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Cell Progression (cell + progression)
Selected AbstractsLoss of the actin regulator HSPC300 results in clear cell renal cell carcinoma protection in Von Hippel-Lindau patients,,HUMAN MUTATION, Issue 6 2007Alberto Cascón Abstract Clear cell renal cell carcinoma (ccRCC) is the most common malignant neoplasm of the kidney. The majority of hereditary and sporadic ccRCC cases are associated with germline and somatic mutations in the Von Hippel-Lindau gene (VHL), respectively. Gross deletions at the VHL locus can result either in ccRCC or in a mild clinical phenotype, with the absence of ccRCC development. Our goal in this study was to identify the molecular basis responsible for these differences in the clinical behavior in order to predict patients' phenotype. Using multiplex ligation-dependent amplification (MLPA), we identified and characterized gross VHL deletions in Spanish VHL families. A candidate gene related to this clinical association, HSPC300, was identified and depleted by RNA interference. It was possible to narrow the susceptibility region related to the mild clinical phenotype down to ,14,kb that included HSPC300 (C3orf10), a regulator of actin dynamics and cytoskeleton organization. Whereas 9 out of 10 families with ccRCC retained HSPC300 in the germline, loss of the HSPC300 locus was associated with mild clinical presentation of the disease in 6 out of 8 families. In fact, genetic depletion of HSPC300 resulted in cytoskeleton abnormalities and cytokinesis arrest in several tumor cell lines including ccRCC cells, suggesting that tumor cell proliferation was compromised in the absence of HSPC300. These clinical and functional data indicate a relevant function of HSPC300 in tumor cell progression, and suggest future therapeutic strategies based upon the inhibition of HSPC300 in renal cell carcinoma and possibly on other cancers. Hum Mutat 28(6), 613,621, 2007. © 2007 Wiley-Liss, Inc. [source] Early Detection of Bone Metastases in a Murine Model Using Fluorescent Human Breast Cancer Cells: Application to the Use of the Bisphosphonate Zoledronic Acid in the Treatment of Osteolytic LesionsJOURNAL OF BONE AND MINERAL RESEARCH, Issue 11 2001Olivier Peyruchaud Abstract A very common metastatic site for human breast cancer is bone. The traditional bone metastasis model requires human MDA-MB-231 breast carcinoma cell inoculation into the left heart ventricle of nude mice. MDA-MB-231 cells usually develop osteolytic lesions 3,4 weeks after intracardiac inoculation in these animals. Here, we report a new approach to study the formation of bone metastasis in animals using breast carcinoma cells expressing the bioluminescent jellyfish protein (green fluorescent protein [GFP]). We first established a subclone of MDA-MB-231 cells by repeated in vivo passages in bone using the heart injection model. On stable transfection of this subclone with an expression vector for GFP and subsequent inoculation of GFP-expressing tumor cells (B02/GFP.2) in the mouse tail vein, B02/GFP.2 cells displayed a unique predilection for dissemination to bone. Externally fluorescence imaging of live animals allowed the detection of fluorescent bone metastases approximately 1 week before the occurrence of radiologically distinctive osteolytic lesions. The number, size, and intensity of fluorescent bone metastases increased progressively with time and was indicative of breast cancer cell progression within bone. Histological examination of fluorescent long bones from B02/GFP.2-bearing mice revealed the occurrence of profound bone destruction. Treatment of B02/GFP.2-bearing mice with the bisphosphonate zoledronic acid markedly inhibited the progression of established osteolytic lesions and the expansion of breast cancer cells within bone. Overall, this new bone metastasis model of breast cancer combining both fluorescence imaging and radiography should provide an invaluable tool to study the effectiveness of pharmaceutical agents that could suppress cancer colonization in bone. [source] Cadherin expression pattern in melanocytic tumors more likely depends on the melanocyte environment than on tumor cell progressionJOURNAL OF CUTANEOUS PATHOLOGY, Issue 1 2004Sven Krengel Background:, Adhesion molecules have been assigned an important role in melanocytic tumor progression. By the loss of E-cadherin, melanocytes might escape the control of neighbouring keratinocytes. Although in vitro data support this hypothesis, there