TP53 undergoes multiple RNA-splicing events, resulting in at least nine mRNA transcripts encoding at least 12 functionally different protein isoforms. Antibodies specific to p53 protein isoforms have proven difficult to develop, thus researchers must rely on the transcript information to infer isoform abundance. In this study, we used deep RNA-seq, droplet digital PCR (ddPCR), and real-time quantitative reverse transcriptase PCR (RT-qPCR) from nine human cell lines and RNA-seq data available for tumors in The Cancer Genome Atlas to analyze TP53 splice variant expression. All three methods detected expression of the FL/40TP53α_T1 variant in most human tumors and cell lines. However, other less abundant variants were only detected with PCR-based methods. Using RNA-seq simulation analysis, we determined why RNA-seq is unable to detect less abundant TP53 transcripts and discuss the implications of these findings for the general interpretation of RNA-seq data. Cancer Res; 76(24); 7151–9. ©2016 AACR.
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Cancer Medicine by Alexandros G.Sfakianakis,Anapafseos 5 Agios Nikolaos,Crete 72100,Greece,tel :00302841026182 & 00306932607174
Πέμπτη 15 Δεκεμβρίου 2016
A Study of TP53 RNA Splicing Illustrates Pitfalls of RNA-seq Methodology
Transglutaminase Interaction with {alpha}6/{beta}4-Integrin Stimulates YAP1-Dependent {Delta}Np63{alpha} Stabilization and Leads to Enhanced Cancer Stem Cell Survival and Tumor Formation
Transglutaminase 2 (TG2) expression is required for epidermal squamous cell carcinoma cancer stem cell survival. However, the molecular signaling mechanisms triggered by TG2 that mediate this survival action are not well understood. Here we show that TG2 is constitutively expressed in ECS cells, where it interacts with α6/β4 integrin to stimulate FAK and Src signaling, leading to PI3K activation of phosphoinositide-dependent kinase 1 (PDK1). PDK1 inhibits Hippo signaling, leading to enhanced nuclear accumulation of YAP1, which interacted with and stabilized ΔNp63α to enhance epidermal squamous cell carcinoma spheroid formation, invasion, and migration. Overall, these findings suggest that constitutive TG2 expression results in stabilization of ΔNp63α, leading to maintenance of cancer stem cell properties and enhanced tumor formation. Cancer Res; 76(24); 7265–76. ©2016 AACR.
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A Hyaluronidase-Responsive Nanoparticle-Based Drug Delivery System for Targeting Colon Cancer Cells
The ability of nanoparticles to target tumors and to enable site-specific drug release provides a unique system for the delivery of effective therapy with reduced toxic side effects. In this study, we used mesoporous silica nanoparticles (MSN) to fabricate a targeted drug delivery system that is responsive to hyaluronidase (HAase). Following engraftment of desthiobiotin onto the surface of MSN, a streptavidin complex was generated, which was functionalized with biotin-modified hyaluronic acid (HA) to enable controlled drug release at cancer cells expressing HAase. Various technologies were used to confirm the successful fabrication of this MSN-based nanocarrier system for targeted drug delivery. In vitro analyses showed that the release of doxorubicin hydrochloride (Dox) was accelerated significantly in the presence of biotin or HAase and accelerated further in the presence of biotin and HAase. Uptake by cancer cells was mediated efficiently by CD44 receptor–mediated endocytosis and the MSN exhibited good biocompatibility in vitro and in vivo. MSN-HA/Dox nanoparticles induced apoptosis in cancer cells more efficiently than free doxorubicin and inhibited tumor growth with minimal systemic toxicity in vivo. Collectively, our findings offered a preclinical proof of concept for a novel targeted drug delivery carrier system for cancer therapy. Cancer Res; 76(24); 7208–18. ©2016 AACR.
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Glucose Metabolism Reprogrammed by Overexpression of IKKϵ Promotes Pancreatic Tumor Growth
Aberrant expression of the kinase IKKε in pancreatic ductal adenocarcinoma (PDAC) has been associated with poor prognosis. In this study, we define a pathobiologic function for IKKε in reprogramming glucose metabolism and driving progression in PDAC. Silencing IKKε in PDAC cells, which overexpressed it endogenously, was sufficient to reduce malignant cell growth, clonogenic potential, glucose consumption, lactate secretion, and expression of genes involved in glucose metabolism, without impacting the basal oxygen consumption rate. IKKε silencing also attenuated c-Myc in a manner associated with diminished signaling through an AKT/GSK3β/c-MYC phosphorylation cascade that promoted MYC nuclear accumulation. In an orthotopic mouse model, IKKε-silenced PDAC exhibited a relative reduction in glucose uptake, tumorigenicity, and metastasis. Overall, our findings offer a preclinical mechanistic rationale to target IKKε to improve the therapeutic management of PDAC in patients. Cancer Res; 76(24); 7254–64. ©2016 AACR.
