Dietary supplementation of tetradecylthioacetic acid increases feed intake but reduces body weight gain and adipose depot sizes in rats fed on high-fat diets.

AIM: The pan-peroxisome proliferator-activated receptor (PPAR) ligand and fatty acid analogue tetradecylthioacetic acid (TTA) may reduce plasma lipids and enhance hepatic lipid metabolism, as well as reduce adipose tissue sizes in rats fed on high-fat diets. This study further explores the effects of TTA on weight gain, feed intake and adipose tissue functions in rats that are fed a high-fat diet for 7 weeks. METHODS: The effects on feed intake and body weight during 7 weeks' dietary supplement with TTA ( approximately 200 mg/kg bw) were studied in male Wistar rats fed on a lard-based diet containing approximately 40% energy from fat. Adipose tissue mass, body composition and expression of relevant genes in fat depots and liver were measured at the end of the feeding. RESULTS: Despite higher feed intake during the final 2 weeks of the study, rats fed on TTA gained less body weight than lard-fed rats and had markedly decreased subcutaneous, epididymal, perirenal and mesenteric adipose depots. The effects of TTA feeding with reduced body weight gain and energy efficiency (weight gain/feed intake) started between day 10 and 13. Body contents of fat, protein and water were reduced after feeding lard plus TTA, with a stronger decrease in fat relative to protein. Plasma lipids, including Non-Esterified Fatty Acids (NEFA), were significantly reduced, whereas fatty acid beta-oxidation in liver and heart was enhanced in lard plus TTA-fed rats. Hepatic UCP3 was expressed ectopically both at protein and mRNA level (>1900-fold), whereas Ucp1 mRNA was increased approximately 30-fold in epididymal and approximately 90-fold in mesenteric fat after lard plus TTA feeding. CONCLUSION: Our data support the hypothesis that TTA feeding may increase hepatic fatty acid beta-oxidation, and thereby reduce the size of adipose tissues. The functional importance of ectopic hepatic UCP3 is unknown, but might be associated with enhanced energy expenditure and thus the reduced feed efficiency.

Thrombospondin-1-mediated metastasis suppression by the primary tumor in human melanoma xenografts.

Some cancer patients show accelerated growth of pre-existing metastases after removal of the primary tumor. The purpose of this study was to investigate whether primary tumor-induced metastasis suppression can be mediated by thrombospondin-1 in melanoma. Human melanoma xenografts (D-12, R-18, and U-25) were used as models of melanoma in humans. Melanoma angiogenesis, lung colonization, and spontaneous pulmonary metastasis were inhibited in mice bearing D-12, U-25, or thrombospondin-1 overexpressing R-18 tumors, which showed high thrombospondin-1 expression and secreted large quantities of thrombospondin-1 into the blood, but not in mice bearing wild-type R-18 tumors, which were negative for thrombospondin-1. D-12 tumors suppressed the growth of their own spontaneous metastases. The anti-angiogenic and anti-metastatic effects of D-12 and U-25 tumors were blocked in mice treated with thrombospondin-1 neutralizing antibody. Dormant avascular microcolonies having an elevated apoptotic activity were seen in the lungs of mice bearing D-12 or U-25 tumors, whereas only neovascularized lung macrocolonies were seen in control and antibody-treated mice. This study suggests that some melanoma patients may benefit from combined local treatment and long-term anti-angiogenic therapy involving thrombospondin-1.

Macromolecule uptake in human melanoma xenografts. relationships to blood supply, vascular density, microvessel permeability and extracellular volume fraction.

The uptake of albumin-Evans blue in human melanoma xenografts was studied and related to blood supply, vascular density, microvessel permeability and extracellular volume fraction in an attempt to identify transport barriers limiting the delivery of macromolecular therapeutic agents to tumours. Three melanoma lines (A-07, R-18, U-25) were included in the study. Tissue concentrations of albumin-Evans blue were determined by spectrophotometry. The [86Rb] uptake method was used to measure tumour blood supply. Vascular density was determined by stereological analysis of histological sections. Microvessel permeability was measured by using the indicator diffusion method. Contrast-enhanced magnetic resonance imaging was used to measure tumour extracellular volume fraction. The fractional volume of the extracellular space governed the uptake of albumin-Evans blue in the tumours. The uptake of albumin-Evans blue in the extracellular space was primarily limited by transport in the vasculature and not by transport across the microvascular wall or the transport through the interstitium. Our study thus suggests that novel strategies for improving the delivery of macromolecular therapeutic agents to tumours should focus on enhancing the tumour blood supply, increasing the half-life of the therapeutic agent in the blood plasma and/or enhancing the volume of the extracellular space available to macromolecules rather than on increasing the permeability of the microvascular wall or improving diffusion conditions in the tumour interstitium.

Computed tomography enhancement characteristics of lymphomatous lymph nodes of the neck.

OBJECTIVES: The objective of this study was to investigate prospectively CT contrast medium enhancement curves of lymphomatous lymph nodes of the neck. MATERIALS AND METHODS: Eleven patients with biopsy-proven lymphoma had their enlarged cervical lymph nodes examined with dynamic CT and compared with a control group. RESULTS: The mean contrast medium enhancement of the lymphomatous nodes was significantly lower than that of the control group in the time interval from 40 s to 180 s after injection. DISCUSSION: The enhancement pattern previously suggested from studies of retroperitoneal lymph nodes was confirmed in this prospective study of cervical nodes.