are yet no conclusive immunohistochemical results on cadherin expression in melanocytic tumors. Objective:, To gain detailed insight in the expression of cadherins and their cytoplasmic binding partners, the catenins, in various types of benign and malignant melanocytic neoplasms. Methods:, Immunohistochemical analysis of the expression of E-, P-, and N-cadherin and ,-, ,-, and ,-catenin in compound and dermal nevi, Spitz nevi, blue nevi, ultraviolet B (UVB)-irradiated nevi, and malignant melanomas of various tumor thickness. Results:, In both nevi and melanomas, E-cadherin expression in melanocytic cells decreased, following a gradient from junctional to deeper dermal localization. The pattern of E-cadherin expression was more heterogeneous in melanomas than in nevi. In some melanomas, E-cadherin was only weakly positive in the epidermal tumor cells. P-cadherin expression was similar to that of E-cadherin. N-cadherin expression in melanocytic lesions was a rare finding, however, a small percentage of melanomas showed expression in some cell nests. Some Spitz nevi exhibited strong N-cadherin immunoreactivity. Most melanocytic cells were ,- and ,-catenin-positive and ,-catenin-negative. UVB irradiation did not influence the expression of cadherins and catenins in melanocytic nevi in vivo. Conclusions:, It is presumed that the gradual loss of E-cadherin expression represents a reaction of melanocytic cells to altered conditions in the dermal environment, e.g. lack of contact to keratinocytes, or new contact with dermal extracellular matrix molecules, respectively. Melanoma cells apparently are less dependent on these environmental factors and, therefore, show a more heterogeneous expression pattern. This might be of importance for the adaptation of the tumor cells to local requirements. However, in view of our results, a causative role of (loss of ) E-cadherin or (gain of ) N-cadherin for melanocytic tumor progression still remains to be proven. [source] Lipid peroxide-induced redox imbalance differentially mediates CaCo-2 cell proliferation and growth arrestCELL PROLIFERATION, Issue 4 2002Yudai Gotoh Dietary oxidants like lipid hydroperoxides (LOOH) can perturb cellular glutathione/glutathione disulphide (GSH/GSSG) status and disrupt mucosal turnover. This study examines the effect of LOOH on GSH/GSSG balance and phase transitions in the human colon cancer CaCo-2 cell. LOOH at 1 or 5 µm were noncytotoxic, but disrupted cellular GSH/GSSG and stimulated proliferative activity at 6 h that paralleled increases in ornithine decarboxylase activity, thymidine incorporation, expression of cyclin D1/cyclin-dependent kinase 4, phosphorylation of retinoblastoma protein, and cell progression from G0/G1 to S. At 24 h, LOOH-induced sustained GSH/GSSG imbalance mediated growth arrest at G0/G1 that correlated with suppression of proliferative activity and enhanced oxidative DNA damage. LOOH-induced cell transitions were effectively blocked by N-acetylcysteine. Collectively, the study shows that subtoxic LOOH levels induce CaCo-2 GSH/GSSG imbalance that elicits time-dependent cell proliferation followed by growth arrest. These results provide insights into the mechanism of hydroperoxide-induced disruption of mucosal turnover with implications for understanding oxidant-mediated genesis of gut pathology. [source] Influence on antiproliferative activity of structural modification and conjugation of gonadotropin-releasing hormone (GnRH) analoguesCELL PROLIFERATION, Issue 5 2000A. Kálnay Abstract The effect of various GnRH analogues, and their conjugates on proliferation, clonogenicity and cell cycle phase distribution of MCF-7 and Ishikawa human cancer cell lines was studied. GnRH-III, a sea lamprey GnRH analogue reduced cell proliferation by 35% and clonogenicity by 55%. Structural modifications either decreased, or did not alter biological activity. Conjugation of GnRH analogues including MI-1544, MI-1892, and GnRH-III with poly(N-vinylpyrrolidone-co-maleic acid) (P) through a tetrapeptide spacer GFLG(X) substantially increased the inhibitory effect of the GnRH analogues. The conjugate P-X-GnRH-III induced significant accumulation of cells in the G2/M phase; from 8% to 15.6% at 24 h and 9.8% to 15% at 48 h. It was concluded that conjugation of various GnRH analogues substantially enhanced their antiproliferative activity, strongly reduced cell clonogenicity and retarded cell progression through the cell division cycle at the G2/M phase. [source] | |||||||||||||