W and Z Boson Production Cross Section Measurements in ATLAS

The electroweak boson inclusive production cross sections and their ratios are described in the electron and muon decay channels. The observation of W and Z bosons in the tau decay channel is also presented. The data from pp collisions at 7 TeV were collected during 2010 using the ATLAS detector at the Large Hadron Collider and the results are compared to predictions at NNLO in perturbative QCD.Comment: 4 pages, 2 figures, Proceedings for the XIX International Workshop on Deep-Inelastic Scattering and Related Subjects, Newport News, VA USA, April 201

W and Z Production in pp Collisions at 7 TeV with the ATLAS Experiment at the LHC

The observation of W and Z bosons and a measurement of the production cross sections in proton proton collisions at E_CM = 7 TeV are presented using data from the ATLAS experiment at the LHC. Results are based on 118 W -> lnu and 125 Z/gamma* -> ll (l=e,mu) candidate events corresponding to an integrated luminosity of about 17 nb^-1 and 225 nb^-1 respectively. The measured values of sigma_W x BR(W -> lnu) = 9.3 \pm 0.9 (stat) \pm 0.6 (syst) \pm 1.0 (lumi) nb and sigma_Z/gamma* x BR(Z/gamma* -> ll, 66<m_ll<116) = 0.83 \pm 0.07 (stat) \pm 0.06 (syst) \pm 0.09 (lumi) nb. A measurement of the W lepton charge asymmetry is also reported. A comparison with theoretical predictions based on NNLO QCD calculations shows agreement with the measurements.Comment: 4 pages, 7 figures. Proceedings of XXX. Physics in Collision 2010, Karlsruhe, Germany, September 201

Editorial: cancer ecosystems

Oncology research pioneers such as Stephen Paget focused on how cancer cells favor particular environments and Judah Folkman on how nutrients are provided to these harsh environments. The tumors consist of a heterogeneous population of cancer cells and a stroma with different cell types that define a specific microenvironment and form a tumoral ecosystem. The evolution of the tumors depends on the interactions of the cancer cells with their tumor microenvironment (TME), determining the progression, eradication, or tumor metastasis. A coral ecosystem is similar to tumors in that it is highly complex and energetically productive. A tropical reef-building coral holobiont is composed of the coral metazoan host (the polyp), its endosymbiotic photosynthetic dinoflagellates (Symbiodiniaceae) and other microorganisms, including protozoans, fungi, bacteria, and archaea. Despite their complexity and very high productivity, corals commonly thrive in nutrient-poor environments, which are similar to what is observed in tumors. The contradiction of high coral productivity and limited nutrient availability has been named as the 'Darwin Paradox,' in reference to its first discoverer. This paradox can be explained by the high uptake and efficient recycling of nutrients by coral reef organisms. A similar paradox has been observed in tumors since it is unclear how this complex ecosystem thrives in such nutrient deprived conditions

Doxycycline, an inhibitor of mitochondrial biogenesis, effectively reduces cancer stem cells (CSCs) in early breast cancer patients : a clinical pilot study

