Insulin-like growth factor-binding protein 2 (IGFBP2) is increasingly recognized as a glioma oncogene, emerging as a target for therapeutic intervention. In this study, we used an integrative approach to characterizing the IGFBP2 network, combining transcriptional profiling of human glioma with validation in glial cells and the replicationcompetent ASLV long terminal repeat with a splice acceptor/tv-a glioma mouse system. We demonstrated that IGFBP2 expression is closely linked to genes in the integrin and integrin-linked kinase (ILK) pathways and that these genes are associated with prognosis. We further showed that IGFBP2 activates integrin β1 and downstream invasion pathways, requires ILK to induce cell motility, and activates NF-κB. Most significantly, the IGFBP2/integrin/ILK/NF-κB network functions as a physiologically active signaling pathway in vivo by driving glioma progression; interfering with any point in the pathway markedly inhibits progression. The results of this study reveal a signaling pathway that is both targetable and highly relevant to improving the survival of glioma patients. E levated insulin-like growth factor-binding protein 2 (IGFBP2) expression is found in many malignancies and can often serve as a prognostic factor (1). It is one of the most consistently elevated proteins in high-grade glioma, and high IGFBP2 expression is directly correlated with poor survival (2, 3). The finding that IGFBP2 is a driver of glioma development and progression in a spontaneous mouse model has provided the most convincing evidence of the significance of IGFBP2 in glioma (4). Given the clinical challenge of treating glioma and the lack of effective therapies, the elucidation of key protein-signaling networks that are essential to tumor growth and maintenance, such as IGFBP2, could provide new approaches to therapeutic intervention and significantly affect clinical outcome.IGFBP2 is a member of the IGF system in which it binds and modulates IGF1 and IGF2 activity (5); however, IGFBP2 is better known for its IGF-independent roles in cancer, such as integrin binding through an arginine-glycine-aspartic acid (RGD) motif in the C terminus (6, 7). The interaction of IGFBP2 with integrin α5 has been reported to promote cellular de-adhesion and migration in Ewing's sarcoma (8), and we previously found that integrin α5 binding to IGFBP2 is responsible for the promigratory characteristics of glioma cells (7). Integrins transduce signaling through proteins such as integrin-linked kinase (ILK), which binds to the cytoplasmic domains of β1 and β3 integrins (9). ILK contributes to the oncogenic phenotype by stimulating invasion and migration, encouraging anchorage-independent growth, and inducing tumor angiogenesis (10). Although the function of ILK has been intimately associated with integrin function, no association with IGFBP2 has been reported.IGFBP2 has been reported to influence multiple transcriptional factors, including the up-regulation of NF-κB (6), which activates the transcription of an array of cancer-pro...

The molecular basis underlying the particularly aggressive nature of pancreatic ductal adenocarcinoma (PDAC) still remains unclear. Here we report evidence that the insulin-like growth factor-binding protein IGFBP2 acts as a potent oncogene to drive its extremely malignant character. We found that elevated IGFBP2 expression in primary tumors was associated with lymph node metastasis and shorter survival in PDAC patients. Enforced expression of IGFBP2 promoted invasion and metastasis of PDAC cells in vitro and in vivo by inducing NF-κB-dependent epithelial-mesenchymal transition (EMT). Mechanistic investigations revealed that IGFBP2 induced the nuclear translocation and phosphorylation of the p65 NF-κB subunit through the PI3K/Akt/IKKβ pathway. Conversely, enforced expression of PTEN blunted this signaling pathway and restored an epithelial phenotype to PDAC cells in the presence of overexpressed IGFBP2. Overall, our results identify IGFBP2 as a pivotal regulator of an EMT axis in PDAC, the activation of which is sufficient to confer the characteristically aggressive clinical features of this disease.

Pre-exposure prophylaxis (PrEP) with antiretroviral (ARV) drugs are effective at preventing human immunodeficiency virus (HIV) transmission. However, implementation of PrEP presents significant challenges due to poor user adherence, low accessibility to ARVs and multiple routes of HIV exposure. To address these challenges, we developed the nanochannel delivery implant (NDI), a subcutaneously implantable device for sustained and constant delivery of tenofovir alafenamide (TAF) and emtricitabine (FTC) for HIV PrEP. Unlike existing drug delivery platforms with finite depots, the NDI incorporates ports allowing for transcutaneous refilling upon drug exhaustion. NDI-mediated drug delivery in rhesus macaques resulted in sustained release of both TAF and FTC for 83 days, as indicated by concentrations of TAF, FTC and their respectively metabolites in plasma, PBMCs, rectal mononuclear cells and tissues associated with HIV transmission. Notably, clinically relevant preventative levels of tenofovir diphosphate were achieved as early as 3 days after NDI implantation. We also demonstrated the feasibility of transcutaneous drug refilling to extend the duration of PrEP drug delivery in NHPs. Overall, the NDI represents an innovative strategy for long-term HIV PrEP administration in both developed and developing countries.

Insulin-like growth factor binding protein 2 (IGFBP2) is a pleiotropic oncogenic protein that has both extracellular and intracellular functions. Despite a clear causal role in cancer development, the tumor-promoting mechanisms of IGFBP2 are poorly understood. The contributions of intracellular IGFBP2 to tumor development and progression are also unclear. Here we present evidence that both exogenous IGFBP2 treatment and cellular IGFBP2 overexpression lead to aberrant activation of EGFR, which subsequently activates STAT3 signaling. Furthermore, we demonstrate that IGFBP2 augments the nuclear accumulation of EGFR to potentiate STAT3 transactivation activities, via activation of the nuclear EGFR signaling pathway. Nuclear IGFBP2 directly influences the invasive and migratory capacities of human glioblastoma cells, providing a direct link between intracellular (and particularly nuclear) IGFBP2 and cancer hallmarks. These activities are also consistent with the strong association between IGFBP2 and STAT3-activated genes derived from the TCGA database for human glioma. A high level of all 3 proteins (IGFBP2, EGFR and STAT3) was strongly correlated with poorer survival in an independent patient dataset. These results identify a novel tumor-promoting function for IGFBP2 of activating EGFR/STAT3 signaling and facilitating EGFR accumulation in the nucleus, thereby deregulating EGFR signaling by 2 distinct mechanisms. As targeting EGFR in glioma has been relatively unsuccessful, this study suggests that IGFBP2 may be a novel therapeutic target.

Mitigating the foreign body response (FBR) to implantable medical devices (IMDs) is critical for successful long‐term clinical deployment. The FBR is an inevitable immunological reaction to IMDs, resulting in inflammation and subsequent fibrotic encapsulation. Excessive fibrosis may impair IMDs function, eventually necessitating retrieval or replacement for continued therapy. Therefore, understanding the implant design parameters and their degree of influence on FBR is pivotal to effective and long lasting IMDs. This review gives an overview of FBR as well as anti‐FBR strategies. Furthermore, we highlight recent advances in biomimetic approaches to resist FBR, focusing on their characteristics and potential biomedical applications.