In the absence of adequate oxygen, cancer cells that are grown in hypoxic solid tumors resist treatment using antitumor drugs (such as doxorubicin, DOX), owing to their attenuated intracellular production of reactive oxygen species (ROS). Hyperbaric oxygen (HBO) therapy favorably improves oxygen transport to the hypoxic tumor tissues, thereby increasing the sensitivity of tumor cells to DOX. However, the use of HBO with DOX potentiates the ROS-mediated cytotoxicity of the drug toward normal tissues. In this work, we hypothesize that regional oxygen treatment by an implanted oxygen-generating depot may enhance the cytotoxicity of DOX against malignant tissues in a highly site-specific manner, without raising systemic oxygen levels. Upon implantation close to the tumor, the oxygen-generating depot reacts with the interstitial medium to produce oxygen in situ, effectively shrinking the hypoxic regions in the tumor tissues. Increasing the local availability of oxygen causes the cytotoxicity of DOX that is accumulated in the tumors to be significantly enhanced by the elevated production of ROS, ultimately allaying the hypoxia-induced DOX resistance in solid malignancies. Importantly, this enhancement of cytotoxicity is limited to the site of the tumors, and this feature of the system that is proposed herein is unique.

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Recent studies demonstrated that long non-coding RNAs (lncRNAs) have a critical role in the regulation of cancer progression and metastasis. However, little is known whether lncRNA regulated nasopharyngeal carcinoma (NPC) cell radioresistance. In the present study, we found that MALAT1 was significantly upregulated in NPC cell lines and tissues. Knockdown of MALAT1 could sensitize NPC cells to radiation both in vitro and in vivo. Interestingly, we found that MALAT1 regulated radioresistance by modulating cancer stem cell (CSC) activity. Furthermore, we found that there was reciprocal repression between MALAT1 and miR-1, and slug was identified as a downstream target of miR-1. Taking these observations into consideration, we proposed that MALAT1 regulated CSC activity and radioresistance by modulating miR-1/slug axis, which indicated that MALAT1 could act as a therapeutic target for NPC patients.

Oncolytic viruses have the potential to induce immunogenic cell death (ICD) that may provoke potent and longlasting anti-cancer immunity. Here we aimed to characterize the ICD-inducing ability of wild-type Adenovirus (Ad), Semliki Forest virus (SFV) and Vaccinia virus (VV). We did so by investigating the cell death and immune-activating properties of virus-killed tumor cells. Ad-infection of tumor cells primarily activates autophagy, but also activate events of necroptotic and pyroptotic cell death. SFV infection on the other hand primarily activates immunogenic apoptosis while VV activates necroptosis. All viruses mediated lysis of tumor cells leading to the release of danger-associated molecular patterns, triggering of phagocytosis and maturation of dendritic cells (DCs). However, only SFV-infected tumor cells triggered significant T helper type 1 (Th1)-cytokine release by DCs and induced antigen-specific T-cell activation. Our results elucidate cell death processes activated upon Ad, SFV, and VV infection and their potential to induce T cell-mediated anti-tumor immune responses. This knowledge provides important insight for the choice and design of therapeutically successful virus-based immunotherapies.

Recent studies demonstrated that long noncoding RNAs (lncRNAs) have a critical role in the regulation of cancer progression and metastasis. However, little is known about the mechanism through which metastasis-associated lung adencarcinoma transcript 1 (MALAT1) exerts its oncogenic activity, and the interaction between MALAT1 and microRNA remains largely unknown. In the present study, we reported that MALAT1 was upregulated in triple-negative breast cancer (TNBC) tissues. Knockdown of MALAT1 inhibited proliferation, motility, and increased apoptosis in vitro. In vivo study indicated that knockdown of MALAT1 inhibited tumor growth and metastasis. Patients with high MALAT1 expression had poorer overall survival time than those with low MALAT1 expression. In addition, our findings demonstrate a reciprocal negative control relationship between MALAT1 and miR-1: downregulation of MALAT1 increased expression of microRNA-1 (miR-1), while overexpression of miR-1 decreased MALAT1 expression. Slug was identified as a direct target of miR-1. We proposed that MALAT1 exerted its function through the miR-1/slug axis. In summary, we proposed that MALAT1 may be a target for TNBC therapy.