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Quantifying the Dynamics of Field Cancerization in Tobacco-Related Head and Neck Cancer: A Multiscale Modeling Approach
High rates of local recurrence in tobacco-related head and neck squamous cell carcinoma (HNSCC) are commonly attributed to unresected fields of precancerous tissue. Because they are not easily detectable at the time of surgery without additional biopsies, there is a need for noninvasive methods to predict the extent and dynamics of these fields. Here, we developed a spatial stochastic model of tobacco-related HNSCC at the tissue level and calibrated the model using a Bayesian framework and population-level incidence data from the Surveillance, Epidemiology, and End Results (SEER) registry. Probabilistic model analyses were performed to predict the field geometry at time of diagnosis, and model predictions of age-specific recurrence risks were tested against outcome data from SEER. The calibrated models predicted a strong dependence of the local field size on age at diagnosis, with a doubling of the expected field diameter between ages at diagnosis of 50 and 90 years, respectively. Similarly, the probability of harboring multiple, clonally unrelated fields at the time of diagnosis was found to increase substantially with patient age. On the basis of these findings, we hypothesized a higher recurrence risk in older than in younger patients when treated by surgery alone; we successfully tested this hypothesis using age-stratified outcome data. Further clinical studies are needed to validate the model predictions in a patient-specific setting. This work highlights the importance of spatial structure in models of epithelial carcinogenesis and suggests that patient age at diagnosis may be a critical predictor of the size and multiplicity of precancerous lesions. Cancer Res; 76(24); 7078–88. ©2016 AACR.
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Preclinical Evidence That 3'-Deoxy-3'-[18F]Fluorothymidine PET Can Visualize Recovery of Hematopoiesis after Gemcitabine Chemotherapy
Molecular imaging with the PET tracer 3′-deoxy-3′-[18F]fluorothymidine ([18F]FLT) allows assessment of the proliferative state of organs in vivo. Although used primarily in the oncology clinic, it can also shed light on the proliferation of other tissues, as demonstrated here for monitoring hematopoietic organs that recover after myelosuppressive chemotherapy. In the NMRI nude mouse model, we observed up to a 4.5-fold increase in [18F]FLT uptake in bone marrow and spleen on days 2, 3, and 5 after treatment with gemcitabine, a chemotherapeutic agent that is powerfully myelosuppressive in the model. Specifically, we observed (i) a reduced spleen weight; (ii) reduced bone marrow cell counts and proliferation (BrdUrd flow cytometry, spleen IHC; 6 hours/day 1); and (iii) reduced leukocytes in peripheral blood (day 5). In conclusion, our results show how [18F]FLT PET can provide a powerful tool to noninvasively visualize the proliferative status of hematopoietic organs after myelosuppressive therapy. Cancer Res; 76(24); 7089–95. ©2016 AACR.
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Alternative Polyadenylation in Triple-Negative Breast Tumors Allows NRAS and c-JUN to Bypass PUMILIO Posttranscriptional Regulation
Alternative polyadenylation (APA) is a process that changes the posttranscriptional regulation and translation potential of mRNAs via addition or deletion of 3′ untranslated region (3′ UTR) sequences. To identify posttranscriptional-regulatory events affected by APA in breast tumors, tumor datasets were analyzed for recurrent APA events. Motif mapping of the changed 3′ UTR regions found that APA-mediated removal of Pumilio regulatory elements (PRE) was unusually common. Breast tumor subtype–specific APA profiling identified triple-negative breast tumors as having the highest levels of APA. To determine the frequency of these events, an independent cohort of triple-negative breast tumors and normal breast tissue was analyzed for APA. APA-mediated shortening of NRAS and c-JUN was seen frequently, and this correlated with changes in the expression of downstream targets. mRNA stability and luciferase assays demonstrated APA-dependent alterations in RNA and protein levels of affected candidate genes. Examination of clinical parameters of these tumors found those with APA of NRAS and c-JUN to be smaller and less proliferative, but more invasive than non-APA tumors. RT-PCR profiling identified elevated levels of polyadenylation factor CSTF3 in tumors with APA. Overexpression of CSTF3 was common in triple-negative breast cancer cell lines, and elevated CSTF3 levels were sufficient to induce APA of NRAS and c-JUN. Our results support the hypothesis that PRE-containing mRNAs are disproportionately affected by APA, primarily due to high sequence similarity in the motifs utilized by polyadenylation machinery and the PUM complex. Cancer Res; 76(24); 7231–41. ©2016 AACR.
