In this study, where we compared three murine malignant tumor models, we show that pO
2 levels in tumor tissues at steady-state correlate with the amount of collagen in the stroma. Thus, stroma-rich KAT-4 carcinomas had six times lower pO
2 levels than B16BB melanomas where no collagenous stroma could be detected. Treatment with imatinib, which affects collagen architecture in KAT-4 carcinoma [
23], significantly increased pO
2 in KAT-4, but had no significant effect on pO
2 in the stroma-poor CT-26 carcinomas, or in B16BB melanomas. Similarly, imatinib had no effect on IFP in B16BB melanomas, but significantly reduced IFP in the other two tumor model systems, moreso in KAT-4 than in CT26 carcinomas.
Tumor interstitial pO
2 is the result of oxygen provided to the tissue minus that used in cellular metabolism [
33]. Our approach measured the pO
2 in the tumor tissue directly, i.e. supply minus metabolism. Reports on the effect of imatinib on metabolism and oxygen consumption are scarce. Edema and dyspnea are the major adverse effects of prolonged imatinib treatment in patients. Such effects have been attributed to cardiotoxicity causing an adverse influence on heart mitochondria [
34,
35], although this view has in fact been disputed [
36,
37]. An uncoupling, or reduction of mitochondrial activity would reduce oxygen consumption and potentially increase pO
2. The plasma C
max
of imatinib in male ICR mice was determined to be 17 μM 2 h after administration of 100 mg/kg
p.o. [
38]. The plasma half-life of imatinib in mice was determined to be 2.3 h [
38], whereas in humans it is around 10 h [
39]. Will et al. [
37] showed that imatinib, in doses below the expected plasma C
max
in mice, had little or no effect on ATP production by cultured rat heart H9c2 undifferentiated myoblasts, neither when grown in glucose-containing medium nor in galactose-containing medium, which causes a shift in metabolism to oxidative phosphorylation. These authors also reported that respiration in isolated rat heart mitochondria was not affected by imatinib when the drug was administered in clinically relevant doses [
37]. Furthermore, imatinib inhibits the expression of the glucose transporter Glut1 in BCR-ABL-positive, but not in BCR-ABL-negative, chronic myeloid leukemia cells [
40]. Imatinib decreases glucose uptake from the media by suppressing glycolytic activity and increasing mitochondrial Krebs cycle activity in cultured cells [
40]. Such an effect by itself should in fact cause a lowering of pO
2, which was in contrast to that observed in the present study. Our present data show that cellular proliferation was unaffected in all three tumor models investigated by a 4-day treatment period with imatinib and, in addition, that pO
2 levels tended to be similar in all three models after imatinib treatment. This then suggests that the increased pO
2 levels in KAT-4 and CT-26 carcinomas were not due to changes in cell metabolism with decreased oxygen consumption. The fractions of apoptotic cells increased after imatinib treatment in all three tumor models but remained below 6% also after treatment. Imatinib induces or sensitizes several types of cells for endoplasmic reticulum stress and to the effect of reactive oxygen species [
35‐
37], potentially explaining the observed increase in the fractions of apoptotic cells. Thus, the findings presented herein strongly suggest that imatinib, in the dose used, does not affect oxygen consumption but rather increases delivery of oxygen to the tumor tissue.
The amount of oxygen provided to a tissue is determined by the blood flow. Oxygen delivery to the tissue is flow-limited, while transport from blood to tissue occurs by diffusion and therefore is not a limiting factor in determining tissue pO
2. The present data on vascular gross morphology in KAT-4 carcinomas and the effects of imatinib are in line with previously published data [
22,
23], showing that vascular parameters are only marginally affected by imatinib treatment and cannot explain the significantly increased delivery of oxygen in these tumors. In the CT-26 carcinomas the pO
2 levels also increased after treatment with imatinib although this increase did not reach statistical significance. The parameters of vascular morphology investigated in these carcinomas were unaffected by treatment with imatinib. Blood flow measured by laser Doppler is based on measurement of red cell velocity and thus does not give a true indication of blood flow in mL/min/g tissue. Although the method has a great advantage of being non-invasive, it is challenging in the current experimental approach when one has to compare the same tissue several days apart, and under conditions where vessel architecture is changing (cf Fig.
4a–f). Nevertheless, we recorded a trend towards an increased blood flow in KAT-4 carcinomas upon imatinib treatment, although the differences did not reach significance due to a large inter- and intra-tumor variation. Taken together, our data strongly suggest that the increased pO
2 levels recorded after treatment of especially KAT-4 carcinomas is due to an increased blood flow. An increased blood flow must in turn mean that the resistance to flow is reduced. The reduced IFP in KAT-4 and CT-26 tumors after imatinib treatment would be expected to cause reduced inflow hindrance to the tumor and thereby result in an increased delivery of oxygen to the tissues.