Background and objectives: Cancer stem cells (CSCs) have been implicated in tumor initiation, recurrence, metastatic spread and poor survival in multiple tumor types, breast cancers included. CSCs selectively overexpress key mitochondrial-related proteins and inhibition of mitochondrial function may represent a new potential approach for the eradication of CSCs. Because mitochondria evolved from bacteria, many classes of FDA-approved antibiotics, including doxycycline, actually target mitochondria. Our study aimed to determine whether short-term pre-operative treatment with oral doxycycline results in reduction of CSCs in early breast cancer patients. Methods: Doxycycline was administered orally for 14 days before surgery for a daily dose of 200 mg. Immuno-histochemical analysis of formalin-fixed paraffin-embedded (FFPE) samples from 15 patients, of which 9 were treated with doxycycline and 6 controls (no treatment), was performed with known biomarkers of “stemness” (CD44, ALDH1), mitochondrial mass (TOMM20), cell proliferation (Ki67, p27), apoptosis (cleaved caspase-3) and neo-angiogenesis (CD31). For each patient, the analysis was performed both on pre-operative specimens (core-biopsies) and surgical specimens. Changes from baseline to post-treatment were assessed with MedCalc 12 (unpaired t-test). Results: Post-doxycycline tumor samples demonstrated a statistically significant decrease in the stemness marker CD44 (p-value &lt; 0.005), when compared to pre-doxycycline tumor samples. More specifically, CD44 levels were reduced between 17.65% and 66.67%, in 8 out of 9 patients treated with doxycycline. In contrast, only one patient showed a rise in CD44, by 15%. Overall, this represents a positive response rate of nearly 90%. Similar results were also obtained with ALDH1, another marker of stemness. In contrast, markers of mitochondrial mass, proliferation, apoptosis and neo-angiogenesis, were all similar between the two groups. Conclusions: Quantitative decreases in CD44 and ALDH1 expression are consistent with pre-clinical experiments and suggest that doxycycline can selectively eradicate CSCs in breast cancer patients in vivo. Future studies (with larger numbers of patients) will be conducted to validate these promising pilot studies

Metabolic Plasticity of Stem Cells and Macrophages in Cancer

In addition to providing essential molecules for the overall function of cells, metabolism plays an important role in cell fate and can be affected by microenvironmental stimuli as well as cellular interactions. As a specific niche, tumor microenvironment (TME), consisting of different cell types including stromal/stem cells and immune cells, is characterized by distinct metabolic properties. This review will be focused on the metabolic plasticity of mesenchymal stromal/stem cells (MSC) and macrophages in TME, as well as on how the metabolic state of cancer stem cells (CSC), as key drivers of oncogenesis, affects their generation and persistence. Namely, heterogenic metabolic phenotypes of these cell populations, which include various levels of dependence on glycolysis or oxidative phosphorylation are closely linked to their complex roles in cancer progression. Besides well-known extrinsic factors, such as cytokines and growth factors, the differentiation and activation states of CSC, MSC, and macrophages are coordinated by metabolic reprogramming in TME. The significance of mutual metabolic interaction between tumor stroma and cancer cells in the immune evasion and persistence of CSC is currently under investigation

Tumor Metabolism in the Microenvironment of Nodal Metastasis in Head and Neck Squamous Cell Carcinoma

ABSTRACT Introduction: Monocarboxylate transporter 4 (MCT4) is a cell membrane transporter of lactate. MCT4 is a tumor-specific marker of oxidative stress, glycolysis and hypoxia in tumor stromal cells. We investigated HPV positive and negative tumors with regional metastases to cervical lymph nodes (LN) to study how the metastatic tumor cells interact with their microenvironment. By selecting cancers with extracapsular extension (ECE), we intended to evaluate the interaction between metastases and the surrounding extranodal tissue. Methods: Clinical data were collected from 24 advanced stage oropharyngeal squamous cell carcinoma (OPSCC) patients with neck LN metastasis. All patients presented with at least N1 disease and had ECE. Sixteen cases were negative for HPV and eight were positive. Ten patients (42%) had ECE \u3c 1 mm, and 14 (58%) had ECE \u3e than 1 mm. The extent of ECE was quantified on H&E stains by distance from the edge of capsule. The paraffin-embedded metastatic LN sections were stained with MCT4 and quantification was accomplished using the Aperio Co-localization algorithm. Results: High stromal MCT4 expression was strongly associated with the extent of ECE regardless of HPV status (p=0.031). The stromal MCT4 expression in ECE area was significantly higher as opposed to the surrounding extranodal tissue adjacent to intact capsule (p\u3c0.001). We also found a borderline difference in expression of MCT4 in HPV- LN with ECE \u3e1mm vs. \u3c1mm(p=0.06). Conclusions: MCT4 is a marker of oxidative stress and higher expression of stromal MCT4 in ECE area is significantly correlated with the extent of ECE. The stromal cells separating nests of cancer cells in ECE area have apparent expression of the MCT4. Together these findings provide new insight into the critical role of stromal MCT4 in nodal metastasis and ECE in OPSCC and it may be useful to develop a novel prognostic marker and new anti-cancer agents

Mitochondrial biomarkers predict tumor progression and poor overall survival in gastric cancers : companion diagnostics for personalized medicine.