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Gemcitabine Mechanism of Action Confounds Early Assessment of Treatment Response by 3'-Deoxy-3'-[18F]Fluorothymidine in Preclinical Models of Lung Cancer
3′-Deoxy-3′-[18F]fluorothymidine positron emission tomography ([18F]FLT-PET) and diffusion-weighted MRI (DW-MRI) are promising approaches to monitor tumor therapy response. Here, we employed these two imaging modalities to evaluate the response of lung carcinoma xenografts in mice after gemcitabine therapy. Caliper measurements revealed that H1975 xenografts responded to gemcitabine treatment, whereas A549 growth was not affected. In both tumor models, uptake of [18F]FLT was significantly reduced 6 hours after drug administration. On the basis of the gemcitabine concentration and [18F]FLT excretion measured, this was presumably related to a direct competition of gemcitabine with the radiotracer for cellular uptake. On day 1 after therapy, [18F]FLT uptake was increased in both models, which was correlated with thymidine kinase 1 (TK1) expression. Two and 3 days after drug administration, [18F]FLT uptake as well as TK1 and Ki67 expression were unchanged. A reduction in [18F]FLT in the responsive H1975 xenografts could only be noted on day 5 of therapy. Changes in ADCmean in A549 xenografts 1 or 2 days after gemcitabine did not seem to be of therapy-related biological relevance as they were not related to cell death (assessed by caspase-3 IHC and cellular density) or tumor therapy response. Taken together, in these models, early changes of [18F]FLT uptake in tumors reflected mechanisms, such as competing gemcitabine uptake or gemcitabine-induced thymidylate synthase inhibition, and only reflected growth-inhibitory effects at a later time point. Hence, the time point for [18F]FLT-PET imaging of tumor response to gemcitabine is of crucial importance. Cancer Res; 76(24); 7096–105. ©2016 AACR.
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CBX4 Suppresses Metastasis via Recruitment of HDAC3 to the Runx2 Promoter in Colorectal Carcinoma
Polycomb chromobox (CBX) proteins participate in the polycomb repressive complex (PRC1) that mediates epigenetic gene silencing and endows PRC1 with distinct oncogenic or tumor suppressor functions in a cell-type–dependent manner. In this study, we report that inhibition of cell migration, invasion, and metastasis in colorectal carcinoma requires CBX4-mediated repression of Runx2, a key transcription factor that promotes colorectal carcinoma metastasis. CBX4 inversely correlated with Runx2 expression in colorectal carcinoma tissues, and the combination of high CBX4 expression and low Runx2 expression significantly correlated with overall survival, more so than either CBX4 or Runx2 expression alone. Mechanistically, CBX4 maintained recruited histone deacetylase 3 (HDAC3) to the Runx2 promoter, which maintained a deacetylated histone H3K27 state to suppress Runx2 expression. This function of CBX4 was dependent on its interaction with HDAC3, but not on its SUMO E3 ligase, its chromodomain, or the PRC1 complex. Disrupting the CBX4–HDAC3 interaction abolished Runx2 inhibition as well as the inhibition of cell migration and invasion. Collectively, our data show that CBX4 may act as a tumor suppressor in colorectal carcinoma, and strategies that stabilize the interaction of CBX4 with HDAC3 may benefit the colorectal carcinoma patients with metastases. Cancer Res; 76(24); 7277–89. ©2016 AACR.
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Surface Expression of TGF{beta} Docking Receptor GARP Promotes Oncogenesis and Immune Tolerance in Breast Cancer
GARP encoded by the Lrrc32 gene is the cell surface docking receptor for latent TGFβ, which is expressed naturally by platelets and regulatory T cells (Treg). Although Lrrc32 is amplified frequently in breast cancer, the expression and relevant functions of GARP in cancer have not been explored. Here, we report that GARP exerts oncogenic effects, promoting immune tolerance by enriching and activating latent TGFβ in the tumor microenvironment. We found that human breast, lung, and colon cancers expressed GARP aberrantly. In genetic studies in normal mammary gland epithelial and carcinoma cells, GARP expression increased TGFβ bioactivity and promoted malignant transformation in immunodeficient mice. In breast carcinoma–bearing mice that were immunocompetent, GARP overexpression promoted Foxp3+ Treg activity, which in turn contributed to enhancing cancer progression and metastasis. Notably, administration of a GARP-specific mAb limited metastasis in an orthotopic model of human breast cancer. Overall, these results define the oncogenic effects of the GARP–TGFβ axis in the tumor microenvironment and suggest mechanisms that might be exploited for diagnostic and therapeutic purposes. Cancer Res; 76(24); 7106–17. ©2016 AACR.
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IDH2 Mutations Define a Unique Subtype of Breast Cancer with Altered Nuclear Polarity
Solid papillary carcinoma with reverse polarity (SPCRP) is a rare breast cancer subtype with an obscure etiology. In this study, we sought to describe its unique histopathologic features and to identify the genetic alterations that underpin SPCRP using massively parallel whole-exome and targeted sequencing. The morphologic and immunohistochemical features of SPCRP support the invasive nature of this subtype. Ten of 13 (77%) SPCRPs harbored hotspot mutations at R172 of the isocitrate dehydrogenase IDH2, of which 8 of 10 displayed concurrent pathogenic mutations affecting PIK3CA or PIK3R1. One of the IDH2 wild-type SPCRPs harbored a TET2 Q548* truncating mutation coupled with a PIK3CA H1047R hotspot mutation. Functional studies demonstrated that IDH2 and PIK3CA hotspot mutations are likely drivers of SPCRP, resulting in its reversed nuclear polarization phenotype. Our results offer a molecular definition of SPCRP as a distinct breast cancer subtype. Concurrent IDH2 and PIK3CA mutations may help diagnose SPCRP and possibly direct effective treatment. Cancer Res; 76(24); 7118–29. ©2016 AACR.
