Citations

Abstract Glioma stem cells (GSC) and epithelial–mesenchymal transition (EMT) are strongly associated with therapy resistance and tumor recurrence, but the underlying mechanisms are incompletely understood. Here, we show that S100A4 is a novel biomarker of GSCs. S100A4+ cells in gliomas are enriched with cancer cells that have tumor-initiating and sphere-forming abilities, with the majority located in perivascular niches where GSCs are found. Selective ablation of S100A4-expressing cells was sufficient to block tumor growth in vitro and in vivo. We also identified S100A4 as a critical regulator of GSC self-renewal in mouse and patient-derived glioma tumorspheres. In contrast with previous reports of S100A4 as a reporter of EMT, we discovered that S100A4 is an upstream regulator of the master EMT regulators SNAIL2 and ZEB along with other mesenchymal transition regulators in glioblastoma. Overall, our results establish S100A4 as a central node in a molecular network that controls stemness and EMT in glioblastoma, suggesting S100A4 as a candidate therapeutic target. Cancer Res; 77(19); 5360–73. ©2017 AACR.

Abstract While growing evidence suggests that tumor microenvironment can modulate stemness and the mesenchymal phenotype, little is known about how these cell states are coordinately regulated. We report that S100A4 controls both stemness and mesenchymal transition in GBM cells. In a spontaneous mouse glioma model and in primary human GBM tumorspheres, S100A4 expression is enriched in tumor-initiating cells and is required for self-renewal and tumor growth in vivo. In addition, greater than 80 percent of S100A4+ cells are associated with the tumor vasculature, a known niche for glioma stem cells, and S100A4 promotes pro-angiogenic factor expression. Interestingly, acidosis induces expression of S100A4 and the EMT regulators SNAIL1/2 and acidosis-induced EMT regulator expression requires S100A4 function. Importantly, S100A4 functions as a molecular switch between the proneural and mesenchymal states in GBM as S100A4 knockdown results in down-regulation of the mesenchymal signature genes, including the “master transcriptional regulators of mesenchymal transition”, and concurrent up-regulation of proneural signature genes. Together, these results indicate that S100A4 sits in a critical node in the molecular network that controls both glioma stem cells and the mesenchymal phenotype. Citation Format: Kin-Hoe Chow, Hee Jung Park, Joshy George, Yuanxin Chen, Andrew Gallup, Wen Jiang, Betty Y. Kim, Kyuson Yun. Regulation of GBM stemness and mesenchymal transition [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4783. doi:10.1158/1538-7445.AM2017-4783

Tumor-initiating cells (TIC) are dynamic cancer cell subsets that display enhanced tumor functions and resilience to treatment but the mechanism of TIC induction or maintenance in lung cancer is not fully understood. In this study, we show the calcium pathway transcription factor NFATc2 is a novel regulator of lung TIC phenotypes, including tumorspheres, cell motility, tumorigenesis, as well as in vitro and in vivo responses to chemotherapy and targeted therapy. In human lung cancers, high NFATc2 expression predicted poor tumor differentiation, adverse recurrence-free and cancer-specific overall survivals. Mechanistic investigations identified NFATc2 response elements in the 3’ enhancer region of SOX2, and NFATc2/SOX2 coupling upregulates ALDH1A1 by binding to its 5’ enhancer. Through this axis, oxidative stress induced by cancer drug treatment is attenuated, leading to increased resistance in a mutation-independent manner. Targeting this axis provides a novel approach for the long-term treatment of lung cancer through TIC elimination.

Background Bowel flaps are a good and reliable method to restore the continuity of the aerodigestive tract. Radiated fields, contaminated recipient sites, or depleted recipient vessels may increase the risk for ischemic injury after transfer. During ischemic events, we believe that bowel conduits with serosa have a delayed neovascularization process at its new recipient site.We conducted an ischemia/reperfusion murine model to understand the difference among bowel conduits with and without serosa. Materials and Methods Two groups of rats were compared: control group (jejunal conduit with serosa) and a target group (jejunal conduit without serosa). These conduits were harvested from the peritoneal cavity and transferred into a subcutaneous pocket. After 72 hours of transfer and pedicle ligation, histological changes related to ischemia/reperfusion were assessed. In addition, tissue markers of angiogenesis (CD34), ischemia (lactate dehydrogenase [LDH]), and inflammation (interleukin [IL]-1β and IL-6) were analyzed. Results Two groups (n = 20) of male rats were analyzed. Histology showed intact jejunal mucosa in the target group. The control group showed decreased number of mucin, globet cells, decreased height, and fragmentation of villi with the absence of intestinal glands. Markers of angiogenesis (CD34) were higher in the target group. In addition, markers of ischemia (LDH) (p = 0.0045) and inflammation (IL-1b, p = 0.0008, and IL-6, p = 0.0008) were significantly lower in the target group as compared with the control group. Conclusions In circumstances in which the recipient site does not offer an adequate and healthy bed or a vascular insult occurs, bowel flaps with less amount of serosa may be able to neovascularize faster thereby increasing its chances of survival.

