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

Journal of Translational Medicine

Research

Linda Stuhr¹  Rolf K. Reed²  P. Olof Olsson³  Kristofer Rubin⁴  Aive Åhgren⁵  Carl-Henrik Heldin⁵  Mikhail Burmakin⁶  Carina Hellberg⁷  Tijs van Wieringen⁷ 

[1] Department of Biomedicine, University of Bergen, Bergen, Norway;Department of Biomedicine, University of Bergen, Bergen, Norway;Centre for Cancer Biomarkers (CCBIO), University of Bergen, Bergen, Norway;Department of Laboratory Medicine, Medicon Village, Lund University, 223 63, Lund, Sweden;Department of Laboratory Medicine, Medicon Village, Lund University, 223 63, Lund, Sweden;Department of Experimental Medical Science, Lund University, BMC D10, 22381, Lund, Sweden;Ludwig Institute for Cancer Research, Science for Life Laboratory, Uppsala University, 751 24, Uppsala, Sweden;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;Ludwig Institute for Cancer Research, Science for Life Laboratory, Uppsala University, 751 24, Uppsala, Sweden;School of Biosciences, University of Birmingham, B15 2TT, Birmingham, UK;

关键词: Hypoxia;    Interstitial fluid pressure;    Receptor tyrosine kinase;    Tumor stroma;   

DOI  :  10.1186/s12967-017-1142-7

 received in 2016-09-22, accepted in 2017-02-07,  发布年份 2017

来源: Springer

【 摘 要 】

BackgroundImatinib 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.MethodsWe 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.ResultsNeither 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.ConclusionOur 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.

【 授权许可】

CC BY   
© The Author(s) 2017