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Ubiquitous Release of Exosomal Tumor Suppressor miR-6126 from Ovarian Cancer Cells
Cancer cells actively promote their tumorigenic behavior by reprogramming gene expression. Loading intraluminal vesicles with specific miRNAs and releasing them into the tumor microenvironment as exosomes is one mechanism of reprogramming whose regulation remains to be elucidated. Here, we report that miR-6126 is ubiquitously released in high abundance from both chemosensitive and chemoresistant ovarian cancer cells via exosomes. Overexpression of miR-6126 was confirmed in healthy ovarian tissue compared with ovarian cancer patient samples and correlated with better overall survival in patients with high-grade serous ovarian cancer. miR-6126 acted as a tumor suppressor by directly targeting integrin-β1, a key regulator of cancer cell metastasis. miR-6126 mimic treatment of cancer cells resulted in increased miR-6126 and decreased integrin-β1 mRNA levels in the exosome. Functional analysis showed that treatment of endothelial cells with miR-6126 mimic significantly reduced tube formation as well as invasion and migration capacities of ovarian cancer cells in vitro. Administration of miR-6126 mimic in an orthotopic mouse model of ovarian cancer elicited a relative reduction in tumor growth, proliferating cells, and microvessel density. miR-6126 inhibition promoted oncogenic behavior by leading ovarian cancer cells to release more exosomes. Our findings provide new insights into the role of exosomal miRNA-mediated tumor progression and suggest a new therapeutic approach to disrupt oncogenic phenotypes in tumors. Cancer Res; 76(24); 7194–207. ©2016 AACR.
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TSC2 Deficiency Unmasks a Novel Necrosis Pathway That Is Suppressed by the RIP1/RIP3/MLKL Signaling Cascade
Tuberous sclerosis complex (TSC) is a genetic multiorgan disorder characterized by the development of neoplastic lesions in kidney, lung, brain, heart, and skin. It is caused by an inactivating mutation in tumor suppressor genes coding the TSC1/TSC2 complex, resulting in the hyperactivation of mTOR- and Raf/MEK/MAPK–dependent signaling that stimulates tumor cell proliferation and metastasis. Despite its oncogenic effect, cells with TSC deficiency were more sensitive to oxidative stress and dependent on mitochondrial metabolism, providing a rationale for a new therapeutic approach. The current study shows that simultaneous inhibition of two major pathways regulating redox homeostasis using l-buthionine-sulfoximine (BSO, glutathione synthesis inhibitor) and auranofin (thioredoxin reductase inhibitor) induces oxidative burst, mitochondrial damage, and necrotic cell death in TSC-deficient cells in a highly synergistic and cell context–specific manner. Furthermore, blocking RIP1/RIP3/MLKL–dependent signaling using chemical inhibitors necrostatin-1 (Nec-1) and necrosulfonamide (NSA) synergizes with BSO and auranofin in killing TSC-deficient cells. Expression analysis demonstrated that RIP1, RIP3, and MLKL protein levels are elevated in cells with TSC2 deficiency, and their inactivation enhances mitochondrial dysfunction in a glutaminolysis-dependent and autophagy-independent manner. Finally, supplementation with the mitochondrial metabolite α-ketoglutarate, whose synthesis is regulated by RIP1/RIP3/MLKL, rescues cells from the sensitizing effect of Nec-1 and NSA. Together, this study identifies a previously unrecognized novel regulated necrotic death pathway that involves mitochondrial homeostasis, is suppressed by the RIP1/RIP3/MLKL signaling in TSC-deficient cells, and could be a promising therapeutic target for TSC-associated tumors. Cancer Res; 76(24); 7130–9. ©2016 AACR.
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FOXD1-ALDH1A3 Signaling Is a Determinant for the Self-Renewal and Tumorigenicity of Mesenchymal Glioma Stem Cells
Glioma stem–like cells (GSC) with tumor-initiating activity orchestrate the cellular hierarchy in glioblastoma and engender therapeutic resistance. Recent work has divided GSC into two subtypes with a mesenchymal (MES) GSC population as the more malignant subtype. In this study, we identify the FOXD1–ALDH1A3 signaling axis as a determinant of the MES GSC phenotype. The transcription factor FOXD1 is expressed predominantly in patient-derived cultures enriched with MES, but not with the proneural GSC subtype. shRNA-mediated attenuation of FOXD1 in MES GSC ablates their clonogenicity in vitro and in vivo. Mechanistically, FOXD1 regulates the transcriptional activity of ALDH1A3, an established functional marker for MES GSC. Indeed, the functional roles of FOXD1 and ALDH1A3 are likely evolutionally conserved, insofar as RNAi-mediated attenuation of their orthologous genes in Drosophila blocks formation of brain tumors engineered in that species. In clinical specimens of high-grade glioma, the levels of expression of both FOXD1 and ALDH1A3 are inversely correlated with patient prognosis. Finally, a novel small-molecule inhibitor of ALDH we developed, termed GA11, displays potent in vivo efficacy when administered systemically in a murine GSC-derived xenograft model of glioblastoma. Collectively, our findings define a FOXD1–ALDH1A3 pathway in controling the clonogenic and tumorigenic potential of MES GSC in glioblastoma tumors. Cancer Res; 76(24); 7219–30. ©2016 AACR.
