title: Using magnetic resonance microscopy to study the growth dynamics of a glioma spheroid in collagen I: A case study.
abstract: BACKGROUND
  Highly malignant gliomas are characterized by rapid growth, extensive local tissue infiltration and the resulting overall dismal clinical outcome. Gaining any additional insights into the complex interaction between this aggressive brain tumor and its microenvironment is therefore critical. Currently, the standard imaging modalities to investigate the crucial interface between tumor growth and invasion in vitro are light and confocal laser scanning microscopy. While immensely useful in cell culture, integrating these modalities with this cancer's clinical imaging method of choice, i.e. MRI, is a non-trivial endeavour. However, this integration is necessary, should advanced computational modeling be able to utilize these in vitro data to eventually predict growth behaviour in vivo. We therefore argue that employing the same imaging modality for both the experimental setting and the clinical situation it represents should have significant value from a data integration perspective. In this case study, we have investigated the feasibility of using a specific form of MRI, i.e. magnetic resonance microscopy or MRM, to study the expansion dynamics of a multicellular tumor spheroid in a collagen type I gel.
  
  
  METHODS
  An U87mEGFR human giloblastoma multicellular spheroid (MTS) containing approximately 4.103 cells was generated and pipetted into a collagen I gel. The sample was then imaged using a T2-weighted 3D spoiled gradient echo pulse sequence on a 14T MRI scanner over a period of 12 hours with a temporal resolution of 3 hours at room temperature. Standard histopathology was performed on the MRM sample, as well as on control samples.
  
  
  RESULTS
  We were able to acquire three-dimensional MR images with a spatial resolution of 24 x 24 x 24 microm3. Our MRM data successfully documented the volumetric growth dynamics of an MTS in a collagen I gel over the 12-hour period. The histopathology results confirmed cell viability in the MRM sample, yet displayed distinct patterns of cell proliferation and invasion as compared to control.
  
  
  CONCLUSIONS
  In this study, we demonstrate that a specific form of MRI, i.e. magnetic resonance microscopy or MRM, can be used to study the dynamic growth of a multicellular tumor spheroid (MTS) with a single cell scale spatial resolution that approaches the level of light microscopy. We argue that MRM can be employed as a complementary non-invasive tool to characterize microscopic MTS expansion, and thus, together with integrative computational modeling, may allow bridging of the experimental and clinical scales more readily.
authors.affiliation: Harvard-MIT (HST) Athinoula A, Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Charlestown, MA 02129, USA. shuning@mit.edu
authors.forename: Shuning
authors.initials: S
authors.lastname: Huang
authors.forename: David
authors.initials: D
authors.lastname: Vader
authors.forename: Zhihui
authors.initials: Z
authors.lastname: Wang
authors.forename: Anat
authors.initials: A
authors.lastname: Stemmer-Rachamimov
authors.forename: David A
authors.initials: DA
authors.lastname: Weitz
authors.forename: Guangping
authors.initials: G
authors.lastname: Dai
authors.forename: Bruce R
authors.initials: BR
authors.lastname: Rosen
authors.forename: Thomas S
authors.initials: TS
authors.lastname: Deisboeck
mesh_terms: D001932:Brain Neoplasms / Q000473:pathology*; D002455:Cell Division; D024042:Collagen Type I; D003287:Contrast Media; D019786:Gadolinium DTPA; D005782:Gels; D005910:Glioma / Q000473:pathology*; D006801:Humans; D021621:Imaging, Three-Dimensional; D008279:Magnetic Resonance Imaging / Q000379:methods*; D018874:Spheroids, Cellular / Q000473:pathology*; D014407:Tumor Cells, Cultured
chemical_list: D024042:Collagen Type I; D003287:Contrast Media; D005782:Gels; D019786:Gadolinium DTPA