The aberrant expression of cyclin-dependent kinase-4 (CDK4) has previously been observed in human brain glioma. Furthermore, it is observed that up-regulation of CDK4 is associated with therapy resistance and relapse. However, the mechanisms behind these phenomena remain unclear. Here, we demonstrated that elevated CDK4 expression is correlated with poor prognosis in glioma after radiotherapy and that CDK4 knockdown conferred radiosensitivity in glioma cell lines. CDK4 was identified as potential downstream target of miR-124 through bioinformatics analysis and dual-firefly luciferase reporter assay. Furthermore, restoration of miR-124 could confer radiosensitivity. Cell differentiation agent-2 (CDA-2) mimicked the effect of miR-124 restoration and CDK4 knockdown, and sensitized xenografts to radiation in an animal model. Our findings demonstrated for the first time that CDK4 was a downstream target of miR-124 and that CDA-2 could radiosensitize Glioblastoma multiforme cells through the MiR-124-CDK4 axis.

Adenovirus serotype 5 (Ad5) is widely used as an oncolytic agent for cancer therapy. However, its infectivity is highly dependent on the expression level of coxsackievirus-adenovirus receptor (CAR) on the surfaces of tumor cells. Furthermore, infected cells overproduce adenovirus fiber proteins, which are released prior to cell lysis. The released fibers block CAR on noninfected neighboring cells, thereby preventing progeny virus entry. Our aim was to add a CAR-independent infection route to Ad5 to increase the infectivity of tumor cells with low CAR expression and prevent the fiber-masking problem. We constructed Ad5 viruses that encode the protein transduction domain (PTD) of the HIV-1 Tat protein (Tat-PTD) in hypervariable region 5 (HVR5) of the hexon protein. Tat-PTD functions as a cell-penetrating peptide, and Tat-PTD-modified Ad5 showed a dramatic increased transduction of CAR-negative cell lines compared to unmodified vector. Moreover, while tumor cell infectivity was severely reduced for Ad5 in the presence of fiber proteins, it was only marginally reduced for Tat-PTD-modified Ad5. Furthermore, because of the sequence alteration in the hexon HVR, coagulation factor X-mediated virus uptake was significantly reduced. Mice harboring human neuroblastoma and neuroendocrine tumors show suppressed tumor growths and prolonged survival when treated with Tat-PTD-modified oncolytic viruses. Our data suggest that modification of Ad5 with Tat-PTD in HVR5 expands its utility as an oncolytic agent.

Glioblastomas are aggressive astrocytomas characterized by endothelial cell proliferation and abnormal vasculature, which can cause brain edema and increase patient morbidity. We identified the heparin-binding cytokine pleiotrophin as a driver of vascular abnormalization in glioma. Pleiotrophin abundance was greater in high-grade human astrocytomas and correlated with poor survival. Anaplastic lymphoma kinase (ALK), which is a receptor that is activated by pleiotrophin, was present in mural cells associated with abnormal vessels. Orthotopically implanted gliomas formed from GL261 cells that were engineered to produce pleiotrophin showed increased microvessel density and enhanced tumor growth compared with gliomas formed from control GL261 cells. The survival of mice with pleiotrophin-producing gliomas was shorter than that of mice with gliomas that did not produce pleiotrophin. Vessels in pleiotrophin-producing gliomas were poorly perfused and abnormal, a phenotype that was associated with increased deposition of vascular endothelial growth factor (VEGF) in direct proximity to the vasculature. The growth of pleiotrophin-producing GL261 gliomas was inhibited by treatment with the ALK inhibitor crizotinib, the ALK inhibitor ceritinib, or the VEGF receptor inhibitor cediranib, whereas control GL261 tumors did not respond to either inhibitor. Our findings link pleiotrophin abundance in gliomas with survival in humans and mice, and show that pleiotrophin promotes glioma progression through increased VEGF deposition and vascular abnormalization.