Microvascular permeability of human melanoma xenografts to macromolecules: relationships to tumor volumetric growth rate, tumor angiogenesis, and VEGF expression.

The effective microvascular permeability of human melanoma xenografts to albumin-Evans blue was measured and related to tumor volumetric growth rate, rate of tumor angiogenesis, and expression of vascular endothelial growth factor (VEGF) in an attempt to identify mechanisms regulating the microvascular permeability of tumors to macromolecules. Three melanoma lines (A-07, R-18, and U-25) were included in the study. Effective microvascular permeability was assessed by using the indicator diffusion method. Intradermal and intratumor angiogenesis assays were used to measure the rate of tumor angiogenesis. VEGF expression was studied by ELISA, immunohistochemistry, Western blotting, and measurement of tumor-induced formation of ascitic fluid. The effective microvascular permeabilities of albumin-Evans blue were determined to be (1.5 +/- 0.2) x 10(-6) cm/s (A-07), (1.1 +/- 0.4) x 10(-6) cm/s (R-18), and (0.9 +/- 0.3) x 10(-6) cm/s (U-25). These values are high compared with those measured for other tumor lines and are not significantly different. Correlations between the effective microvascular permeability of albumin-Evans blue and tumor volumetric growth rate, rate of tumor angiogenesis, or VEGF expression were not found. The three last-mentioned parameters differed significantly among the melanoma lines and covered a broad range of values relative to those of other experimental tumors. Our study suggests that the effective microvascular permeability of macromolecules can be high even in slowly growing tumors, poorly angiogenic tumors, and tumors showing low VEGF expression.

Temporal heterogeneity in oxygen tension in human melanoma xenografts.

The spatial heterogeneity of the oxygen tension (pO(2)) in human and experimental tumours has been studied extensively, whereas studies of the temporal heterogeneity in pO(2) are sparse. In the work reported here, pO(2) was measured continuously over periods of at least 60 min in A-07 human melanoma xenografts by using the OxyLite fibre-optic oxygen-sensing device. The main purpose of the work was to establish the usefulness of the OxyLite system in measuring the temporal heterogeneity in pO(2) in tissues and to characterise the fluctuations in tissue pO(2) in A-07 tumours. The OxyLite device was found to be suitable for studies of the temporal heterogeneity in pO(2) in tumours. However, potential pitfalls were identified, and reliable pO(2) measurements require that precautions are taken to avoid these pitfalls, that is, erroneous pO(2) readings caused by tissue trauma induced by the probe, probe movements induced by reflex actions of the host mouse and occasional probe drift. Significant fluctuations in pO(2) were detected in the majority of the 70 tumour regions subjected to measurement. The fluctuations in different regions of the same tumour were in general temporally independent, implying that they were caused primarily by redistribution of the tumour perfusion rather than fluctuations in global perfusion. Fourier analysis of the pO(2) traces showed that the pO(2) usually fluctuated at frequencies lower than 1.5-2.0 mHz, corresponding to less than 0.1 cycle min(-1). Haemodynamic effects may cause pO(2) fluctuations in this frequency range, and hence, the redistribution of the perfusion could have been caused by morphological abnormalities of the tumour microvasculature. Moreover, acute hypoxia, that is, pO(2) fluctuations around 10 or 5 mmHg, was detected in 20 of 70 regions, that is, 29% (10 mmHg), or 27 of 70 regions, that is, 39% (5 mmHg). The median fraction of the time these regions were acutely hypoxic was 73% (10 mmHg) or 53% (5 mmHg). Consequently, if A-07 tumours are adequate models of tumours in man, acute hypoxia may be a commonly occurring phenomenon in neoplastic tissues, and hence, acute hypoxia is likely to cause resistance to radiation therapy and promote tumour aggressiveness.

Intratumour heterogeneity in the uptake of macromolecular therapeutic agents in human melanoma xenografts.

Intratumour heterogeneity in the uptake of blood-borne technetium-labelled human serum albumin ((99m)Tc-HSA) was studied in human melanoma xenografts in an attempt to identify transport barriers leading to inadequate and heterogeneous uptake of macromolecular therapeutic agents in tumours. The Bioscope imaging system, which can detect the distribution of (99m)Tc in 10-microm-thick tissue sections with a spatial resolution of just above 50 microm, was used to image the (99m)Tc-HSA uptake. Xenografted tumours of four human melanoma cell lines were included in the study. Significant intratumour heterogeneity in the uptake of (99m)Tc-HSA was detected. The heterogeneity had two distinctly different components, one random and one radial component. The uptake was lowest in the centre of the tumours and increased towards the tumour periphery. This radial heterogeneity was superimposed by a random heterogeneity, that is, spots with high uptake colocalised with spots with high vascular density and regions without significant uptake colocalised with necrotic regions. The magnitude of the heterogeneity did not change significantly with time after the administration of (99m)Tc-HSA. The tumours showed a random and a radial heterogeneity in blood perfusion similar to that in the uptake of (99m)Tc-HSA. The observations reported here suggest that the intratumour heterogeneity in the distribution of (99m)Tc-HSA was initiated primarily because of heterogeneity in the supply of (99m)Tc-HSA through the microvasculature, and that the presence of severe transport barriers in the tumour interstitium prevented significant equalisation of the initial heterogeneity with time. Consequently, strategies for improving the delivery of macromolecular therapeutic agents to tumours should focus on increasing the tumour blood perfusion to increase the total uptake and improving the diffusion conditions in the tumour interstitium to diminish the heterogeneity in the uptake.