Here, we employed a bioinformatics approach to identify novel molecular determinants to predict tumor progression and overall survival in gastric cancer patients. In particular, we directly assessed whether nuclear-derived mRNA species encoding proteins involved in mitochondrial protein translation and OXPHOS are able to successfully predict clinical outcome in gastric cancer. As such, using in silico validation, we have now established the prognostic value of these mitochondrial biomarkers, in a defined population of gastric cancer patients. In this context, we interrogated 5 year follow-up data collected from a group of N = 359 gastric cancer patients. Importantly, in this group of cancer patients, Ki67 and PCNA (conventional markers of cell proliferation) were associated with tumor progression, as might be expected. Using this simplified informatics approach, we identified ∼75 new individual mitochondrial gene probes that effectively predicted tumor progression, with hazard-ratios (HR) of up to 2.22 (p < 2.1e-10). These mitochondrial mRNA transcripts included heat shock proteins/chaperones, membrane proteins, anti-oxidants, enzymes involved in genome maintenance, as well as mitochondrial ribosomal proteins (MRPs) and numerous members of the OXPHOS complexes. In addition, we combined 8 mitochondrial protein transcripts (NDUFS5, VDAC3, ATP5O, IMMT, MRPL28, COX5B, MRPL52, PRKDC), to generate a compact gastric mitochondrial gene signature, associated with a HR of 2.77 (p = 1.4e-14). As a result of this analysis and validation, we strongly suggest that proteins involved in mitochondrial protein translation and OXPHOS should be considered as targets for new drug discovery, for the treatment of gastric cancers. The mitochondrial markers we identified here could also be used as companion diagnostics, to predict clinical outcomes, as well as the patient response to therapy. This should allow a more successful and personalized approach to gastric cancer diagnosis and therapy

Cancer stem cells (CSCs) : metabolic strategies for their identification and eradication

Phenotypic and functional heterogeneity is one of the most relevant features of cancer cells within different tumor types and is responsible for treatment failure. Cancer stem cells (CSCs) are a population of cells with stem cell-like properties that are considered to be the root cause of tumor heterogeneity, because of their ability to generate the full rep- ertoire of cancer cell types. Moreover, CSCs have been invoked as the main drivers of metastatic dissemination and therapeutic resistance. As such, targeting CSCs may be a useful strategy to improve the effectiveness of classical anticancer therapies. Recently, metabolism has been considered as a relevant player in CSC biology, and indeed, onco- genic alterations trigger the metabolite-driven dissemination of CSCs. More interestingly, the action of metabolic pathways in CSC maintenance might not be merely a conse- quence of genomic alterations. Indeed, certain metabotypic phenotypes may play a causative role in maintaining the stem traits, acting as an orchestrator of stemness. Here, we review the current studies on the metabolic features of CSCs, focusing on the bio- chemical energy pathways involved in CSC maintenance and propagation. We provide a detailed overview of the plastic metabolic behavior of CSCs in response to microenvironment changes, genetic aberrations, and pharmacological stressors. In addition, we describe the potential of comprehensive metabolic approaches to identify and selectively eradicate CSCs, together with the possibility to ‘force’ CSCs within certain metabolic dependences, in order to effectively target such metabolic biochemical inflexibilities. Finally, we focus on targeting mitochondria to halt CSC dissemination and effectively eradicate cancer

