title: The Tyrosine Kinase Inhibitor Imatinib Augments Extracellular Fluid Exchange and Reduces Average Collagen Fibril Diameter in Experimental Carcinoma.
abstract: A typical obstacle to cancer therapy is the limited distribution of low molecular weight anticancer drugs within the carcinoma tissue. In experimental carcinoma, imatinib (STI571) increases efficacy of synchronized chemotherapy, reduces tumor interstitial fluid pressure, and increases interstitial fluid volume. STI571 also increases the water-perfusable fraction in metastases from human colorectal adenocarcinomas. Because the mechanism(s) behind these effects have not been fully elucidated, we investigated the hypothesis that STI571 alters specific properties of the stromal extracellular matrix. We analyzed STI571-treated human colorectal KAT-4/HT-29 experimental carcinomas, known to have a well-developed stromal compartment, for solute exchange and glycosaminoglycan content, as well as collagen content, structure, and synthesis. MRI of STI571-treated KAT-4/HT-29 experimental carcinomas showed a significantly increased efficacy in dynamic exchanges of solutes between tumor interstitium and blood. This effect was paralleled by a distinct change of the stromal collagen network architecture, manifested by a decreased average collagen fibril diameter, and increased collagen turnover. The glycosaminoglycan content was unchanged. Furthermore, the apparent effects on the stromal cellular composition were limited to a reduction in an NG2-positive stromal cell population. The current data support the hypothesis that the collagen network architecture influences the dynamic exchanges of solutes between blood and carcinoma tissue. It is conceivable that STI571 reprograms distinct nonvascular stromal cells to produce a looser extracellular matrix, ultimately improving transport characteristics for traditional chemotherapeutic agents. Mol Cancer Ther; 15(10); 2455-64. ©2016 AACR.
authors.affiliation: Department of Laboratory Medicine, Translational Cancer Research, Lund University, Lund, Sweden.
authors.forename: P Olof
authors.initials: PO
authors.lastname: Olsson
authors.affiliation: Department of Laboratory Medicine, Translational Cancer Research, Lund University, Lund, Sweden.
authors.forename: Renata
authors.initials: R
authors.lastname: Gustafsson
authors.affiliation: Bioimaging Center, Lund University, Lund, Sweden.
authors.forename: René
authors.initials: R
authors.lastname: In 't Zandt
authors.affiliation: Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden.
authors.forename: Tomas
authors.initials: T
authors.lastname: Friman
authors.affiliation: Department of Experimental Medical Sciences, Matrixbiology, Lund University, Lund, Sweden.
authors.forename: Marco
authors.initials: M
authors.lastname: Maccarana
authors.affiliation: Department of Experimental Medical Sciences, Matrixbiology, Lund University, Lund, Sweden.
authors.forename: Emil
authors.initials: E
authors.lastname: Tykesson
authors.affiliation: Department of Experimental Medical Sciences, Matrixbiology, Lund University, Lund, Sweden.
authors.forename: Åke
authors.initials: Å
authors.lastname: Oldberg
authors.affiliation: Department of Laboratory Medicine, Translational Cancer Research, Lund University, Lund, Sweden. Kristofer.Rubin@med.lu.se.
authors.forename: Kristofer
authors.initials: K
authors.lastname: Rubin
authors.affiliation: Department of Medical Biochemistry and Microbiology, SciLife Laboratories, Uppsala University, Uppsala, Sweden.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Kalamajski
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002277:Carcinoma / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D003094:Collagen / Q000378:metabolism*; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000378:metabolism; D045604:Extracellular Fluid / Q000378:metabolism*; D005260:Female; D006801:Humans; D000068877:Imatinib Mesylate / Q000494:pharmacology*; D007150:Immunohistochemistry; D051379:Mice; D020286:Pericytes / Q000187:drug effects / Q000378:metabolism; D066329:Protein Aggregates; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D017154:Stromal Cells / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D066329:Protein Aggregates; D047428:Protein Kinase Inhibitors; D000068877:Imatinib Mesylate; D003094:Collagen