			Home About us Contact

Secondary Sites (secondary + site)

Distribution by Scientific Domains

Medical Sciences	75%

Selected Abstracts

Involvement of E-cadherin, ,-catenin, Cdc42 and CXCR4 in the progression and prognosis of cutaneous melanoma

BRITISH JOURNAL OF DERMATOLOGY, Issue 6 2007
M.G. Tucci
Summary Background, A key event in cancer metastasis is the migration of tumour cells from their original location to a secondary site. The development of melanoma may be viewed as a consequence of the disruption of homeostatic mechanisms in the skin of the original site. Objectives, To investigate whether dysregulation of cell motility (Cdc42 expression), escaping the control of cell,cell and cell,matrix interactions (E-cadherin, ,-catenin expression), enhances melanoma progression, and whether chemokine receptors (CXCR4) mediate cell migration and activation during invasion and metastasis development. Methods, The immunohistochemical expression of Cdc42, E-cadherin, ,-catenin and CXCR4 was investigated in 30 patients with surgically treated nodular melanoma, 18 alive and disease free and 12 with a fatal outcome due to metastatic disease. Results, E-cadherin expression was significantly reduced (P < 0·05) and cytoplasmic ,-catenin was increased in the patients who had died compared with disease-free individuals, while membrane expression of ,-catenin was similar in the two groups. Patients with fatal outcome had increased Cdc42 (P < 0·01) and CXCR4 (P < 0·05). In this group a positive correlation was found between melanocytic Cdc42 expression and Breslow thickness (r = 0·598, P < 0·05) and between CXCR4 expression and Breslow thickness (r = 0·583, P < 0·05). Conclusions, Findings suggest that primary cutaneous melanoma with a high Breslow thickness is characterized by tumour cells with high motility and invasion ability, in line with the hypothesis that low E-cadherin levels and overexpression of Cdc42 and CXCR4 could be prognostic markers of poor outcome. [source]

Snail controls differentiation of hepatocytes by repressing HNF4, expression

JOURNAL OF CELLULAR PHYSIOLOGY, Issue 1 2006
Carla Cicchini
Epithelial-to-mesenchymal transition (EMT) is a coordinated process, occurring both during morphogenesis and tumor progression, that allows epithelial cells to dissociate from initial contacts and migrate to secondary sites. The transcriptional repressors of the Snail family induce EMT in different epithelial cell lines and their expression is strictly correlated with EMT during the development and progression of carcinomas. We have previously shown that EMT in hepatocytes correlates with the downregulation of hepatic differentiation key factors HNFs (hepatocyte nuclear factors), and in particular of HNF4,. Here, we demonstrate that Snail overexpression is sufficient (i) to induce EMT in hepatocytes with conversion of morphology, downregulation of several epithelial adhesion molecules, reduction of proliferation and induction of matrix metalloproteinase 2 expression and, (ii) most relevantly, to repress the transcription of the HNF4, gene through a direct binding to its promoter. These finding demonstrate that Snail is at the crossroads of the regulation of EMT in hepatocytes by a dual control of epithelial morphogenesis and differentiation. J. Cell. Physiol. 209: 230,238, 2006. © 2006 Wiley-Liss, Inc. [source]

ETHANOL-INDUCED SUPEROXIDE RADICALS IN FETAL CORTICAL NEURONS: CELLULAR ROS NETWORK

ALCOHOLISM, Issue 2008
Amina E Jamali
Alcohol exposure to the developing brain compromises both neurons and glial functions. While neurons are considered the primary targets, microglia may play a neurotoxic role in this process. Previous studies demonstrated that neuron death is due to oxidative stress and mitochondrially mediated (Intrinsic). These studies showed a rapid increase (within minutes) in reactive oxygen species (ROS). Due to the diffusive nature of ethanol and multiple sources of free radicals, we sought to determine the primary source of superoxide targeted by ethanol. Confocal studies of neurons suggest that the superoxide radicals may originate from the mitochondria. Using whole neurons in a luminol-based chemiluminescence assay (Diogenes) we detected superoxide radicals in the extracellular mileu. We observed a two-three fold transient increase in the steady state generation of superoxide radicals between 20 minutes to one hour of ethanol exposure (4mg/ml). However, the presence of Rotenone (mitochondrial complex I inhibitor) and DPI (an inhibitor of all flavinoids) blocked the release of these superoxide radicals. Interestingly, cortical microglia treated identically with ethanol, showed a greater than five fold increase in superoxide generation with a maximum at one hour. Moreover, since ethanol is known to induce hydrogen peroxide generation, it was used as a mimetic. Hydrogen peroxide also induced the production of superoxide different time kinetics. Thus, together these data demonstrate that ethanol induces the steady state production of superoxide radicals in the extracellular mileu in a mitochondrial dependent manner. Since NOX2 an NADPH oxidase is expressed in neurons, it is a potential candidate for the secondary sites of superoxide generation. The ROS network between mitochondria and the plasma membrane highlights new therapeutical targets to counter ethanol toxicity. [source]

Uveal melanoma and macular degeneration: molecular biology and potential therapeutic applications

ACTA OPHTHALMOLOGICA, Issue 8 2008
Mario-Alexander Economou
Abstract. Uveal melanoma is the most common primary intraocular malignant tumor in adults with 30% to 50% of patients that ultimately succumb to metastatic disease, mainly to the liver. (Shields et al. 1991) Although new diagnostic and therapeutic tools have been developed during the most recent years, only the eye conservation rate has been achieved, while the survival rate remains poor. The reason for this liver-homing is largely unknown, but it is conceivable that hepatic environmental factors may be implicated in the growth, dissemination, and progression of this malignancy. The insulin-like growth factor (IGF-1) that binds to the IGF-1 receptor (IGF-1R) is mainly produced in the liver. It has been shown to be crucial for tumor transformation, maintenance of malignant phenotype, promotion of cell growth, and prevention of apoptosis. (Baserga 1995) The hepatocyte growth factor/scatter factor (HGF/SF) is another growth factor produced in the liver and exerts its biological effects through binding to the plasma membrane receptor c-Met. The activation of this receptor by HGF/SF ligand can induce proliferation, motility, adhesion, and invasion of tumor cells. (Cruz et al. 2003) Metastasis is a process involving many components, including tumor cell adhesion, migration, extracellular matrix (ECM) proteolysis, and invasion. The tumor cells undergo intravasation, disperse via the vascular and the lymphatic systems, and finally extravasate to invade the secondary sites. In all these steps, proteolytic enzyme systems are involved, including the matrix metalloproteinase (MMP) system and the plasminogen activation system. The migration of a malignant cell through the ECM and the basement membrane requires proteolytic activities. (Stetler-Stevenson et al. 1993). Efforts to target the IGF-I system has been made with different types of cancer but not with uveal melanoma. [source]