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Shiraishi T.,Johns Hopkins University | Verdone J.E.,Johns Hopkins University | Kahlert U.D.,Johns Hopkins Hospital | Hernandez J.R.,Johns Hopkins University | And 10 more authors.
Oncotarget | Year: 2015

The ability of a cancer cell to detach from the primary tumor and move to distant sites is fundamental to a lethal cancer phenotype. Metabolic transformations are associated with highly motile aggressive cellular phenotypes in tumor progression. Here, we report that cancer cell motility requires increased utilization of the glycolytic pathway. Mesenchymal cancer cells exhibited higher aerobic glycolysis compared to epithelial cancer cells while no significant change was observed in mitochondrial ATP production rate. Higher glycolysis was associated with increased rates of cytoskeletal remodeling, greater cell traction forces and faster cell migration, all of which were blocked by inhibition of glycolysis, but not by inhibition of mitochondrial ATP synthesis. Thus, our results demonstrate that cancer cell motility and cytoskeleton rearrangement is energetically dependent on aerobic glycolysis and not oxidative phosphorylation. Mitochondrial derived ATP is insufficient to compensate for inhibition of the glycolytic pathway with regard to cellular motility and CSK rearrangement, implying that localization of ATP derived from glycolytic enzymes near sites of active CSK rearrangement is more important for cell motility than total cellular ATP production rate. These results extend our understanding of cancer cell metabolism, potentially providing a target metabolic pathway associated with aggressive disease. Source

Zheng F.,Vrije Universiteit Brussel | Zheng F.,Inflammation Research Center | Sparkes A.,Vrije Universiteit Brussel | Sparkes A.,Inflammation Research Center | And 15 more authors.
Molecular Imaging and Biology | Year: 2016

Purpose: Kupffer cells (KCs), the liver resident macrophages, are important mediators of tissue homeostasis and pathogen clearance. However, depending on the inflammatory stimuli, KCs have been involved in divergent hepato-protective or hepato-destructive immune responses. The versatility of KCs in response to environmental triggers, in combination with the specific biomarkers they express, make these macrophages attractive in vivo targets for non-invasive monitoring of liver inflammation or pathogenicity. This study aims to determine whether V-set and Ig domain-containing 4 (Vsig4) and C-type lectin domain family (Clec) 4, member F (Clec4F) can be used as imaging biomarkers for non-invasive monitoring of KCs during distinct liver inflammation models. Procedure: Flow cytometry (FACS), immuno-histochemistry (IHC), and single-photon emission computed tomography (SPECT) with Tc-99m labeled anti-Vsig4 or anti-Clec4F nanobodies (Nbs) was performed to evaluate in mice KC dynamics in concanavalin A (ConA)-induced hepatitis and in non-alcoholic steatohepatitis induced via methionine choline deficiency (MCD). Results: In homeostatic mice, Nbs targeting Clec4F were found to accumulate and co-localize with Vsig4-targeting Nbs only in the liver. Upon induction of acute hepatitis using ConA, down-regulation of the in vivo Nb imaging signal was observed, reflecting reduction in KC numbers as confirmed by FACS and IHC. On the other hand, induction of steatohepatitis resulted in higher signals in the liver corresponding to higher density of KCs. The Nb-imaging signals returned to normal levels after resolution of the investigated liver diseases. Conclusions: Anti-Clec4F and anti-Vsig4 Nbs targeting KCs as molecular imaging biomarkers could allow non-invasive monitoring/staging of liver pathogenesis. © 2016 World Molecular Imaging Society Source

Penet M.-F.,In Vivo Cellular and Molecular Imaging Center | Penet M.-F.,Johns Hopkins University | Chen Z.,In Vivo Cellular and Molecular Imaging Center | Chen Z.,Sidney Kimmel Comprehensive Cancer Center | And 3 more authors.
Future Oncology | Year: 2011

One of the earliest documented observations of the importance of the microenvironment in metastasis was made by Stephen Paget in 1889. More than a century later, the metastatic cascade remains a major cause of mortality from cancer. Cancer meets the criterion of a successful organization that is able to survive by adapting to changing environments. In fact, the tumor microenvironment and stroma are co-opted and shaped by cancer cells to derive a survival advantage. Cohesive strategies integrating advances in molecular biology and chemistry, with noninvasive multimodality imaging, provide new insights into the role of the tumor microenvironment in promoting metastasis from primary tumors as well as insights into environments that attract and permit cancer cells to establish colonies in distant organs. This article provides an overview of molecular and functional imaging characterization of microenvironments that can promote or permit cancer cells to metastasize and the microenvironmental characteristics of distant metastases. © 2011 Future Medicine Ltd. Source

Keereman V.,Ghent University | Keereman V.,In Vivo Cellular and Molecular Imaging Center | Fierens Y.,Ghent University | Fierens Y.,In Vivo Cellular and Molecular Imaging Center | And 6 more authors.
Molecular Imaging | Year: 2012

Attenuation correction is necessary for quantification in micro-single-photon emission computed tomography (micro-SPECT). In general, this is done based on micro-computed tomographic (micro-CT) images. Derivation of the attenuation map from magnetic resonance (MR) images is difficult because bone and lung are invisible in conventional MR images and hence indistinguishable from air. An ultrashort echo time (UTE) sequence yields signal in bone and lungs. Micro-SPECT, micro-CT, and MR images of 18 rats were acquired. Different tracers were used: hexamethylpropyleneamine oxime (brain), dimercaptosuccinic acid (kidney), colloids (liver and spleen), and macroaggregated albumin (lung). The micro-SPECT images were reconstructed without attenuation correction, with micro-CT-based attenuation maps, and with three MR-based attenuation maps: uniform, non-UTE-MR based (air, soft tissue), and UTE-MR based (air, lung, soft tissue, bone). The average difference with the micro-CT-based reconstruction was calculated. The UTE-MR- based attenuation correction performed best, with average errors ≤ 8% in the brain scans and ≤ 3% in the body scans. It yields nonsignificant differences for the body scans. The uniform map yields errors of ≤ 6% in the body scans. No attenuation correction yields errors ≥ 15% in the brain scans and ≥ 25% in the body scans. Attenuation correction should always be performed for quantification. The feasibility of MR-based attenuation correction was shown. When accurate quantification is necessary, a UTE-MR-based attenuation correction should be used. © 2012 Decker Publishing. Source

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