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Dysregulation of RUNX2/Activin-A Axis upon miR-376c Downregulation Promotes Lymph Node Metastasis in Head and Neck Squamous Cell Carcinoma
Epigenetic correlates of the head and neck cancer may illuminate its pathogenic roots. Through a gene set enrichment analysis, we found that the oncogenic transcription factor RUNX2 is widely upregulated in the head and neck squamous cell carcinoma (HNSCC) with lymph node metastasis, where it also predicts poor prognosis in patients with HNSCC. Enforced expression of ectopic RUNX2 promoted the metastatic capabilities of HNSCC, whereas RUNX2 silencing inhibited these features. Mechanistic investigations showed that manipulating levels of activin A (INHBA) could rescue or compromise the RUNX2-mediated metastatic capabilities of HNSCC cells. Furthermore, we found that miR-376c-3p encoded within the 3′-untranslated region of RUNX2 played a pivotal role in regulating RUNX2 expression in highly metastatic HNSCC cells, where it was downregulated commonly. Restoring miR-376c expression in this setting suppressed expression of RUNX2/INHBA axis along with metastatic capability. Clinically, we observed an inverse relationship between miR-376c-3p expression and the RUNX2/INHBA axis in HNSCC specimens. In summary, our results defined a novel pathway in which dysregulation of the RUNX2/INHBA axis due to miR-376c downregulation fosters lymph node metastasis in HNSCC. Cancer Res; 76(24); 7140–50. ©2016 AACR.
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Mechanisms through Which Hypoxia-Induced Caveolin-1 Drives Tumorigenesis and Metastasis in Hepatocellular Carcinoma
In solid tumors, hypoxia triggers an aberrant vasculogenesis, enhances malignant character, and elevates metastatic risk. The plasma membrane organizing protein caveolin-1 (Cav1) is increased in a variety of cancers, including hepatocellular carcinoma (HCC), where it contributes to metastatic capability. However, the reason for elevation of Cav1 in tumor cells and the mechanistic basis for its contributions to metastatic risk are not fully understood. Here, we show that in HCC cells, hypoxia elevates expression of Cav1, which then acts through the calcium-binding protein S100P to promote metastasis. Hypoxic regions of HCC xenografts displayed elevated expression of Cav1. Hypoxia promoted HCC cell migration and invasion and distant pulmonary metastases, whereas Cav1 silencing abolished these effects. Gene expression profiling revealed that hypoxia-induced Cav1 functioned as a positive regulator of S100P via activation of the NF-κB pathway. S100P elevation under hypoxic conditions was abrogated by silencing of Cav1 or NF-κB function. Conversely, restoring S100P in Cav1-silenced cells rescued the migratory potential of HCC cells along with tumor formation and lung metastasis. In clinical specimens of HCC, we observed S100P overexpression to correlate with venous invasion, microsatellites, direct liver invasion, and absence of tumor encapsulation. Collectively, our findings demonstrated how hypoxia-induced expression of Cav1 in HCC cells enhances their invasive and metastatic potential. Cancer Res; 76(24); 7242–53. ©2016 AACR.
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A Study of TP53 RNA Splicing Illustrates Pitfalls of RNA-seq Methodology
TP53 undergoes multiple RNA-splicing events, resulting in at least nine mRNA transcripts encoding at least 12 functionally different protein isoforms. Antibodies specific to p53 protein isoforms have proven difficult to develop, thus researchers must rely on the transcript information to infer isoform abundance. In this study, we used deep RNA-seq, droplet digital PCR (ddPCR), and real-time quantitative reverse transcriptase PCR (RT-qPCR) from nine human cell lines and RNA-seq data available for tumors in The Cancer Genome Atlas to analyze TP53 splice variant expression. All three methods detected expression of the FL/40TP53α_T1 variant in most human tumors and cell lines. However, other less abundant variants were only detected with PCR-based methods. Using RNA-seq simulation analysis, we determined why RNA-seq is unable to detect less abundant TP53 transcripts and discuss the implications of these findings for the general interpretation of RNA-seq data. Cancer Res; 76(24); 7151–9. ©2016 AACR.
