title: Evaluation of Tumor-associated Stroma and Its Relationship with Tumor Hypoxia Using Dynamic Contrast-enhanced CT and (18)F Misonidazole PET in Murine Tumor Models.
abstract: OBJECTIVE
  To determine the relationship between the fractional interstitial volume (Fis), as calculated at dynamic contrast material-enhanced (DCE) computed tomography (CT), and tumor-associated stroma and to analyze its spatial relationship with tumor hypoxia in several xenograft tumor models.
  
  
  METHODS
  All animal experiments were approved by the animal research committee. Mice with three different xenograft tumors (U251, CFPAC-1, and BxPC-3; n = 6, n = 8, and n = 6, respectively) underwent DCE CT then hypoxia imaging with fluorine 18 ((18)F) fluoromisonidazole (FMISO) positron emission tomography (PET) within 24 hours. Immunohistochemical analysis was performed in harvested tumors to detect hypoxia markers and to quantify microvascular and stromal density. Two DCE CT parameters (amount of interstitial space associated with the amount of stroma [Fis] and flow velocity [Fv]) were identified and quantitatively validated by using immunohistochemistry. FMISO uptake within the tumor was also assessed in relation to DCE CT parameters. Imaging and immunohistochemical parameters were assessed by using the Kruskal-Wallis test, Wilcoxon rank-sum test with Bonferroni correction, and Pearson correlation coefficient.
  
  
  RESULTS
  Almost no α-smooth muscle actin-positive cells were found in the U251 xenograft, while abundant stroma was found in the entire BxPC-3 xenograft and in the periphery of the CFPAC-1 xenograft. Quantitative analysis showed a significant correlation (R = 0.83, P < .0001) between Fis and stromal density. FMISO uptake had a negative correlation with Fis (R = -0.58, P < .0001) and Fv (R = -0.53, P < .0001).
  
