Resveratrol prevents inflammation-dependent hepatic melanoma metastasis by inhibiting the secretion and effects of interleukin-18

Background: Implantation and growth of metastatic cancer cells at distant organs is promoted by inflammation-dependent mechanisms. A hepatic melanoma metastasis model where a majority of metastases are generated via interleukin-18-dependent mechanisms was used to test whether anti-inflammatory properties of resveratrol can interfere with mechanisms of metastasis. Methods: Two experimental treatment schedules were used: 1) Mice received one daily oral dose of 1 mg/kg resveratrol after cancer cell injection and the metastasis number and volume were determined on day 12. 2) Mice received one daily oral dose of 1 mg/kg resveratrol along the 5 days prior to the injection of cancer cells and both interleukin-18 (IL-18) concentration in the hepatic blood and microvascular retention of luciferase-transfected B16M cells were determined on the 18(th) hour. In vitro, primary cultured hepatic sinusoidal endothelial cells were treated with B16M-conditioned medium to mimic their in vivo activation by tumor-derived factors and the effect of resveratrol on IL-18 secretion, on vascular cell adhesion molecule-1 (VCAM-1) expression and on tumor cell adhesion were studied. The effect of resveratrol on melanoma cell activation by IL-18 was also studied. Results: Resveratrol remarkably inhibited hepatic retention and metastatic growth of melanoma cells by 50% and 75%, respectively. The mechanism involved IL-18 blockade at three levels: First, resveratrol prevented IL-18 augmentation in the blood of melanoma cell-infiltrated livers. Second, resveratrol inhibited IL-18-dependent expression of VCAM-1 by tumor-activated hepatic sinusoidal endothelium, preventing melanoma cell adhesion to the microvasculature. Third, resveratrol inhibited adhesion-and proliferation-stimulating effects of IL-18 on metastatic melanoma cells through hydrogen peroxide-dependent nuclear factor-kappaB translocation blockade on these cells. Conclusions: These results demonstrate multiple sites for therapeutic intervention using resveratrol within the prometastatic microenvironment generated by tumor-induced hepatic IL-18, and suggest a remarkable effect of resveratrol in the prevention of inflammation-dependent melanoma metastasis in the liver.

Expression and activity profiles of DPP IV/CD26 and NEP/CD10 glycoproteins in the human renal cancer are tumor-type dependent

Background: Cell-surface glycoproteins play critical roles in cell-to-cell recognition, signal transduction and regulation, thus being crucial in cell proliferation and cancer etiogenesis and development. DPP IV and NEP are ubiquitous glycopeptidases closely linked to tumor pathogenesis and development, and they are used as markers in some cancers. In the present study, the activity and protein and mRNA expression of these glycoproteins were analysed in a subset of clear-cell (CCRCC) and chromophobe (ChRCC) renal cell carcinomas, and in renal oncocytomas (RO). Methods: Peptidase activities were measured by conventional enzymatic assays with fluorogen-derived substrates. Gene expression was quantitatively determined by qRT-PCR and membrane-bound protein expression and distribution analysis was performed by specific immunostaining. Results: The activity of both glycoproteins was sharply decreased in the three histological types of renal tumors. Protein and mRNA expression was strongly downregulated in tumors from distal nephron (ChRCC and RO). Moreover, soluble DPP IV activity positively correlated with the aggressiveness of CCRCCs (higher activities in high grade tumors). Conclusions: These results support the pivotal role for DPP IV and NEP in the malignant transformation pathways and point to these peptidases as potential diagnostic markers.

Three-dimensional growth as multicellular spheroid activates the proangiogenic phenotype of colorectal carcinoma cells via LFA-1-dependent VEGF: implications on hepatic micrometastasis

Background: The recruitment of vascular stromal and endothelial cells is an early event occurring during cancer cell growth at premetastatic niches, but how the microenvironment created by the initial three-dimensional (3D) growth of cancer cells affects their angiogenesis-stimulating potential is unclear. Methods: The proangiogenic profile of CT26 murine colorectal carcinoma cells was studied in seven-day cultured 3D-spheroids of <300 mu m in diameter, produced by the hanging-drop method to mimic the microenvironment of avascular micrometastases prior to hypoxia occurrence. Results: Spheroid-derived CT26 cells increased vascular endothelial growth factor (VEGF) secretion by 70%, which in turn increased the in vitro migration of primary cultured hepatic sinusoidal endothelium (HSE) cells by 2-fold. More importantly, spheroid-derived CT26 cells increased lymphocyte function associated antigen (LFA)-1-expressing cell fraction by 3-fold; and soluble intercellular adhesion molecule (ICAM)-1, given to spheroid-cultured CT26 cells, further increased VEGF secretion by 90%, via cyclooxygenase (COX)-2-dependent mechanism. Consistent with these findings, CT26 cancer cells significantly increased LFA-1 expression in non-hypoxic avascular micrometastases at their earliest inception within hepatic lobules in vivo; and angiogenesis also markedly increased in both subcutaneous tumors and hepatic metastases produced by spheroid-derived CT26 cells. Conclusion: 3D-growth per se enriched the proangiogenic phenotype of cancer cells growing as multicellular spheroids or as subclinical hepatic micrometastases. The contribution of integrin LFA-1 to VEGF secretion via COX-2 was a micro environmental-related mechanism leading to the pro-angiogenic activation of soluble ICAM-1-activated colorectal carcinoma cells. This mechanism may represent a new target for specific therapeutic strategies designed to block colorectal cancer cell growth at a subclinical micrometastatic stage within the liver.

