Imatinib increases oxygen delivery in extracellular matrix-rich but not in matrix-poor experimental carcinoma

Research output: Contribution to journalArticle

Abstract

Background: 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. Methods: 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. Results: 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 pO2 was 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 pO2 in 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. Conclusion: 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.

Details

Authors
  • Mikhail Burmakin
  • Tijs van Wieringen
  • Olof Olsson
  • Linda Stuhr
  • Aive Åhgren
  • Carl-Henrik Heldin
  • Rolf K Reed
  • Kristofer Rubin
  • Carina Hellberg
Organisations
External organisations
  • Uppsala University
  • Karolinska Institutet
  • University of Birmingham
  • University of Bergen
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Cancer and Oncology

Keywords

  • Hypoxia, Interstitial fluid pressure, Receptor tyrosine kinase, Tumor stroma
Original languageEnglish
Article number47
JournalJournal of Translational Medicine
Volume15
Issue number1
Publication statusPublished - 2017 Feb 23
Publication categoryResearch
Peer-reviewedYes