ObjectiveDegeneration of oligodendroglial distal processes has been identified as an early event in multiple sclerosis (MS) lesion development. Our objective was to further define the development of the “dying‐back” oligodendrocyte lesion in situ and to model the development and potential reversibility of such responses using dissociated cultures of adult human brain‐derived oligodendrocytes.MethodsIn situ analyses were performed on glutaraldehyde‐fixed thin sections of clinically acute and pathologically active cases of MS. In vitro studies were conducted using adult human brain‐derived oligodendrocytes challenged by metabolic stress conditions (low nutrient/glucose).ResultsIn situ analyses indicated a spectrum of myelin changes in the presence of morphologically intact oligodendrocytes; these included degeneration of the inner cytoplasmic tongue with increasing sizes of intramyelinic bleb formation that could result in radial fractures of the myelin sheath. Macrophages with ingested myelin fragments were identified only once the fragmentation was established. In vitro studies indicated that oligodendrocyte process retraction, which was linked to reduced glycolytic respiratory activity, is reversible until a critical time point. Subsequent cell death was not linked to caspase‐3–dependent programs. Gene expression studies conducted at the latest reversible time point revealed reduced expression of pathways associated with cell process outgrowth and myelination, as well as with metabolic activity.InterpretationOur findings reveal the potential to protect and possibly restore myelin elaborated by existent oligodendrocytes in early and evolving MS lesions, and suggest the necessity of ongoing studies of the mechanisms underlying subsequent adult human oligodendrocyte cell death. Ann Neurol 2017;81:811–824

AbstractBackgroundWe sought to determine whether adolescents with metastatic alveolar rhabdomyosarcoma (ARMS) or embryonal RMS (ERMS) had a different event‐free survival (EFS) compared with younger patients, and to identify treatment‐related factors (adverse events, AEs) that may be associated with differences in outcome.MethodsThe prevalence of AEs in adolescents older than 13 years was compared with that in patients less than or equal to 13 years of age (Fisher exact test) in patients enrolled onto ARST0431. EFS by age and histology was compared by log–rank test.ResultsOf 109 patients, 60 (55%) were older than 13 years; they were more likely to have nausea (17 vs. 4%, P = 0.06) and pain (20 vs. 6%, P = 0.05) compared with younger patients. Adolescents were less likely to complete therapy (63 vs. 76%) and more likely to have unplanned dose modifications outside of protocol guidelines (23 vs. 2.7%). The 3‐year EFS was 26% (95% confidence interval [CI]: 15–38) for adolescents compared with 46% (95% CI: 32–60) for those less than or equal to 13 years (P = 0.011). Forty‐two (59%) adolescents with ARMS had a 3‐year EFS of 13% (95% CI: 2–23) compared with 30% (95% CI: 10–51) for those less than or equal to 13 years (P = 0.032). EFS was comparable between older and younger patients with ERMS (64 vs. 55%, P = 0.53).ConclusionsAlthough there was a significant difference in EFS and protocol compliance by age, the differences in age‐related toxicity are unlikely to account for this. Observed differences in pain and nausea by age could be real or be dependent on patient reporting of symptoms. Future studies in RMS should include patient‐reported outcomes to better evaluate health‐related quality of life.

A multiple‐slit collimator (MSC) design was introduced for scatter reduction in cone‐beam computed tomography (CBCT). Unlike most other collimators, the open and closed septa of the proposed MSC are placed in an equi‐angular interval on a circular track of the central sagittal plane. Therefore, one gantry rotation provides only the half of necessary dataset and two gantry rotations are needed to obtain full information. During the first gantry rotation, the MSC position relative to the source is fixed. For the second rotation, the MSC is rotated by the equi‐angle interval. We assume signals under the closed septa are totally attributed to scatter radiation. Then, scatter contributions under open septa are determined by interpolating them.Monte Carlo (MC) simulations for two virtual phantoms (one with a simple geometry and the other with two heterogeneities simulating the bone and the lung) were performed to evaluate the effectiveness of the system. Using the method developed, we could obtain images with significant scatter reduction. Contrast ratio (CR) improvement factors were 1.165 in a 2D projection view, and 1.210 and 1.223 at the central and peripheral slice of the reconstructed CBCT image of the simple geometry phantom.This preliminary study demonstrated that the proposed MSC, together with the imaging process technique, had a great potential to reduce scatter contribution in CBCT. Further studies will be performed to investigate the effect of various factors, such as reducing the detector size, increasing the number of history of MC simulation, and including many structures with different densities.PACS number: 87.57.C