Simulation of heterogeneous molecular delivery in tumours using µCT reconstructions and MRI validation.

PRIMARY OBJECTIVE: Utilizing the detailed vascular network obtained from micro-computed tomography (µCT) to establish a mathematical model of the temporal molecular distribution within a murine C3H mammary carcinoma. PROCEDURES: Female CDF1 mice with a C3H mammary carcinoma on the right rear foot were used in this study. Dynamic information for each tumour was achieved by Dynamic Contrast Enhanced-Magnetic Resonance Imaging (DCE-MRI) on a 16.4 T system. Detailed morphologic information on the tumour vasculature was obtained by ex vivo µCT and compared to CD34 immunohistochemical staining of tissue sections. The reconstructed vascular network served as origin for the diffusion (described by the apparent diffusion coefficient) within the tumour (the restricted volume described by the interstitial volume fraction derived from DCE-MRI). The resulting partial differential equation was solved using Finite-Element and a combined mathematical graph describing molecular distribution within the tumour was obtained. RESULTS: The established molecular distribution model predicted a heterogeneous distribution throughout the tumour related to the layout of the vascular network. Central tumour section concentration-time curves estimated from the established molecular distribution model were compared with physical measurements obtained by DCE-MRI of the same tumours and showed excellent correlation. CONCLUSIONS: A mathematical model describing temporal molecular distribution based on detailed vascular network structures was established and compared to DCE-MRI. The improved morphological insight will enhance future studies of heterogeneous tumours.

Inhibition of tumor lactate oxidation: consequences for the tumor microenvironment.

BACKGROUND AND PURPOSE: Tumor cells are recognized as being highly glycolytic. However, recently it was suggested that lactate produced in hypoxic tumor areas may be taken up by the monocarboxylate transporter MCT1 and oxidized in well-oxygenated tumor parts. Furthermore, it was shown that inhibition of lactate oxidation using the MCT1 inhibitor α-cyano-hydroxycinnamate (CHC) can radio-sensitize tumors possibly by forcing a switch from lactate oxidization to glycolysis in oxygenated cells, which in turn improves tumor oxygenation and indirectly kills radio-resistant hypoxic tumor cells from glucose starvation. MATERIAL AND METHODS: To provide direct evidence for the existence of a targetable energetic symbiosis, mice bearing SiHa or FaDu(dd) tumors were treated with CHC for different time periods. One hour prior to sacrifice, mice were administered with the glucose analog fluorodeoxyglucose (FDG) and the hypoxia-marker pimonidazole. Tumor cryosections were analyzed for regional glucose retention (FDG autoradiograms), hypoxia (pimonidazole retention) and glucose and lactate levels (bioluminescence imaging). RESULTS: Treatment did not influence metabolite concentrations, necrosis or extent of hypoxia, but pixel-by-pixel analysis comparing FDG retention and hypoxia (a measure of the apparent in vivo Pasteur effect) showed that CHC treatment caused a transient reduction in the Pasteur effect in FaDu(dd) 1.5 h following CHC administration whereas a reduction was only observed in SiHa following repeated treatments. CONCLUSIONS: In summary, our data show that CHC is able to influence the intratumoral distribution of glucose use between hypoxic and non-hypoxic tumor areas. That is in accordance with a functional tumor lactate-shuttle, but the absence of any detectable changes in hypoxic extent and tissue metabolites was unexpected and warrants further investigation.

Assessing hypoxia in animal tumor models based on pharmocokinetic analysis of dynamic FAZA PET.

UNLABELLED: Positron emission tomography (PET) allows non-invasive detection and mapping of tumor hypoxia. However, slow tracer kinetics and low resolution, results in limited tumor-to-normal tissue contrast and the risk of missing areas where hypoxic cells are intermixed with necrosis. The shape of tumor time activity curves (TACs), as deduced from dynamic scans, may allow further separation of tumors/tumor sub-volumes that are inseparable based on static scans. This study was designed to define the added value of dynamic scans. MATERIAL AND METHODS: Three squamous cell carcinoma tumor models were grown in mice. Mice were injected with the (18)F-labeled PET hypoxia-tracer fluoroazomycin arabinoside (FAZA) and the immunologically-detectable hypoxia-marker pimonidazole, and PET scanned dynamically for three to six hours. Subsequently, microregional tracer retention (autoradiography) and the distribution of pimonidazole-retaining cells (immunohistology) and necrosis were analyzed in tumor tissue sections. Dynamic PET data were analysed based on a two-compartment model with irreversible tracer binding generating estimates of the putative hypoxia surrogate markers k(3) (tracer trapping rate constant) and K(i) (influx rate constant from plasma into irreversible bound tracer). RESULTS/DISCUSSION: High tumor-to-reference tissue ratios and a strong linear correlation (R∼0.7 to 0.95) between density of hypoxic cells and FAZA concentration was observed three hours after tracer administration, suggesting that late time PET images provides an accurate measure of hypoxia against which kinetic model estimates can be validated. Tumor TACs varied widely (ranging from distinctly wash-out to accumulative type) among tumor types although pimonidazole-stainings revealed extensive hypoxia in all models. Kinetic analysis of tumor sub-volumes showed that k(3) correlated poorly with late time FAZA retention regionally in two of the three tumor models. The influx rate constant K(i) displayed far less variability and correlated strongly with late time FAZA retention (hypoxia) in two of three tumor models, whereas a non-consistent relationship was observed in the last tumor model. Our study demonstrates the potential usefulness of dynamic PET, but also that a simple two-compartment model may be inappropriate in some tumor models.