The TSC2/mTOR pathway drives endothelial cell transformation induced by the Kaposi's sarcoma-associated herpesvirus G protein-coupled receptor.
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):133-43.The TSC2/mTOR pathway drives endothelial cell transformation induced by the Kaposi's sarcoma-associated herpesvirus G protein-coupled receptor.1, , , , , , , , , .1Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland 20892, USA.AbstractThe Kaposi's sarcoma-associated herpesvirus (KSHV), the infectious causative agent of Kaposi's sarcoma (KS), encodes a G protein-coupled receptor (vGPCR) implicated in the initiation of KS. Here we demonstrate that Kaposi's sarcomagenesis involves stimulation of tuberin (TSC2) phosphorylation by vGPCR, promoting the activation of mTOR through both direct and paracrine mechanisms. Pharmacologic inhibition of mTOR with rapamycin prevented vGPCR sarcomagenesis, while overactivation of this pathway was sufficient to render endothelial cells oncogenic. Moreover, mice haploinsufficient for TSC2 are predisposed to vascular sarcomas remarkably similar to KS. Collectively, these results implicate mTOR in KS initiation and suggest that the sarcomagenic potential of KSHV may be a direct consequence of the profound sensitivity of endothelial cells to vGPCR dysregulation of the TSC2/mTOR pathway.PMID:
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External link. Please review our .TP53 disruptive mutations lead to head and neck cancer treatment failure through inhibition of radiation-induced senescence.
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2012 Jan 1;18(1):290-300. doi: 10.32.CCR-11-2260. Epub
2011 Nov 16.TP53 disruptive mutations lead to head and neck cancer treatment failure through inhibition of radiation-induced senescence.1, , , , , , , , , .1Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.AbstractPURPOSE: Mortality of patients with head and neck squamous cell carcinoma (HNSCC) is primarily driven by tumor cell radioresistance leading to locoregional recurrence (LRR). In this study, we use a classification of TP53 mutation (disruptive vs. nondisruptive) and examine impact on clinical outcomes and radiation sensitivity.EXPERIMENTAL DESIGN: Seventy-four patients with HNSCC treated with surgery and postoperative radiation and 38 HNSCC cell
for each, TP53 was sequenced and the in vitro radioresistance measured using clonogenic assays. p53 protein expression was inhibited using short hairpin RNA (shRNA) and overexpressed using a retrovirus. Radiation-induced apoptosis, mitotic cell death, senescence, and reactive oxygen species (ROS) assays were carried out. The effect of the drug metformin on overcoming mutant p53-associated radiation resistance was examined in vitro as well as in vivo, using an orthotopic xenograft model.RESULTS: Mutant TP53 alone was not predictive of LRR; however, disruptive TP53 mutation strongly predicted LRR (P = 0.03). Cell lines with disruptive mutations were significantly more radioresistant (P & 0.05). Expression of disruptive TP53 mutations significantly decreased radiation-induced senescence, as measured by SA-β-gal staining, p21 expression, and release of ROS. The mitochondrial agent metformin potentiated the effects of radiation in the presence of a disruptive TP53 mutation partially via senescence. Examination of our patient cohort showed that LRR was decreased in patients taking metformin.CONCLUSIONS: Disruptive TP53 mutations in HNSCC tumors predicts for LRR, because of increased radioresistance via the inhibition of senescence. Metformin can serve as a radiosensitizer for HNSCC with disruptive TP53, presaging the possibility of personalizing HNSCC treatment.(C) 2011 AACR.PMID:
[PubMed - indexed for MEDLINE] (A) LRR in the study population in patients with either wild type TP53 or any TP53 mutation (p=0.9). (B) LRR in the same group of patients with the indicated TP53 status.Clin Cancer Res. ;18(1):290-300.(A) A panel of 38 HNSCC cell lines was sequenced for TP53 status and evaluated for radiosensitivity using standard clonogenic assays. Each cell line was then grouped by TP53 status, and the average clonogenic survival data for each group is shown. (B) The effect of stable inhibition of wild type p53 expression (shp53) on radiosensitivity in HN 30 and UMSCC1 17A cells. (C) The effect of forced expression of wild type, R175H, R282W, or C176F TP53 in p53 null UMSCC1 cells on radiosensitivity. (D) The effect of stable inhibition of p53 expression (shp53) on radiosensitivity in FADU and HN 31 cells (disruptive TP53).Clin Cancer Res. ;18(1):290-300.