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Transglutaminase Interaction with {alpha}6/{beta}4-Integrin Stimulates YAP1-Dependent {Delta}Np63{alpha} Stabilization and Leads to Enhanced Cancer Stem Cell Survival and Tumor Formation
Transglutaminase 2 (TG2) expression is required for epidermal squamous cell carcinoma cancer stem cell survival. However, the molecular signaling mechanisms triggered by TG2 that mediate this survival action are not well understood. Here we show that TG2 is constitutively expressed in ECS cells, where it interacts with α6/β4 integrin to stimulate FAK and Src signaling, leading to PI3K activation of phosphoinositide-dependent kinase 1 (PDK1). PDK1 inhibits Hippo signaling, leading to enhanced nuclear accumulation of YAP1, which interacted with and stabilized ΔNp63α to enhance epidermal squamous cell carcinoma spheroid formation, invasion, and migration. Overall, these findings suggest that constitutive TG2 expression results in stabilization of ΔNp63α, leading to maintenance of cancer stem cell properties and enhanced tumor formation. Cancer Res; 76(24); 7265–76. ©2016 AACR.
http://ift.tt/2gOVp3i
HER2/HER3 pathway in biliary tract malignancies; systematic review and meta-analysis: a potential therapeutic target?
Abstract
Human epidermal growth factor receptor 2 (HER2) overexpression and amplification have been reported as predictive markers for HER2-targeted therapy in breast and gastric cancer, whereas human epidermal growth factor receptor 3 (HER3) is emerging as a potential resistance factor. The aim of this study was to perform a systematic review and meta-analysis of the HER2 and HER3 overexpression and amplification in biliary tract cancers (BTCs). An electronic search of MEDLINE, American Society of Clinical Oncology (ASCO), European Society of Medical Oncology Congress (ESMO), and American Association for Cancer Research (AACR) was performed to identify studies reporting HER2 and/or HER3 membrane protein expression by immunohistochemistry (IHC) and/or gene amplification by in situ hybridization (ISH) in BTCs. Studies were classified as "high quality" (HQ) if IHC overexpression was defined as presence of moderate/strong staining or "low quality" (LQ) where "any" expression was considered positive. Of 440 studies screened, 40 met the inclusion criteria. Globally, HER2 expression rate was 26.5 % (95 % CI 18.9–34.1 %). When HQ studies were analyzed (n = 27 studies), extrahepatic BTCs showed a higher HER2 overexpression rate compared to intrahepatic cholangiocarcinoma: 19.9 % (95 % CI 12.8–27.1 %) vs. 4.8 % (95 % CI 0–14.5 %), respectively, p value 0.0049. HER2 amplification rate was higher in patients selected by HER2 overexpression compared to "unselected" patients: 57.6 % (95 % CI 16.2–99 %) vs. 17.9 % (95 % CI 0.1–35.4 %), respectively, p value 0.0072. HER3 overexpression (4/4 HQ studies) and amplification rates were 27.9 % (95 % CI 9.7–46.1 %) and 26.5 % (one study), respectively. Up to 20 % of extrahepatic BTCs appear to be HER2 overexpressed; of these, close to 60 % appear to be HER2 amplified, while HER3 is overexpressed or amplified in about 25 % of patients. Clinical relevance for targeted therapy should be tested in prospective clinical trials.
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HER2/HER3 pathway in biliary tract malignancies; systematic review and meta-analysis: a potential therapeutic target?
Abstract
Human epidermal growth factor receptor 2 (HER2) overexpression and amplification have been reported as predictive markers for HER2-targeted therapy in breast and gastric cancer, whereas human epidermal growth factor receptor 3 (HER3) is emerging as a potential resistance factor. The aim of this study was to perform a systematic review and meta-analysis of the HER2 and HER3 overexpression and amplification in biliary tract cancers (BTCs). An electronic search of MEDLINE, American Society of Clinical Oncology (ASCO), European Society of Medical Oncology Congress (ESMO), and American Association for Cancer Research (AACR) was performed to identify studies reporting HER2 and/or HER3 membrane protein expression by immunohistochemistry (IHC) and/or gene amplification by in situ hybridization (ISH) in BTCs. Studies were classified as "high quality" (HQ) if IHC overexpression was defined as presence of moderate/strong staining or "low quality" (LQ) where "any" expression was considered positive. Of 440 studies screened, 40 met the inclusion criteria. Globally, HER2 expression rate was 26.5 % (95 % CI 18.9–34.1 %). When HQ studies were analyzed (n = 27 studies), extrahepatic BTCs showed a higher HER2 overexpression rate compared to intrahepatic cholangiocarcinoma: 19.9 % (95 % CI 12.8–27.1 %) vs. 4.8 % (95 % CI 0–14.5 %), respectively, p value 0.0049. HER2 amplification rate was higher in patients selected by HER2 overexpression compared to "unselected" patients: 57.6 % (95 % CI 16.2–99 %) vs. 17.9 % (95 % CI 0.1–35.4 %), respectively, p value 0.0072. HER3 overexpression (4/4 HQ studies) and amplification rates were 27.9 % (95 % CI 9.7–46.1 %) and 26.5 % (one study), respectively. Up to 20 % of extrahepatic BTCs appear to be HER2 overexpressed; of these, close to 60 % appear to be HER2 amplified, while HER3 is overexpressed or amplified in about 25 % of patients. Clinical relevance for targeted therapy should be tested in prospective clinical trials.
