title: Imatinib increases oxygen delivery in extracellular matrix-rich but not in matrix-poor experimental carcinoma.
abstract: Imatinib causes increased turnover of stromal collagen, reduces collagen fibril diameter, enhances extracellular fluid turnover and lowers interstitial fluid pressure (IFP) in the human colonic carcinoma KAT-4/HT-29 (KAT-4) xenograft model.
  
  
  
  We compared the effects of imatinib on oxygen levels, vascular morphology and IFP in three experimental tumor models differing in their content of a collagenous extracellular matrix.
  
  
  
  Neither the KAT4 and CT-26 colonic carcinoma models, nor B16BB melanoma expressed PDGF β-receptors in the malignant cells. KAT-4 tumors exhibited a well-developed ECM in contrast to the other two model systems. The collagen content was substantially higher in KAT-4 than in CT-26, while collagen was not detectable in B16BB tumors. The pO2was on average 5.4, 13.9 and 19.3 mmHg in KAT-4, CT-26 and B16BB tumors, respectively. Treatment with imatinib resulted in similar pO2-levels in all three tumor models but only in KAT-4 tumors did the increase reach statistical significance. It is likely that after imatinib treatment the increase in pO2in KAT-4 tumors is caused by increased blood flow due to reduced vascular resistance. This notion is supported by the significant reduction observed in IFP in KAT-4 tumors after imatinib treatment. Vessel area varied between 4.5 and 7% in the three tumor models and was not affected by imatinib treatment. Imatinib had no effect on the fraction of proliferating cells, whereas the fraction of apoptotic cells increased to a similar degree in all three tumor models.
  
  
  
  Our data suggest that the effects of imatinib on pO2-levels depend on a well-developed ECM and provide further support to the suggestion that imatinib acts by causing interstitial stroma cells to produce a less dense ECM, which would in turn allow for an increased blood flow. The potential of imatinib treatment to render solid tumors more accessible to conventional treatments would therefore depend on the degree of tumor desmoplasia.
authors.affiliation: Ludwig Institute for Cancer Research, Science for Life Laboratory, Uppsala University, 751 24, Uppsala, Sweden.|Division of Vascular Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institute, 171 77, Stockholm, Sweden.
authors.forename: Mikhail
authors.initials: M
authors.lastname: Burmakin
authors.affiliation: Ludwig Institute for Cancer Research, Science for Life Laboratory, Uppsala University, 751 24, Uppsala, Sweden.|School of Biosciences, University of Birmingham, Birmingham, B15 2TT, UK.
authors.forename: Tijs
authors.initials: T
authors.lastname: van Wieringen
authors.affiliation: Department of Laboratory Medicine, Medicon Village, Lund University, 223 63, Lund, Sweden.
authors.forename: P Olof
authors.initials: PO
authors.lastname: Olsson
authors.affiliation: Department of Biomedicine, University of Bergen, Bergen, Norway.
authors.forename: Linda
authors.initials: L
authors.lastname: Stuhr
authors.affiliation: Ludwig Institute for Cancer Research, Science for Life Laboratory, Uppsala University, 751 24, Uppsala, Sweden.
authors.forename: Aive
authors.initials: A
authors.lastname: Åhgren
authors.affiliation: Ludwig Institute for Cancer Research, Science for Life Laboratory, Uppsala University, 751 24, Uppsala, Sweden.
authors.forename: Carl-Henrik
authors.initials: CH
authors.lastname: Heldin
authors.affiliation: Department of Biomedicine, University of Bergen, Bergen, Norway.|Centre for Cancer Biomarkers (CCBIO), University of Bergen, Bergen, Norway.
authors.forename: Rolf K
authors.initials: RK
authors.lastname: Reed
authors.affiliation: Department of Laboratory Medicine, Medicon Village, Lund University, 223 63, Lund, Sweden. Kristofer.Rubin@med.lu.se.|Department of Experimental Medical Science, Lund University, BMC D10, 22381, Lund, Sweden. Kristofer.Rubin@med.lu.se.
authors.forename: Kristofer
authors.identifier: 0000-0003-2789-6276
authors.initials: K
authors.lastname: Rubin
authors.affiliation: Ludwig Institute for Cancer Research, Science for Life Laboratory, Uppsala University, 751 24, Uppsala, Sweden.|School of Biosciences, University of Birmingham, Birmingham, B15 2TT, UK.
authors.forename: Carina
authors.initials: C
authors.lastname: Hellberg
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D003094:Collagen / Q000378:metabolism; D003110:Colonic Neoplasms / Q000098:blood supply / Q000378:metabolism* / Q000473:pathology; D045604:Extracellular Fluid / Q000187:drug effects / Q000378:metabolism; D005109:Extracellular Matrix / Q000187:drug effects / Q000378:metabolism*; D000068877:Imatinib Mesylate / Q000494:pharmacology*; D016513:Mice, SCID; D009374:Neoplasms, Experimental / Q000098:blood supply / Q000378:metabolism* / Q000473:pathology; D010100:Oxygen / Q000494:pharmacology*; D011312:Pressure; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000378:metabolism; D017154:Stromal Cells / Q000378:metabolism; D047368:Tumor Burden / Q000187:drug effects; D014867:Water
chemical_list: D014867:Water; D000068877:Imatinib Mesylate; D003094:Collagen; D020797:Receptor, Platelet-Derived Growth Factor beta; D010100:Oxygen
keywords: Hypoxia; Interstitial fluid pressure; Receptor tyrosine kinase; Tumor stroma