(A) Representative light microscopy showing SA-Gal staining. (B) Percentage of SA-Gal positive cells per total number of cells in a high power field after 4 Gy of radiation for the times indicated in UMSCC1 cells expressing representative wild type and mutant TP53 constructs and HN 30 (WT), Detroit (R175H) and HN 31 (C176F) where p53 is inhibited. (C) Representative microscopy showing SA-Gal staining, DAPI fluorescence, and GFP. (D) Percentage of cells either SA-Gal positive (S alone), exhibiting micronuclei (M alone) or both at 4 days after 4 Gy of radiation in HN 30 and HN 31 cells where p53 expression is inhibited and UMSCC1 cells expressing representative wild type and mutant TP53 constructs. * - significantly elevated over baseline (p&0.05), + - significantly different from null at the indicated time point (p&0.05), # - significantly different from HN 30 control.Clin Cancer Res. ;18(1):290-300.(A) p21 protein expression and p21 luciferase reporter activity in UMSCC1 cells expressing the indicated TP53 constructs treated with the indicated doses of radiation for 24h unless otherwise stated. (B) ROS production measured as indicated in the methods after 2 Gy of radiation. (C) Percentage of cells either SA-Gal positive (S alone), exhibiting micronuclei (MC alone) or both at 4 days after 4 Gy of radiation. Cells were treated with the indicated dose of NAC starting 2 h after radiation and treatment continued overnight. (D) Clonogenic survival after 2 Gy of radiation. Cells were treated with NAC in an identical manner to (C). * - significantly increased over unirradiated control (p&0.05), + - significantly different from UMSCC1 wild type in the same group (p&0.05). # - significantly increased compared to non-NAC treated group (p&0.001).Clin Cancer Res. ;18(1):290-300.(A) Clonogenic survival after treatment with radiation at the indicated doses along with metformin for 24 hours in HN 30 and HN 31 cells in which p53 expression is inhibited using shRNA (shp53). (B) Percentage of SA-beta-gal positive cells per total number of cells in a high power field 4 days following 4 Gy of radiation and the indicated doses of metformin. * - significantly different from unirradiated control (p&0.05), + - significantly changed compared to no metformin treatment (p&0.05). (C) Tumor volume in mice with orthotopic tumors derived from HN 31 cells (C176F) after treatment with radiation (6 Gy), metformin (250 mg/kg, intraperitoneal) or both. * - significantly different from radiation alone (p&0.05), + -significantly different from metformin treatment alone (p&0.05). (D) LRR in patients taking metformin during treatment compared to the remainder of the study population as well as patients matched for tumor and nodal stage, surgical margin status, and TP53 status to the metformin treated group (p=0.04).Clin Cancer Res. ;18(1):290-300.Publication TypesMeSH TermsSubstancesGrant SupportFull Text SourcesMedicalMiscellaneous
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External link. Please review our .New therapies for dedifferentiated papillary thyroid cancer.
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2015 Mar 17;16(3):6153-82. doi: 10.3390/ijms.New therapies for dedifferentiated papillary thyroid cancer.1, 2, 3, 4, 5, 6, 7, 8, 9.1Department of Clinical and Experimental Medicine, University of Pisa, Via Savi, 10, 56126 Pisa, Italy. poupak@int.med.unipi.it.2Department of Clinical and Experimental Medicine, University of Pisa, Via Savi, 10, 56126 Pisa, Italy. .3Department of Clinical & Experimental Medicine, Section of Endocrinology, University of Messina, Piazza Pugliatti, 1, 98122 Messina, Italy. roberto.vita@yahoo.it.4Department of Clinical and Experimental Medicine, University of Pisa, Via Savi, 10, 56126 Pisa, Italy. sm.ferrari@int.med.unipi.it.5Department of Surgical, Medical, Molecular Pathology and Critical Area, University of Pisa, Via Savi, 10, 56126 Pisa, Italy. .6Department of Surgical, Medical, Molecular Pathology and Critical Area, University of Pisa, Via Savi, 10, 56126 Pisa, Italy. .7Department of Clinical & Experimental Medicine, Section of Endocrinology, University of Messina, Piazza Pugliatti, 1, 98122 Messina, Italy. sbenvenga@unime.it.8Department of Surgical, Medical, Molecular Pathology and Critical Area, University of Pisa, Via Savi, 10, 56126 Pisa, Italy. paolo.miccoli@dc.unipi.it.9Department of Clinical and Experimental Medicine, University of Pisa, Via Savi, 10, 56126 Pisa, Italy. alessandro.antonelli@med.unipi.it.AbstractThe number