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Valproate is a common antiepileptic drug whose adverse effects include liver steatosis and dyslipidaemia. The aim of our study was to see how natural flavonoid antioxidant naringin would interact with valproate and attenuate these adverse effects. For this reason we treated male C57BL6 mice with a combination of 150 mg/kg of valproate and 25 mg/kg naringin every day for 10 days and compared their serum triglycerides, cholesterol, LDL, HDL, VLDL, and liver PPAR-alpha, PGC-1 alpha, ACOX1, Nrf2, SOD, CAT, GSH, and histological signs of steatosis. Valproate increased lipid peroxidation parameters and caused pronounced microvesicular steatosis throughout the hepatic lobule in all acinar zones, but naringin co-administration limited steatosis to the lobule periphery. In addition, it nearly restored total serum cholesterol, LDL, and triglycerides and liver ACOX1 and MDA to control levels. and upregulated PPAR-alpha and PGC-1 alpha, otherwise severely downregulated by valproate. It also increased SOD activity. All these findings suggest that naringin modulates key lipid metabolism regulators and should further be investigated in this model, either alone or combined with other lipid regulating drugs or molecules.

Halting tumor growth by interfering with tumor-induced angiogenesis is an attractive therapeutic approach. Such treatments include humanized antibodies blocking the activity of vascular endothelial growth factor (VEGF)-A (bevacizumab), soluble VEGF receptor (VEGFR) constructs (VEGF-Trap), or small-molecule inhibitors of VEGFR signaling, including PTK787/ZK222584 (PTK/ZK), sorafenib, and sunitinib. PTK/ZK has been shown previously to specifically block VEGF-induced phosphorylation of VEGFR-1, -2 and -3 and thereby to inhibit endothelial cell proliferation, differentiation, and tumor angiogenesis. We have investigated the effect of PTK/ZK on tumor angiogenesis and tumor lymphangiogenesis using the Rip1Tag2 transgenic mouse model of pancreatic beta cell carcinogenesis. In Rip1Tag2 mice, tumor angiogenesis is predominantly mediated by VEGF-A, and as expected, PTK/ZK efficiently impaired tumor blood vessel angiogenesis and tumor growth. Double-transgenic Rip1Tag2;Rip1VEGF-C and Rip1Tag2;Rip1VEGF-D mice not only exhibit VEGF-A-dependent blood vessel angiogenesis but also tumor lymphangiogenesis induced by the transgenic expression of VEGF-C or -D. In these mouse models, PTK/ZK also repressed tumor blood vessel angiogenesis and tumor growth yet failed to affect tumor lymphangiogenesis and lymphogenic metastasis. Adenoviral delivery of soluble VEGFR-3 also did not prevent tumor lymphangiogenesis in these mice. In contrast, spontaneous tumor lymphangiogenesis, as observed by the stochastic expression of VEGF-C and -D in tumors of neural cell adhesion molecule-deficient Rip1Tag2 mice, was repressed by PTK/ZK and soluble VEGFR-3. The results indicate that the time of onset and the levels of VEGF-C/D expression may be critical variables in efficiently repressing tumor lymphangiogenesis and that pathways other than VEGFR signaling may be involved in tumor lymphangiogenesis.

Reduced expression of neural cell adhesion molecule (NCAM) has been implicated in the progression to tumor malignancy in cancer patients. Previously, we have shown that the loss of NCAM function causes the formation of lymph node metastasis in a transgenic mouse model of pancreatic beta cell carcinogenesis (Rip1Tag2). Here we show that tumors of NCAM-deficient Rip1Tag2 transgenic mice exhibit up-regulated expression of the lymphangiogenic factors vascular endothelial growth factor (VEGF)-C and -D (17% in wild-type versus 60% in NCAM-deficient Rip1Tag2 mice) and, with it, increased lymphangiogenesis (0% in wild-type versus 19% in NCAM-deficient Rip1Tag2 mice). Repression of VEGF-C and -D function by adenoviral expression of a soluble form of their cognate receptor, VEGF receptor-3, results in reduced tumor lymphangiogenesis (56% versus 28% in control versus treated mice) and lymph node metastasis (36% versus 8% in control versus treated mice). The results indicate that the loss of NCAM function causes lymph node metastasis via VEGF-C- and VEGF-D-mediated lymphangiogenesis. These results also establish Rip1Tag2;NCAM-deficient mice as a unique model for stochastic, endogenous tumor lymphangiogenesis and lymph node metastasis in immunocompetent mice.

In this review we have attempted to summarize some of the recent developments in using novel technologies to unravel the molecular mechanisms of tumor progression, in particular the formation of tumor metastasis. In order to push forward the frontiers in cancer research, it is obvious that several fields have to be further developed and interconnected: (1) clinical, epidemiological and pathological studies which mainly use innovative technologies, including microarray technology and nanotechnology to determine as many parameters as possible, (2) the development of improved and suitable bioassays and better animal models and (3) the use of novel computation and bioinformatics methods to sample and integrate the exponentially growing sets of data coming from such investigations. Fashionable as scientists are, this new endeavor may be called systems biology.

Aim: To find genetic alterations in PTC or other genes of the Shh/PTCH pathway in tumorous and non- tumorous samples from three families and to correlate them with the varying expression of disorders in presented nevoid basal cell carcinoma syndrome (NBCCS) phenotypes., Method: DNA was extracted from archival paraffin-embedded tissues, tumor tissue or peripheral blood leukocytes, and the loss of heterozygosity (LOH) and single strand conformational polymorphism analysis was performed using PCR with primers for polymorphic 9q22.3 markers (D9S196, D9S287, D9S180, D9S127); PTCH exons 3, 6, 8, 13, 15, 16; and smo (smoothened) exon 1. G-banding tecnique was used for cytogenetic analysis of the peripheral blood lymphocytes., Results: We found a LOH for PTCH in several cases and variability in smo in one case. In one case NBCCS could reasonably be ascribed to hemizygous PTCH inactivation, while in other two families this typical correlation between the syndrome phenotype and the observed genetic alterations could not been established., Conclusions: Further analysis of relatively sparse cases of NBCCS is needed before the symptoms of the syndrome could be convincingly explained by genetic alterations in the Shh/PTCH signalling pathway.