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

• Published in: Journal of translational medicine 2017-02, Vol.15 (1), p.47-47, Article 47
• Main Authors: Burmakin, Mikhail, van Wieringen, Tijs, Olsson, P Olof, Stuhr, Linda, Åhgren, Aive, Heldin, Carl-Henrik, Reed, Rolf K, Rubin, Kristofer, Hellberg, Carina
• Format: Article
• Language: English
• Subjects: Analysis; Animals; Apoptosis - drug effects; Cancer and Oncology; Cancer och onkologi; Care and treatment; Cell Line, Tumor; Clinical Medicine; Collagen - metabolism; Colonic Neoplasms - blood supply; Colonic Neoplasms - metabolism; Colonic Neoplasms - pathology; Dosage and administration; Extracellular Fluid - drug effects; Extracellular Fluid - metabolism; Extracellular Matrix - drug effects; Extracellular Matrix - metabolism; Hypoxia; Imatinib mesylate; Imatinib Mesylate - pharmacology; Interstitial fluid pressure; Klinisk medicin; Medical and Health Sciences; Medicin och hälsovetenskap; Melanoma; Mice, SCID; Neoplasms, Experimental - blood supply; Neoplasms, Experimental - metabolism; Neoplasms, Experimental - pathology; Oxygen - pharmacology; Pressure; Receptor tyrosine kinase; Receptor, Platelet-Derived Growth Factor beta - metabolism; Stromal Cells - metabolism; Tumor Burden - drug effects; Tumor stroma; Water
• ISSN: 1479-5876; 1479-5876
• DOI: 10.1186/s12967-017-1142-7

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 pO 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 pO -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 pO 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. Our data suggest that the effects of imatinib on pO -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.