Work

698. Eliminating TLR9+ Prostate Cancer Stem Cells In Vivo Using NF-kB/RELA- or STAT3-Targeting CpG-siRNA Conjugates

Year: 2015

Type: article

Abstract: Treatment of hormone-refractory and frequently reoccurring prostate cancers is a major clinical challenge. Here, we demonstrate that Toll-like Receptor 9 (TLR9) is commonly upregulated in late-stage prostate cancers and provides a potential therapeutic target. As a sensor of immunogenic cell death, TLR9 bridges intra-prostatic inflammation to cancer stem cell phenotype. Our limited dilution/serial transplantation experiments in vivo demonstrate that TLR9 is essential for prostate cancer cells’ potential to propagate and self-renew. In addition, low expression or silencing of TLR9 limits the clonogenic potential and mesenchymal stem cell-like properties of prostate cancer cells. Genome-wide transcriptional analysis of cancer cells isolated from xenotransplanted prostate tumors revealed a unique TLR9-dependent gene expression signature. Further analysis of the TLR9 downstream signaling indicated that tumorigenic transcription factors NF-kB/RELA and STAT3 cooperate to orchestrate expression of stem cell-related genes. Both RELA and STAT3 bound and co-regulated promoters of NKX3.1 and KLF4 prostate cancer stem cell-related genes. We further demonstrated the feasibility of targeting prostate cancer-propagating potential in vivo by TLR9-targeted siRNA delivery using CpG-siRNA conjugates. Local administration of CpG-RELAsiRNA or CpG-STAT3siRNA but not control conjugates, inhibited tumor growth and cancer cell clonogenic potential in two xenotransplanted prostate cancer models. Selective elimination of tumor-propagating cells using TLR9-targeted blockade of NF-?B/RELA and STAT3 signaling has potential for clinical translation to benefit patients with late-stage prostate cancers.

Source: Molecular Therapy

DOI: 10.1016/s1525-0016(16)34307-6