The molecular mechanisms governing acquired tumor resistance during radiotherapy remain to be elucidated. In breast cancer patients, overexpression of HER2 (human epidermal growth factor receptor 2) is correlated with aggressive tumor growth and increased recurrence. In the present study, we demonstrate that HER2 expression can be induced by radiation in breast cancer cells with a low basal level of HER2. Furthermore, HER2-postive tumors occur at a much higher frequency in recurrent invasive breast cancer (59%) compared to the primary tumors (41%). Interestingly, NF-κB is required for radiation-induced HER2 transactivation. HER2 was found to be co-activated with basal and radiation-induced NF-κB activity in radioresistant but not radiosensitive breast cancer cell lines after long-term radiation exposure, indicating that NF-κB-mediated HER2 overexpression is involved in radiation-induced repopulation in heterogeneous tumors. Finally, we found that inhibition of HER2 resensitizes the resistant cell lines to radiation. Since HER2 is shown to activate NF-κB, our data suggest a loop-like HER2-NF-κB-HER2 pathway in radiation-induced adaptive resistance in breast cancer cells.

Emerging evidence suggests that epithelial-mesenchymal transitions (EMTs) play important roles in tumor metastasis and recurrence. Understanding molecular mechanisms that regulate the EMT process is crucial for improving treatment of hepatocellular carcinoma (HCC). MicroRNAs (miRNAs) play important roles in HCC; however, the mechanisms by which miRNAs target the EMT and their therapeutic potential remains largely unknown. To better explore the roles of miRNAs in the EMT process, we established an EMT model in HCC cells by transforming growth factor beta 1 treatment and found that several tumor-related miRNAs were significantly decreased. Among these miRNAs, miR-125b expression was most strongly suppressed. We also found down-regulation of miR-125b in most HCC cells and clinical specimens, which correlated with cellular differentiation in HCC patients. We then demonstrated that miR-125b overexpression attenuated EMT phenotype in HCC cancer cells, whereas knockdown of miR-125b promoted the EMT phenotype in vitro and in vivo. Moreover, we found that miR-125b attenuated EMT-associated traits, including chemoresistance, migration, and stemness in HCC cells, and negatively correlated with EMT and cancer stem cell (CSC) marker expressions in HCC specimens. miR-125b overexpression could inhibit CSC generation and decrease tumor incidence in the mouse xenograft model. Mechanistically, our data revealed that miR-125b suppressed EMT and EMT-associated traits of HCC cells by targeting small mothers against decapentaplegic (SMAD)2 and 4. Most important, the therapeutic delivery of synthetic miR-125b mimics decreased the target molecule of CSC and inhibited metastasis in the mice model. These findings suggest a potential therapeutic treatment of miR-125b for liver cancer. Conclusion: miR-125b exerts inhibitory effects on EMT and EMT-associated traits in HCC by SMAD2 and 4. Ectopic expression of miR125b provides a promising strategy to treat HCC. (HEPATOLOGY 2015;62:801-815) H epatocellular carcinoma (HCC) is the fifthmost common cancer in the world and has a high mortality because of a lack of effective treatments. 1 Most HCC patients display symptoms of intrahepatic metastases or postsurgical recurrence with a low survival rate. Emerging evidence suggests that the epithelial-mesenchymal transition (EMT) contributes to tumor metastasis and recurrence, including in liver

As systemic cancer therapies improve and are able to control metastatic disease outside the central nervous system, the brain is increasingly the first site of relapse. The blood–brain barrier (BBB) represents a major challenge to the delivery of therapeutics to the brain. Macrophages originating from circulating monocytes are able to infiltrate brain metastases while the BBB is intact. Here, we show that this ability can be exploited to deliver both diagnostic and therapeutic nanoparticles specifically to experimental brain metastases of breast cancer.

Background Previous studies demonstrated the dependence of cancer on nerve. Recently, a growing number of studies reveal that cancer cells share the property and regulatory network with neural stem/progenitor cells. However, relationship between the property of neural stemness and cell tumorigenicity is unknown. Results We show that neural stem/progenitor cells, but not non-neural embryonic or somatic stem/progenitor cell types, exhibit tumorigenicity and the potential for differentiation into tissue types of all germ layers when they are placed in non-native environment by transplantation into immunodeficient nude mice. Likewise, cancer cells capable of tumor initiation have the property of neural stemness because of their abilities in neurosphere formation in neural stem cell-specific serum-free medium and in differentiation potential, in addition to their neuronal differentiation potential that was characterized previously. Moreover, loss of a pro-differentiation factor in myoblasts, which have no tumorigenicity, lead to the loss of myoblast identity, and gain of the property of neural stemness, tumorigenicity and potential for re-differentiation. By contrast, loss of neural stemness via differentiation results in the loss of tumorigenicity. These suggest that the property of neural stemness contributes to cell tumorigenicity, and tumor phenotypic heterogeneity might be an effect of differentiation potential of neural stemness. Bioinformatic analysis reveals that neural genes in general are correlated with embryonic development and cancer, in addition to their role in neural development; whereas non-neural genes are not. Most of neural specific genes emerged in typical species representing transition from unicellularity to multicellularity during evolution. Genes in Monosiga brevicollis, a unicellular species that is a closest known relative of metazoans, are biased toward neural cells. Conclusions We suggest that the property of neural stemness is the source of cell tumorigenicity. This is due to that neural biased unicellular state is the ground state for multicellularity and hence cell type diversification or differentiation during evolution, and tumorigenesis is a process of restoration of neural ground state in somatic cells along a default route that is pre-determined by an evolutionary advantage of neural state.