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Emphysematous pancreatitis: classic findings
Description
A 55-year-old man with diabetes presented to our hospital with recent onset acute abdominal pain and recurrent vomiting. He was immediately admitted to the intensive care unit for ionotropic and invasive respiratory support. He had an acutely tender abdomen with distension. Haematological examination showed leucopenia (880/mm3), thrombocytopenia (64 000/mm3), elevated C reactive protein (68 mg/mL), metabolic acidosis (pH: 6.88) with a severely elevated blood lactate (14 mmol/L), estimated creatinine clearance <14 mL/min, hyperlipidaemia (1280 U/L) and serum amylase levels of 5134 U/L. Plain CT revealed extensive gas in the pancreatic bed extending into the lesser sac and adjacent retroperitoneal space (figure 1A, B). A diagnosis of acute severe emphysematous pancreatitis was made; although the patient was aggressively treated, unfortunately he died. Retrospective blood cultures were positive for Enterobacter aerogenes.
Figure 1
(A) CT image showing the presence of air lucencies in the epigastric region at the level of L1–L2 vertebral...
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Unexplained lymphadenopathies: autoimmune lymphoproliferative syndrome in an adult patient
Autoimmune lymphoproliferative syndrome (ALPS) is characterised by massive enlargement of the lymphoid organs, autoimmune cytopenias and a predisposition to develop lymphoid malignancies. The basic defect is a disturbance of the lymphocyte apoptosis, and a high number of circulating TCRab CD3+CD4–CD8– T-cells (double-negative T cells (DNT cells)). We describe a case of a 41-year-old man with fever, hepatosplenomegaly, multiple lymphadenopathy, autoimmune haemolytic anaemia and severe thrombocytopenia. Peripheral blood immunophenotyping revealed elevation of the characteristic DNT cells in 8% and high levels of interleukin 10. Histopathological analysis of lymph nodes showed lymphadenitis with paracortical hyperplasia. It was assumed as a probable diagnosis of ALPS, and the procedure was to medicate the patient with steroids. As a result, a significant clinical improvement was achieved, and he has been in remission for 2 years. To our knowledge, this is the first case reported in a Portuguese adult patient.
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Concomitant multiple myeloma, gastric adenocarcinoma and Evan's syndrome in a patient presenting with anaemia
An association between multiple myeloma (MM) and solid tumours has been previously described.1 Furthermore, autoimmune disorders can precede plasma cell dyscrasias, and the pathogenesis of MM maybe linked to chronic immune stimulation. 2 We describe a case of concomitant MM and gastric adenocarcinoma preceded by Evan's syndrome. A previously healthy woman presented to the emergency room with symptomatic anaemia. Her initial workup was compatible with autoimmune haemolytic anaemia and monoclonal gammopathy of undetermined significance. On progression of the anaemia and development of thrombocytopenia, she was diagnosed with Evan's syndrome. Two months later, she presented with severe back pain and her MRI revealed L4–5 vertebral collapse. The clinical picture was compatible with MM. Occult blood was repeatedly positive in stools, and she underwent oesophagogastroduodenoscopy and was found to have gastric adenocarcinoma. The patient refused surgical resection of the adenocarcinoma and refused active treatment for MM.
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Rare cause of neck pain: tumours of the posterior elements of the cervical spine
Here we present two cases of primary bone tumours of the cervical spine in patients who had persistent neck pain—in one case, lasting 8 years. In each case, there was a delay in diagnosis and referral to a spine specialist was prolonged. Primary bone tumours of the spine are rare, which is in contrast to the wide prevalence of cervical neck pain. Many primary care providers may go an entire career without encountering a symptomatic primary cervical spine tumour. In this paper, we discuss the clinical course and treatment of each patient and review the current literature on primary bone tumours of the spine. Owing to the subtle roentgenographic findings of primary cervical tumours, we highlight the importance of advanced imaging in the clinical work-up of simple axial neck pain lasting >6 weeks to avoid misdiagnosis of serious pathology.
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Boari flap reconstruction in a male infant with solitary kidney and associated megaureter
A 1-year-old male infant presented with fever and abdominal lump for 3 months with increased leucocyte count (15 300/mm3) and serum creatinine (0.83 mg%). Abdominal ultrasound and renal scan demonstrated solitary left kidney with dilated tortuous left ureter. Voiding cystourethrogram was unequivocal. Left percutaneous nephrostomy was placed after poor response to perurethral catheterisation. His serum creatinine dropped to 0.58 mg/dL. Subsequent percutaneous nephrostogram and CT nephrostogram showed dilated left pelvicalyceal system, dilated, tortuous left ureter. A diagnosis of obstructed megaureter was made and ureteric plication and reimplantation planned. Intraoperatively, there were primitive ureteral valves until proximal one-third of the ureter. The distance between the upper ureter and bladder was ~6 cm. This defect was bridged by Boari flap. The postoperative period was uneventful and now after 6 months of follow-up, he is doing fine.
