Cryo-image Analysis of Tumor Cell Migration, Invasion, and Dispersal in a Mouse Xenograft Model of Human Glioblastoma Multiforme

Qutaish, Mohammed Q.; Sullivant, Kristin E.; Burden-Gulley, Susan M.; Lu, Hong; Roy, Debashish; Wang, Jing; Basilion, James P.; Brady‐Kalnay, Susann M.; Wilson, David L.

doi:10.1007/s11307-011-0525-z

Cited by 18 publications

(21 citation statements)

References 17 publications

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“…Cryo-imaging (CryoViz ™ , BioInVision, Inc.) [11–16, 21, 24] was used to acquire image data for our experiments. CryoViz ™ consists of a digital cryo-microtome (DigitomePro ™ , BioInVision Inc.) housed within a −20C freezer chamber, a microscopic imaging system consisting of a high numerical aperture (NA) objective and a low-noise, cooled camera, a robotic XYZ positioner, and control system.…”

Section: Experimental Methodsmentioning

confidence: 99%

Automatic Stem Cell Detection in Microscopic Whole Mouse Cryo-Imaging

Wuttisarnwattana

Gargesha

Hof

et al. 2016

IEEE Trans. Med. Imaging

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With its single cell sensitivity over volumes as large as or larger than a mouse, cryo-imaging enables imaging of stem cell biodistribution, homing, engraftment, and molecular mechanisms. We developed and evaluated a highly automated software tool to detect fluorescently labeled stem cells within very large (~200GB) cryo-imaging datasets. Cell detection steps are: preprocess, remove immaterial regions, spatially filter to create features, identify candidate pixels, classify pixels using bagging decision trees, segment cell patches, and perform 3D labeling. There are options for analysis and visualization. To train the classifier, we created synthetic images by placing realistic digital cell models onto cryo-images of control mice devoid of cells. Very good cell detection results were (precision=98.49%, recall=99.97%) for synthetic cryo-images, (precision=97.81%, recall=97.71%) for manually evaluated, actual cryo-images, and <1% false positives in control mice. An α-multiplier applied to features allows one to correct for experimental variations in cell brightness due to labeling. On dim cells (37% of standard brightness), with correction, we improved recall (49.26%→99.36%) without a significant drop in precision (99.99%→99.75%). With tail vein injection, multipotent adult progenitor cells in a graft-versus-host-disease model in the first days post injection were predominantly found in lung, liver, spleen, and bone marrow. Distribution was not simply related to blood flow. The lung contained clusters of cells while other tissues contained single cells. Our methods provided stem cell distribution anywhere in mouse with single cell sensitivity. Methods should provide a rational means of evaluating dosing, delivery methods, cell enhancements, and mechanisms for therapeutic cells.

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Section: Experimental Methodsmentioning

confidence: 99%

Automatic Stem Cell Detection in Microscopic Whole Mouse Cryo-Imaging

Wuttisarnwattana

Gargesha

Hof

et al. 2016

IEEE Trans. Med. Imaging

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“…We recently developed methods for segmentation and visualization of the vasculature, main tumor mass, and dispersing cells (10). To segment the main tumor mass, we used a 3-D seeded region growing algorithm recently developed (10).…”

Section: Methodsmentioning

confidence: 99%

“…To segment the main tumor mass, we used a 3-D seeded region growing algorithm recently developed (10). Results were reviewed in individual slice images and manually edited if necessary.…”

Section: Methodsmentioning

confidence: 99%

“…To segment dispersed tumor cells and clusters, we applied a high pass filter and thresholded the result, excluding the binary volume consisting of the main tumor. To create a 3-D volume of the brain vasculature, brightfield images from each brain specimen were processed using algorithms developed for vessel edge detection and volume rendering (10). These algorithms resulted in a 3-D reconstruction of the brain vasculature.…”

Section: Methodsmentioning

confidence: 99%

“…We recently described the development of algorithms to reconstruct the 3-D architecture of blood vessels and tumor cell dispersal within the mouse brain (10). We used those algorithms to characterize how commonly used human (Gli36Δ5, U-87 MG, LN-229) and rodent (CNS-1) glioma cell lines disperse in the mouse brain.…”

Section: Introductionmentioning

confidence: 99%

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Novel Cryo-Imaging of the Glioma Tumor Microenvironment Reveals Migration and Dispersal Pathways in Vivid Three-Dimensional Detail

et al. 2011

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Traditional methods of imaging cell migration in the tumor microenvironment include serial sections of xenografts and standard histologic stains. Current molecular imaging techniques suffer from low resolution and difficulty in imaging through the skull. Here we show how computer algorithms can be used to reconstruct images from tissue sections obtained from mouse xenograft models of human glioma and can be rendered into three-dimensional images offering exquisite anatomic detail of tumor cell dispersal. Our findings identify human LN-229 and rodent CNS-1 glioma cells as valid systems to study the highly dispersive nature of glioma tumor cells along blood vessels and white matter tracts in vivo. This novel cryo-imaging technique provides a valuable tool to evaluate therapeutic interventions targeted at limiting tumor cell invasion and dispersal. Cancer Res; 71(17); 5932-40. Ó2011 AACR.

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Single cell molecular recognition of migrating and invading tumor cells using a targeted fluorescent probe to receptor PTPmu

Burden-Gulley

Qutaish

Sullivant

et al. 2012

Intl Journal of Cancer

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Detection of an extracellular cleaved fragment of a cell-cell adhesion molecule represents a new paradigm in molecular recognition and imaging of tumors. We previously demonstrated that probes that recognize the cleaved extracellular domain of PTPmu label human glioblastoma brain tumor sections and the main tumor mass of intracranial xenograft gliomas. In this manuscript, we examine whether one of these probes, SBK2, can label dispersed glioma cells that are no longer connected to the main tumor mass. Live mice with highly dispersive glioma tumors were injected intravenously with the fluorescent PTPmu probe to test the ability of the probe to label the dispersive glioma cells in vivo. Analysis was performed using a unique 3-D cryo-imaging technique to reveal highly migratory and invasive glioma cell dispersal within the brain and the extent of co-labeling by the PTPmu probe. The PTPmu probe labeled the main tumor site and dispersed cells up to 3.5 mm away. The cryo-images of tumors labeled with the PTPmu probe provide a novel, high-resolution view of molecular tumor recognition, with excellent 3-D detail regarding the pathways of tumor cell migration. Our data demonstrate that the PTPmu probe recognizes distant tumor cells even in parts of the brain where the blood-brain barrier is likely intact. The PTPmu probe has potential translational significance for recognizing tumor cells to facilitate molecular imaging, a more complete tumor resection and to serve as a molecular targeting agent to deliver chemotherapeutics to the main tumor mass and distant dispersive tumor cells.

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Cryo-image Analysis of Tumor Cell Migration, Invasion, and Dispersal in a Mouse Xenograft Model of Human Glioblastoma Multiforme

Cited by 18 publications

References 17 publications

Automatic Stem Cell Detection in Microscopic Whole Mouse Cryo-Imaging

Automatic Stem Cell Detection in Microscopic Whole Mouse Cryo-Imaging

Novel Cryo-Imaging of the Glioma Tumor Microenvironment Reveals Migration and Dispersal Pathways in Vivid Three-Dimensional Detail

Single cell molecular recognition of migrating and invading tumor cells using a targeted fluorescent probe to receptor PTPmu

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