In this paper, we present an ultrasonically powered implantable micro-oxygen generator (IMOG) that is capable of in situ tumor oxygenation through water electrolysis. Such active mode of oxygen generation is not affected by increased interstitial pressure or abnormal blood vessels that typically limit the systemic delivery of oxygen to hypoxic regions of solid tumors. Wireless ultrasonic powering (2.15 MHz) was employed to increase the penetration depth and eliminate the directional sensitivity associated with magnetic methods. In addition, ultrasonic powering allowed for further reduction in the total size of the implant by eliminating the need for a large area inductor. IMOG has an overall dimension of 1.2 mm × 1.3 mm × 8 mm, small enough to be implanted using a hypodermic needle or a trocar. In vitro and ex vivo experiments showed that IMOG is capable of generating more than 150 μA which, in turn, can create 0.525 μL/min of oxygen through electrolytic disassociation. In vivo experiments in a well-known hypoxic pancreatic tumor models (1 cm (3) in size) also verified adequate in situ tumor oxygenation in less than 10 min.

Stem cells have emerged as a potential therapy for a range of neural insults, but their application in Alzheimer's disease (AD) is still limited and the mechanisms underlying the cognitive benefits of stem cells remain to be elucidated. Here, the effects of clinical‐grade human umbilical cord‐derived mesenchymal stem cells (hUC‐MSCs) on the recovery of cognitive ability in SAMP8 mice, a senescence‐accelerated mouse model of AD is explored. A functional assay identifies that the core functional factor hepatocyte growth factor (HGF) secreted from hUC‐MSCs plays critical roles in hUC‐MSC‐modulated recovery of damaged neural cells by down‐regulating hyperphosphorylated tau, reversing spine loss, and promoting synaptic plasticity in an AD cell model. Mechanistically, structural and functional recovery, as well as cognitive enhancements elicited by exposure to hUC‐MSCs, are at least partially mediated by HGF in the AD hippocampus through the activation of the cMet‐AKT‐GSK3β signaling pathway. Taken together, these data strongly implicate HGF in mediating hUC‐MSC‐induced improvements in functional recovery in AD models.

Polycomb group (PcG) proteins are epigenetic transcriptional repressors that orchestrate numerous developmental processes and have been implicated in the maintenance of embryonic stem (ES) cell state. More recent evidence suggests that a subset of PcG proteins engages in transcriptional activation in some cellular contexts, but how this property is exerted remains largely unknown. Here, we generated ES cells with single or combined disruption of polycomb group RING finger protein 3 (Pcgf3) and Pcgf5 with the CRISPR-Cas9 technique. We report that although these mutant cells maintained their self-renewal and colony-forming capacity, they displayed severe defects in mesoderm differentiation and Using RNA-seq to analyze transcriptional profiles of ES cells with single or combined Pcgf3/5 deficiencies, we found that in contrast to the canonical role of the related polycomb repressive complex 1 (PRC1) in gene repression, Pcgf3/5 mainly function as transcriptional activators driving expression of many genes involved in mesoderm differentiation. Proteomic approaches and promoter occupancy analyses helped to establish an extended Pcgf3/5 interactome and identified several novel Pcgf3/5 interactors. These included testis-expressed 10 (Tex10), which may directly contribute to transcriptional activation via the transcriptional co-activator p300. Furthermore, Pcgf3/5 deletion in ES cells substantially reduced the occupancy of Tex10 and p300 at target genes. Finally, we demonstrated that Pcgf3/5 are essential for regulating global levels of the histone modifier H2AK119ub1 in ES cells. Our findings establish Pcgf3/5 as transcriptional activators that interact with Tex10 and p300 in ES cells and point to redundant activity of Pcgf3/5 in pluripotency maintenance.

Alzheimer's disease (AD) is an incurable neurodegenerative disease and many types of stem cells have been used in AD therapy with some favorable effects. In this study, we investigated the potential therapeutical effects of human dental pulp stem cells (hDPSCs) on AD cellular model which established by okadaic acid (OA)-induced damage to human neuroblastoma cell line, SH-SY5Y, in vitro for 24 h. After confirmed the AD cellular model, the cells were co-culture with hDPSCs by transwell co-culture system till 24 h for treatment. Then the cytomorphology of the hDPSCs-treated cells were found to restore gradually with re-elongation of retracted dendrites. Meanwhile, Cell Counting Kit-8 assay and Hoechst 33258 staining showed that hDPSCs caused significant increase in the viability and decrease in apoptosis of the model cells, respectively. Observation of DiI labeling also exhibited the prolongation dendrites in hDPSCs-treated cells which were obviously different from the retraction dendrites in AD model cells. Furthermore, specific staining of α-tubulin and F-actin demonstrated that the hDPSCs-treated cells had the morphology of restored neurons, with elongated dendrites, densely arranged microfilaments, and thickened microtubular fibrils. In addition, results from western blotting revealed that phosphorylation at Ser 396 of Tau protein was significantly suppressed by adding of hDPSCs. These results indicate that hDPSCs may promote regeneration of damaged neuron cells in vitro model of AD and may serve as a useful cell source for treatment of AD.