  
  CONCLUSIONS
  DCE CT can be used to quantify parameters associated with tumor-associated stroma. Tumor hypoxia was Complementarily localized in tumor-associated stroma in these models.
authors.affiliation: From the Departments of Diagnostic Imaging and Nuclear Medicine (S.K., Y.N., T.N., K.S., K.T.), Gastroenterology and Hepatology (Y.T.), and Radiation Oncology and Image-Applied Therapy (H.H.), Graduate School of Medicine, Division of Molecular Imaging, Radioisotope Research Center (H.K), Clinical Radiology Service, Kyoto University Hospital (K.K.); and Department of Bioartificial Organs, Institute for Frontier Medical Science (M.H.), Kyoto University, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan.
authors.forename: Sho
authors.initials: S
authors.lastname: Koyasu
authors.affiliation: From the Departments of Diagnostic Imaging and Nuclear Medicine (S.K., Y.N., T.N., K.S., K.T.), Gastroenterology and Hepatology (Y.T.), and Radiation Oncology and Image-Applied Therapy (H.H.), Graduate School of Medicine, Division of Molecular Imaging, Radioisotope Research Center (H.K), Clinical Radiology Service, Kyoto University Hospital (K.K.); and Department of Bioartificial Organs, Institute for Frontier Medical Science (M.H.), Kyoto University, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan.
authors.forename: Yoshihisa
authors.initials: Y
authors.lastname: Tsuji
authors.affiliation: From the Departments of Diagnostic Imaging and Nuclear Medicine (S.K., Y.N., T.N., K.S., K.T.), Gastroenterology and Hepatology (Y.T.), and Radiation Oncology and Image-Applied Therapy (H.H.), Graduate School of Medicine, Division of Molecular Imaging, Radioisotope Research Center (H.K), Clinical Radiology Service, Kyoto University Hospital (K.K.); and Department of Bioartificial Organs, Institute for Frontier Medical Science (M.H.), Kyoto University, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Harada
authors.affiliation: From the Departments of Diagnostic Imaging and Nuclear Medicine (S.K., Y.N., T.N., K.S., K.T.), Gastroenterology and Hepatology (Y.T.), and Radiation Oncology and Image-Applied Therapy (H.H.), Graduate School of Medicine, Division of Molecular Imaging, Radioisotope Research Center (H.K), Clinical Radiology Service, Kyoto University Hospital (K.K.); and Department of Bioartificial Organs, Institute for Frontier Medical Science (M.H.), Kyoto University, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Nakamoto
authors.affiliation: From the Departments of Diagnostic Imaging and Nuclear Medicine (S.K., Y.N., T.N., K.S., K.T.), Gastroenterology and Hepatology (Y.T.), and Radiation Oncology and Image-Applied Therapy (H.H.), Graduate School of Medicine, Division of Molecular Imaging, Radioisotope Research Center (H.K), Clinical Radiology Service, Kyoto University Hospital (K.K.); and Department of Bioartificial Organs, Institute for Frontier Medical Science (M.H.), Kyoto University, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan.
authors.forename: Tomomi
authors.initials: T
authors.lastname: Nobashi
authors.affiliation: From the Departments of Diagnostic Imaging and Nuclear Medicine (S.K., Y.N., T.N., K.S., K.T.), Gastroenterology and Hepatology (Y.T.), and Radiation Oncology and Image-Applied Therapy (H.H.), Graduate School of Medicine, Division of Molecular Imaging, Radioisotope Research Center (H.K), Clinical Radiology Service, Kyoto University Hospital (K.K.); and Department of Bioartificial Organs, Institute for Frontier Medical Science (M.H.), Kyoto University, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kimura
authors.affiliation: From the Departments of Diagnostic Imaging and Nuclear Medicine (S.K., Y.N., T.N., K.S., K.T.), Gastroenterology and Hepatology (Y.T.), and Radiation Oncology and Image-Applied Therapy (H.H.), Graduate School of Medicine, Division of Molecular Imaging, Radioisotope Research Center (H.K), Clinical Radiology Service, Kyoto University Hospital (K.K.); and Department of Bioartificial Organs, Institute for Frontier Medical Science (M.H.), Kyoto University, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan.
authors.forename: Kohei
authors.initials: K
authors.lastname: Sano
authors.affiliation: From the Departments of Diagnostic Imaging and Nuclear Medicine (S.K., Y.N., T.N., K.S., K.T.), Gastroenterology and Hepatology (Y.T.), and Radiation Oncology and Image-Applied Therapy (H.H.), Graduate School of Medicine, Division of Molecular Imaging, Radioisotope Research Center (H.K), Clinical Radiology Service, Kyoto University Hospital (K.K.); and Department of Bioartificial Organs, Institute for Frontier Medical Science (M.H.), Kyoto University, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Koizumi
authors.affiliation: From the Departments of Diagnostic Imaging and Nuclear Medicine (S.K., Y.N., T.N., K.S., K.T.), Gastroenterology and Hepatology (Y.T.), and Radiation Oncology and Image-Applied Therapy (H.H.), Graduate School of Medicine, Division of Molecular Imaging, Radioisotope Research Center (H.K), Clinical Radiology Service, Kyoto University Hospital (K.K.); and Department of Bioartificial Organs, Institute for Frontier Medical Science (M.H.), Kyoto University, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan.
authors.forename: Masatsugu
authors.initials: M
authors.lastname: Hamaji
authors.affiliation: From the Departments of Diagnostic Imaging and Nuclear Medicine (S.K., Y.N., T.N., K.S., K.T.), Gastroenterology and Hepatology (Y.T.), and Radiation Oncology and Image-Applied Therapy (H.H.), Graduate School of Medicine, Division of Molecular Imaging, Radioisotope Research Center (H.K), Clinical Radiology Service, Kyoto University Hospital (K.K.); and Department of Bioartificial Organs, Institute for Frontier Medical Science (M.H.), Kyoto University, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan.
authors.forename: Kaori
authors.initials: K
authors.lastname: Togashi
mesh_terms: D000230:Adenocarcinoma / Q000000981:diagnostic imaging* / Q000473:pathology; D000818:Animals; D045744:Cell Line, Tumor; D003287:Contrast Media; D004195:Disease Models, Animal; D005260:Female; D005909:Glioblastoma / Q000000981:diagnostic imaging* / Q000473:pathology; D000860:Hypoxia / Q000473:pathology; D007150:Immunohistochemistry; D051379:Mice; D008920:Misonidazole / Q000031:analogs & derivatives; D010190:Pancreatic Neoplasms / Q000000981:diagnostic imaging* / Q000473:pathology; D049268:Positron-Emission Tomography / Q000379:methods*; D011838:Radiation-Sensitizing Agents; D011857:Radiographic Image Interpretation, Computer-Assisted; D014057:Tomography, X-Ray Computed / Q000379:methods*
chemical_list: D003287:Contrast Media; D011838:Radiation-Sensitizing Agents; C031843:fluoromisonidazole; D008920:Misonidazole