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%0 Thesis
%A Schröder, Anne
%T Inhibition of the IL-6/STAT3 signaling pathway for therapeutic intervention in prostate carcinogenesis and cancer cell differentiation
%C Aachen
%I Publikationsserver der RWTH Aachen University
%M RWTH-CONV-144746
%P VI, 139 S. : Ill., graph. Darst.
%D 2013
%Z Aachen, Techn. Hochsch., Diss., 2013
%X Prostate cancer is the most common cause of male cancer-related deaths in Western countries. Current treatment relies on targeting the androgen receptor (AR) signaling by hormone deprivation therapy. However, hormone depletion results in the selection of drug resistant, highly metastatic tumor cells that survive targeted therapy. Hence, the initial response to treatment is almost always followed by tumor relapse, which is called hormone refractory prostate cancer (HRPC). The development of HRPC is not well understood and remains a challenge for prostate cancer therapy. One model to explain HRPC development proposes the survival of so called cancer stem cells (CSC). CSCs share phenotypical features with embryonic stem cells, are highly drug resistant, and have been suggested to resupply the highly proliferative tumor cell population. STAT3 has been shown to maintain the pluripotent state of glioblastoma stem cells. Moreover, the IL-6/STAT3 signaling pathway has been emphasized to play a critical role in the progression of prostate tumors. In this study, the role of the IL-6/STAT3 signaling pathway in the initiation, progression and recurrence of prostate cancer upon hormone ablation therapy was determined. It was demonstrated that down-regulation of AR by either hormone deprivation therapy or gene-silencing results in the up-regulation of IL-6/STAT3 signaling. Overactive IL-6/STAT3 signal transduction coincided with CSC phenotype development. CSC marker expressions were up-regulated in tumors treated with anti-androgens, metastatic tumor cells as well as human prostate cancer. In human prostate cancer tissues, elevated cancer stem cell markers coincided with those cells exhibiting high STAT3 activity and low AR expression, supporting an opposing role of AR and STAT3 in prostate cancer stem cell development. Targeting the IL-6/STAT3 signaling pathway by gene silencing or using an IL-6 receptor fusion protein (IL-6RFP) resulted in significantly reduced tumor growth which was associated with decreased proliferation, angiogenesis and anti-apoptosis. It was found that overexpression of STAT3beta, a dominant-negative form of STAT3alpha, resulted in diminished prostate tumor growth, reduced angiogenesis and metastasis. Moreover, STAT3 inhibition by either using IL-6RFP or gene-silencing resulted in decreased CSC phenotype development in vitro and in vivo. Application of a combined therapy using the IL-6RFP and the anti-androgen bicalutamide improved tumor growth delay compared to the respective mono-therapies. In addition, IL-6 inhibition by IL-6RFP overwrote the anti-androgen induced CSC phenotype development.
%K Krebsforschung (SWD)
%K Prostatakrebs (SWD)
%K Interleukin 6 (SWD)
%K Androgen-Rezeptor (SWD)
%F PUB:(DE-HGF)11
%9 Dissertation / PhD Thesis
%U https://publications.rwth-aachen.de/record/229870