Atomistic Simulation On Size-Dependent Yield Strength And Defects Evolution Of Metal Nanowires

A simple derivation based on continuum mechanics is given, which shows the surface stress is critical for yield strength at ultra-small scales. Molecular dynamics (MD) simulations with modified embedded atom method (MEAM) are employed to investigate the mechanical behaviors of single-crystalline metal nanowires under tensile loading. The calculated yield strengths increasing with the decrease of the cross-sectional area of the nanowires are in accordance with the theoretical prediction. Reorientation induced by stacking faults is observed at the nanowire edge. In addition. the mechanism of yielding is discussed in details based on the snapshots of defects evolution. The nanowires in different crystallographic orientations behave differently in stretching deformation. This study on the plastic properties of metal nanowires will be helpful to further understanding of the mechanical properties of nanomaterials. (C) 2009 Elsevier B.V. All rights reserved.

Size- And Temperature-Dependent Thermal Expansion Coefficient Of A Nanofilm

The thermal expansion coefficient (TEC) of an ideal crystal is derived by using a method of Boltzmann statistics. The Morse potential energy function is adopted to show the dependence of the TEC on the temperature. By taking the effects of the surface relaxation and the surface energy into consideration, the dimensionless TEC of a nanofilm is derived. It is shown that with decreasing thickness, the TEC can increase or decrease, depending on the surface relaxation of the nanofilm.

Orientation-Dependent Adhesion Strength Of A Rigid Cylinder In Non-Slipping Contact With A Transversely Isotropic Half-Space

Recently, Chen and Gao [Chen, S., Gao, H., 2007. Bio-inspired mechanics of reversible adhesion: orientation-dependent adhesion strength for non-slipping adhesive contact with transversely isotropic elastic materials. J. Mech. Phys. solids 55, 1001-1015] studied the problem of a rigid cylinder in non-slipping adhesive contact with a transversely isotropic solid subjected to an inclined pulling force. An implicit assumption made in their study was that the contact region remains symmetric with respect to the center of the cylinder. This assumption is, however, not self-consistent because the resulting energy release rates at two contact edges, which are supposed to be identical, actually differ from each other. Here we revisit the original problem of Chen and Gao and derive the correct solution by removing this problematic assumption. The corrected solution provides a proper insight into the concept of orientation-dependent adhesion strength in anisotropic elastic solids. (c) 2008 Elsevier Ltd. All rights reserved.

Stock assessment of Lates niloticus (L.), Oreochromis niloticus (L.) and Rastrineobola argentea (Pellegrin) using fishery dependent data from the Tanzanian waters of Lake Victoria

Catch data were collected from three beaches in the Mwanza area of lake Victoria, Tanzania for Oreochromis niloticus (L.), Rastrineobola argentea (Pellegrin) and Lates niloticus (L.). Sampling took place in October 1997 and February, June and September 1998. The CPUE for O. niloticus was 3.9 to 6kg boat super(-1) and for R. argentea from 98 to 282 kg boat super(-1). There was no obvious trend in catch rates for L. niloticus. The modal length for O. niloticus recorded at Chole beach was 34cm TL. In February, fish were larger (41-45 cm) than in the other surveys. Rastrineobola argentea caught in October 1997 had modal length at 65 mm TL with some smaller fish. In February and June prominent length modes occurred at 45 and 58 mm respectively, which may represent the same cohort as the small fish caught in October 1997. In September 1998, there were two length modes at 46 and 60 mm. The 60 mm fish may represent the same cohort seen in previous surveys, suggesting growth from approximately 30 mm to 60 mm in an eleven-month period. Lates niloticus landed at Kayenze beach over the four surveys had a modal length of 46 cm TL. Fish species encountered on the three beaches during the surveys were O. niloticus, R. argentea, Bagrus docmak Forsskall, Clarias gariepinus (Burchell), Protopterus aethiopicus Heckel, Labeo victorians Boulenger, Synodontis afrofischeri Hilgendorf, Synodontis victoriae Boulanger, Schilbe intermedius (L.), Brycinus jacksonii (Boulanger), Mormyrus kannume Forsskall and Haplochromine cichlids