The distortion of growth factor signalling is the most important prerequisite in tumour progression. Transforming growth factor-beta (TGFbeta) signalling regulates tumour progression by a tumour cell-autonomous mechanism or through tumour-stroma interaction, and has either a tumour-suppressing or tumour-promoting function depending on cellular context. Such inherent complexity of TGFbeta signalling results in arduous, but promising, assignments for developing therapeutic strategies against malignant tumours. As numerous cellular context-dependent factors tightly maintain the balance of TGFbeta signalling and contribute to the regulation of TGFbeta-induced cell responses, in this Review we discuss how they maintain the balance of TGFbeta signalling and how their collapse leads to tumour progression.

Despite aggressive surgery, radiotherapy, and chemotherapy, treatment of malignant glioma remains formidable. Although the concept of cancer stem cells reveals a new framework of cancer therapeutic strategies against malignant glioma, it remains unclear how glioma stem cells could be eradicated. Here, we demonstrate that autocrine TGF-beta signaling plays an essential role in retention of stemness of glioma-initiating cells (GICs) and describe the underlying mechanism for it. TGF-beta induced [corrected] expression of Sox2, a stemness gene, and this induction was mediated by Sox4, a direct TGF-beta target gene. Inhibitors of TGF-beta signaling drastically deprived tumorigenicity of GICs by promoting their differentiation, and these effects were attenuated in GICs transduced with Sox2 or Sox4. Furthermore, GICs pretreated with TGF-beta signaling inhibitor exhibited less lethal potency in intracranial transplantation assay. These results identify an essential pathway for GICs, the TGF-beta-Sox4-Sox2 pathway, whose disruption would be a therapeutic strategy against gliomas.

High-mobility group box 1 (HMGB1) is a DNA-binding protein abundantly expressed in the nucleus that has gained much attention for its regulation of immunity and inflammation. Despite this, whether and how HMGB1 contributes to protective and/or pathological responses in vivo is unclear. In this study, we constructed Hmgb1-floxed (Hmgb1 f/f ) mice to achieve the conditional inactivation of the gene in a cell-and tissue-specific manner by crossing these mice with an appropriate Cre recombinase transgenic strain. Interestingly, although mice with HMGB1 ablation in myeloid cells apparently develop normally, they are more sensitive to endotoxin shock compared with control mice, which is accompanied by massive macrophage cell death. Furthermore, these mice also show an increased sensitivity to Listeria monocytogenes infection. We also provide evidence that the loss of HMGB1 in macrophages results in the suppression of autophagy, which is commonly induced by lipopolysaccharide stimulation or L. monocytogenes infection. Thus, intracellular HMGB1 contributes to the protection of mice from endotoxemia and bacterial infection by mediating autophagy in macrophages. These newly generated HMGB1 conditional knockout mice will serve a useful tool with which to study further the in vivo role of this protein in various pathological conditions. LPS | IL-1β | IL-18

The interferon-regulatory factor (IRF) family, originally identified as transcriptional regulators of the type I interferon system, consists of nine members in mammals. A large number of studies have revealed the versatile and critical functions performed by this transcription factor family in immunity and other biological processes. Most notably, the advances in the study of signal transducing innate immune receptors have placed many IRF members as central mediators in the regulation of innate immune responses. In parallel, mechanistic studies have made it clearer that many IRFs exert their function either in cooperation or competition with other factors. In this article, we discuss current advances on the multipurpose and critical functions of IRFs in the regulation of innate immunity, particularly as they instruct adaptive immunity.