STAT3 is essential for the maintenance of neurosphere‐initiating tumor cells in patients with glioblastomas: A potential for targeted therapy?

Abstract

Glioblastoma (GBM), the highest-grade form of gliomas, is the most frequent and the most aggressive. Recently, a subpopulation of cells with stem cells characteristics, commonly named ''tumor-initiating stem cells'' (TISCs) or ''cancer stem cells'' (CSCs) were identified in GBM. These cells were shown to be highly resistant to chemotherapeutic drugs and to ionizing radiations. Consequently, the knowledge of the signals that regulate the functions and survival of TISCs is crucial. In our work, we describe a neurosphere-initiating cell (NS-IC) assay to quantify TISC/CSCs from patients with GBM and show that these cells are tumorigenic in vivo. We demonstrate that the intracellular signal transducer and activator of transcription STAT3 is constitutively activated by phosphorylation preferentially on serine 727 in these cells. Moreover, we demonstrate that the selective inhibition of STAT3 by the chemical compound Stattic or by siRNA STAT3 abrogates TISC/CSC proliferation and NS-IC suggesting that self-renewal of GBM ''stem-like'' cells depends on the presence of STAT3 for their maintenance. Finally, we show that inhibition of STAT3 by Stattic sensitizes TISC/CSCs to the inhibitory action of Temozolomide with a strong synergistic effect of both drugs. Overall, these results suggest that strategies focused on STAT3 inhibition are efficient at the level of ''stem-like'' cells and could be of interest for therapeutic purposes in patients with malignant GBM.

High expression of leptin receptor leads to temozolomide resistance with exhibiting stem/progenitor cell features in gliobalastoma

“…34 Villalva et al further indicated that stem cells derived from GBM expressed a constitutively phosphorylated STAT3, which was essential for the proliferative and the self-renewal capacity. 35 Thus, STAT3 activation appears as a common feature of CSC-GBM. Furthermore, ObR had full signaling capabilities and was able to activate the JAK/STAT3 pathway, the major pathway used by leptin to exert its effects.…”

Potent Targeting of the STAT3 Protein in Brain Cancer Stem Cells: A Promising Route for Treating Glioblastoma

“…In addition, a growing body of recent evidence gathered using a variety of different small molecules that indirectly inhibit STAT3 by targeting upstream molecules such as the JaK family members 6 strongly suggest that STAT3 signaling is crucial for the survival and proliferation of BTSCs and GBM both in vitro and in vivo. 7 However, because of their broad targeting nature, these drugs have limited translational potential due to numerous side effects. Hence, drugs with the ability to more specifically block STAT3 activity may provide effective treatment of GBM.…”

C1q/TNF‐related peptide 8 (CTRP8) promotes temozolomide resistance in human glioblastoma

“…The STAT3 signaling pathway is associated with TMZ chemoresistance in GBM, but the underlying mechanisms are unclear (Villalva et al ., 2011). Here, we show that RXFP1 agonist CTRP8 (Glogowska et al ., 2013) mitigated the ability of first‐line GBM drug TMZ to induce DNA damage.…”