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Unusual case of bilateral maxillary fungus ball
An otherwise healthy 34-year-old man was referred to our ear, nose and throat (ENT) clinic for a bilateral maxillary radiologic opacity. This condition was accidentally discovered with a panoramic radiography performed during a follow-up visit after a bilateral endodontic treatment. The patient did not report any specific sinonasal symptom such as purulent nasal discharge, loss of smell and cough, apart from an unspecific sinus pressure. The CT scans showed a bilateral inflammatory process into the maxillary-ethmoidal sinuses and an iron-like density within the maxillary sinuses, while nasal endoscopy showed purulent discharge in the ostiomeatal complex. The patient underwent functional endoscopic sinus surgery under general anaesthesia and the inflammatory material collected was histologically diagnosed as a rare case of bilateral fungus ball. The patient was dismissed the following day with no complications; there were not any sign of recurrence or symptoms during a 4 month follow-up.
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Large intraocular foreign body following a firecracker injury
Description
An 8-year-old girl child presented with the history of firecracker injury to the right eye. There was a sudden loss of vision associated with pain, redness and watering. Primarily, she was diagnosed as panophthalmitis and started of intravenous antibiotics, but as the condition worsened she was referred to a tertiary eye hospital. Initial examination was painful tense upper and lower eyelid oedema (figure 1A) along with severely chemosed conjunctiva and with severely restricted extraocular motility in all the gazes; the child denied any perception of light in the right eye, whereas left eye was normal. Ultrasonography showed a large high-amplitude opacity filling almost two-third of the vitreous cavity with shadowing posterior. (figure 1B). Subsequent CT of the orbit showed large hyperdense foreign body almost filling the entire vitreous cavity. (figure 1C). The patient was started on intravenous antibiotics injection vancomycin 40 mg/kg...
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Pulmonary sarcoidosis: calcification within the galaxy sign
Description
A 34-year-old woman had breathlessness, dry cough and low-grade fever for 6 months. Chest X-ray showed bilateral hilar lymphadenopathy and patchy alveolar right mid-zone shadows along with bilateral lower zone nodular opacities (figure 1A). Contrast-enhanced high-resolution CT(HRCT) of thorax demonstrated enlarged, non-necrotic right paratracheal, subcarinal and bilateral hilar lymph nodes. The lung window in right upper lobe revealed a large nodule with irregular margins encircled by multiple small nodules suggestive of 'galaxy' sign (figure 1B). In addition, mediastinal window divulged dense calcification within the nodule and mediastinal lymphnodes (figure 1C). Fibreoptic bronchoscopy visualised multiple endobronchial granulomatous lesions throughout the tracheobronchial tree (figure 2A) and was confirmed on biopsy (figure 2B). The diagnosis of pulmonary sarcoidosis was based on (1) chest imaging, (2) elevated serum ACE levels (126 IU/mL [8–65 IU/mL]), (3) negative tuberculin test and (4) visible endobronchial lesions and...
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Melphalan-induced cardiotoxicity: ventricular arrhythmias
Description
A 61-year-old man, with multiple myeloma (IgA lambda), was planned for autologous stem cell transplantation (ASCT). He also suffered a left thalamic haemorrhagic stroke in 1998 secondary to aneurysmal bleed. Following melphalan infusion of 200 mg at 45 mL/min, he developed acute onset rhythm abnormalities (intermittent ventricular ectopic and ventricular tachycardia). The patient's premelphalan evaluation was unremarkable with normal ECG (1A), ejection fraction (55%) and renal/hepatic function. He was evaluated by sequential 2D echocardiography and troponin I (immediately, 2, 4, 12 and 24 hours) which were normal excluding acute STEMI. These rhythm abnormalities were dynamic probably secondary to the plasma melphalan concentrations and normalised by 18 h postinfusion (figure 1B–F). There has been no recurrence of these rhythm abnormalities thereafter. He was transplanted with abbreviated melphalan conditioning.
Figure 1
(A) Normal ECG before starting melphalan infusion. (B) ECG after 200 mg of melphalan infusion, showing acute onset ventricular rhythm...
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Rare case of glioblastoma multiforme located in posterior corpus callosum presenting with depressive symptoms and visual memory deficits
Most of the primary brain tumours are located in the supratentorial region, and it is uncommon to see tumour growth on deep brain structures such as posterior corpus callosum (PCC). In addition, lesions in PCC are also difficult to recognise, because construction apraxia, visuospatial perception and attentional capacity impairment may be the only presenting symptoms. Here, we represent a rare case of gliobastoma multiforme located in PCC, which solely presents with depressive symptoms and visual memory deficits. Initial manifestations of primary brain tumours with psychiatric symptoms and memory disturbances, in addition to headaches and seizures, should be kept in mind.
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Cancers, Vol. 8, Pages 114: Erratum: Roche, J. et al. Global Decrease of Histone H3K27 Acetylation in ZEB1-Induced Epithelial to Mesenchymal Transition in Lung Cancer Cells. Cancers, 2013, 5, 334–356
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Case 38-2016: A 52-Year-Old Woman with Recurrent Oligodendroglioma
Presentation of Case. Dr. Andrew S. Chi: A 52-year-old woman with a history of oligodendroglioma was seen in the outpatient neuro-oncology clinic of this hospital for routine follow-up. Twelve years earlier, the patient presented with a generalized tonic–clonic seizure 4 days after she had…
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