Abstract SY06-02: Revisiting the STATs of cancer: Emergence of stem-like cancer cells

Abstract

Abstract Activation of the STAT3 signaling pathway is now well established as an important factor in cancer progression and as a promising molecular target for cancer therapy. Persistent STAT3 activation in tumor cells prevents apoptosis and promotes cell proliferation. In the tumor microenvironment, STAT3 activation enhances angiogenesis and suppresses anti-tumor immune responses. Communication between tumor cells and stromal cells in the tumor microenvironment, by inflammatory cytokines like interleukin (IL)-6, results in a feed-forward loop that enhances cancer progression and confers resistance to therapy. Recently, we have uncovered another critical role for STAT3 in cancer progression and resistance to therapy. We now show that activation of STAT3 signaling promotes a stem-like cell phenotype in prostate cancer, concomitant with loss of androgen receptor (AR) expression. AR is important for prostate cancer progression, and androgen deprivation often leads to drug resistance and eventual cancer recurrence. We demonstrate that loss of AR expression as a consequence of androgen ablation results in STAT3 activation in prostate cancer cells. This STAT3 activation in turn leads to development of prostate cancer stem-like cells. AR downregulation-induced STAT3 activation is mediated through increased IL-6 expression in the tumor microenvironment. Elevated stem-like cell markers in human prostate tumor specimens coincides with high STAT3 activity and low AR expression. Treatment of mice with soluble IL-6 receptor or silencing STAT3 in tumor cells suppresses prostate tumor growth and inhibits development of stem-like cancer cells. In sum, our results demonstrate that blockade of AR mediates activation of STAT3 signaling through up-regulation of IL-6, which is associated with development of a stem-like cancer cell phenotype. Conversely, inhibition of the IL-6/STAT3 pathway diminishes the stem-like cancer cell population, and results in reduced tumor growth. Our findings provide new mechanistic insights into the role of STAT3 activation upon AR blockade on prostate cancer relapse and drug resistance. We further propose inhibition of STAT3 signaling in combination with anti-androgens as a potential strategy to prevent emergence of drug-resistant recurrent prostate cancer. Citation Format: Richard Jove. Revisiting the STATs of cancer: Emergence of stem-like cancer cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr SY06-02. doi:10.1158/1538-7445.AM2014-SY06-02