Exploiting mitochondrial targeting signal(s), TPP and bis-TPP, for eradicating cancer stem cells (CSCs)

Tri-phenyl-phosphonium (TPP) is a non-toxic chemical moiety that functionally behaves as a mitochondrial targeting signal (MTS) in living cells. Here, we explored the hypothesis that TPP-related compounds could be utilized to inhibit mitochondria in cancer stem cells (CSCs). We randomly selected 9 TPP-related compounds for screening, using an ATP depletion assay. Based on this approach, five compounds were identified as "positive hits"; two had no detectable effect on ATP production. Remarkably, this represents a >50% hit rate. We validated that the five positive hit compounds all inhibited oxygen consumption rates (OCR), using the Seahorse XFe96 metabolic flux analyzer. Interestingly, these TPP-related compounds were non-toxic and had little or no effect on ATP production in normal human fibroblasts, but selectively targeted adherent "bulk" cancer cells. Finally, these positive hit compounds also inhibited the propagation of CSCs in suspension, as measured functionally using the 3D mammosphere assay. Therefore, these TPP-related compounds successfully inhibited anchorage-independent growth, which is normally associated with a metastatic phenotype. Interestingly, the most effective molecule that we identified contained two TPP moieties (i.e., bis-TPP). More specifically, 2-butene-1,4-bis-TPP potently and selectively inhibited CSC propagation, with an IC-50 < 500 nM. Thus, we conclude that the use of bis-TPP, a "dimeric" mitochondrial targeting signal, may be a promising new approach for the chemical eradication of CSCs. Future studies on the efficacy of 2-butene-1,4-bis-TPP and its derivatives are warranted. In summary, we show that TPP-related compounds provide a novel chemical strategy for effectively killing both i) "bulk" cancer cells and ii) CSCs, while specifically minimizing or avoiding off-target side-effects in normal cells. These results provide the necessary evidence that "normal" mitochondria and "malignant" mitochondria are truly biochemically distinct, removing a significant barrier to therapeutically targeting cancer metabolism

Fructose 2,6-bisphosphate in cancer cell metabolism

For a long time, pioneers in the field of cancer cell metabolism, such as Otto Warburg, have focused on the idea that tumor cells maintain high glycolytic rates even with adequate oxygen supply, in what is known as aerobic glycolysis or the Warburg effect. Recent studies have reported a more complex situation, where the tumor ecosystem plays a more critical role in cancer progression. Cancer cells display extraordinary plasticity in adapting to changes in their tumor microenvironment, developing strategies to survive and proliferate. The proliferation of cancer cells needs a high rate of energy and metabolic substrates for biosynthesis of biomolecules. These requirements are met by the metabolic reprogramming of cancer cells and others present in the tumor microenvironment, which is essential for tumor survival and spread. Metabolic reprogramming involves a complex interplay between oncogenes, tumor suppressors, growth factors and local factors in the tumor microenvironment. These factors can induce overexpression and increased activity of glycolytic isoenzymes and proteins in stromal and cancer cells which are different from those expressed in normal cells. The fructose-6-phosphate/fructose-1,6-bisphosphate cycle, catalyzed by 6-phosphofructo-1-kinase/fructose 1,6-bisphosphatase (PFK1/FBPase1) isoenzymes, plays a key role in controlling glycolytic rates. PFK1/FBpase1 activities are allosterically regulated by fructose-2,6-bisphosphate, the product of the enzymatic activity of the dual kinase/phosphatase family of enzymes: 6-phosphofructo-2-kinase/fructose 2,6-bisphosphatase (PFKFB1-4) and TP53-induced glycolysis and apoptosis regulator (TIGAR), which show increased expression in a significant number of tumor types. In this review, the function of these isoenzymes in the regulation of metabolism, as well as the regulatory factors modulating their expression and activity in the tumor ecosystem are discussed. Targeting these isoenzymes, either directly or by inhibiting their activating factors, could be a promising approach for treating cancers