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The Tyrosine Kinase Inhibitor Imatinib Augments Extracellular Fluid Exchange and Reduces Average Collagen Fibril Diameter in Experimental Carcinoma
Lund Univ, Dept Lab Med, Translat Canc Res, Lund, Sweden..
Lund Univ, Dept Lab Med, Translat Canc Res, Lund, Sweden..
Lund Univ, Bioimaging Ctr, Lund, Sweden..
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
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2016 (English)In: Molecular Cancer Therapeutics, ISSN 1535-7163, E-ISSN 1538-8514, Vol. 15, no 10, 2455-2464 p.Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
2016. Vol. 15, no 10, 2455-2464 p.
National Category
Cancer and Oncology
Identifiers
URN: urn:nbn:se:uu:diva-307740DOI: 10.1158/1535-7163.MCT-16-0026ISI: 000385636300018PubMedID: 27474147OAI: oai:DiVA.org:uu-307740DiVA: diva2:1048396
Funder
Swedish Cancer SocietySwedish Research CouncilThe Crafoord FoundationMagnus Bergvall FoundationÅke Wiberg Foundation
Available from: 2016-11-21 Created: 2016-11-21 Last updated: 2016-11-21Bibliographically approved

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Friman, TomasKalamajski, Sebastian
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Department of Pharmaceutical BiosciencesDepartment of Medical Biochemistry and MicrobiologyScience for Life Laboratory, SciLifeLab
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