)
Natarajan Muthusamy (Committee Member)
Tridandapani Susheela (Committee Member)
191 p.
Cellular Biology

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Citations

  • Yang, J. (2016). Targeted Therapeutics against Biliary Cancer Elicit Concurrent Tumor Extrinsic Effects on Immune Suppression and Cancer Cachexia [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1461777433

    APA Style (7th edition)

  • Yang, Jennifer. Targeted Therapeutics against Biliary Cancer Elicit Concurrent Tumor Extrinsic Effects on Immune Suppression and Cancer Cachexia. 2016. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1461777433.

    MLA Style (8th edition)

  • Yang, Jennifer. "Targeted Therapeutics against Biliary Cancer Elicit Concurrent Tumor Extrinsic Effects on Immune Suppression and Cancer Cachexia." Doctoral dissertation, Ohio State University, 2016. http://rave.ohiolink.edu/etdc/view?acc_num=osu1461777433

    Chicago Manual of Style (17th edition)

osu1461777433
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© 2016, all rights reserved.
This open access ETD is published by The Ohio State University and OhioLINK.