of thyroid cancers is increasing. Standard treatment usually includes primary surgery, thyroid-stimulating hormone suppressive therapy, and ablation of the thyroid remnant with radioactive iodine (RAI). Despite the generally good prognosis of thyroid carcinoma, about 5% of patients will develop metastatic disease, which fails to respond to RAI, exhibiting a more aggressive behavior. The lack of specific, effective and well-tolerated drugs, the scarcity of data about the association of multi-targeting drugs, and the limited role of radioiodine for dedifferentiated thyroid cancer, call for further efforts in the field of new drugs development. Rearranged during transfection (RET)/papillary thyroid carcinoma gene rearrangements, BRAF (B-RAF proto-oncogene, serine/threonine kinase) gene mutations, RAS (rat sarcoma) mutations, and vascular endothelial growth factor receptor 2 angiogenesis pathways are some of the known pathways playing a crucial role in the development of thyroid cancer. Targeted novel compounds have been demonstrated to induce clinical responses and stabilization of disease. Sorafenib has been approved for differentiated thyroid cancer refractory to RAI. PMID:
[PubMed - indexed for MEDLINE] Molecular targets and tyrosine kinase inhibitors in the signaling pathways involved in dedifferentiated papillary thyroid cancer.Int J Mol Sci. ):.Publication TypesMeSH TermsSubstancesSupplementary ConceptsFull Text SourcesMedical
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External link. Please review our .Stereotyped patterns of B-cell receptor in splenic marginal zone lymphoma.
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):1792-6. doi: 10.3324/haematol.. Epub
2010 May 29.Stereotyped patterns of B-cell receptor in splenic marginal zone lymphoma.1, , , , , , , , , , , , , , , , , , , , , , .1Division of Hematology, Department of Oncohematology, Fondazione IRCCS Policlinico San Matteo, University of Pavia, Viale Golgi 19, Pavia, Italy.AbstractAntigen stimulation may be important for splenic marginal zone lymphoma pathogenesis. To address this hypothesis, the occurrence of stereotyped B-cell receptors was investigated in 133 SMZL (26 HCV+) compared with 4,414 HCDR3 sequences from public databases. Sixteen SMZL (12%) showed stereotyped BCR; 7 of 86 (8%) SMZL sequences retrieved from public databases also belonged to stereotyped HCDR3 subsets. Three categories of subsets were identified: i) "SMZL-specific subsets" (n=5), composed only of 12 SMZL (9 HCV-from our series); ii) "Non-Hodgkin's lymphoma-like subsets" (n=5), comprising 5 SMZL (4 from our series) clustering with othe iii) "CLL-like subsets" (n=6), comprising 6 SMZL (3 from our series) that belonged to known CLL subsets (n=4) or clustered with public CLL sequences. Immunoglobulin 3D modeling of 3 subsets revealed similarities in antigen binding regions not limited to HCDR3. Overall, data suggest that the pathogenesis of splenic marginal zone lymphoma may involve also HCV-unrelated epitopes or an antigenic trigger common to other indolent lymphomas.PMID:
[PubMed - indexed for MEDLINE] (A) Three-dimensional models of immunoglobulins belonging to subsets N1, N3 and N9. Antigen binding regions (panel A) and mutation analysis (panels B.1 and B.2) of modeled antibodies are shown. In all cases, Igs belonging to the same HCDR3 subset display an overall similarity, both in sequence and structure, that is not limited to the HCDR3 region. Samples
and PV3 in subset N1 (panel A) have a positively charged antigen binding site (Abs) with a protruding and hydrophobic H3 loop (black arrow). Subset N3 (cases PV25 and PV52, panel A) presents nearly identical Abs. A negatively charged pocket is in the center of the binding site (black arrow). Cases PV69 and 4468 (subset N9, panel A), though presenting a less remarkable similarity, share some common features. The Abs is formed by a negatively charged central protruding region surrounded by a positive area (black arrow). Panel B.1: common mutations (i.e. replacement of the same specific residue of Igs in the same group deriving from the same germline) and convergent mutations (i.e. replacement of a residue in an Ig increasing its similarity to another Ig belonging to the same group but deriving from a different germline) are depicted in green and red, respectively, on the superimposed backbones of all the Igs in each group. Blue circled area highlights the mos a close-up of the same region is in panel B.2, where relevant mutations are reported in a ball-and-stick representation mapped on a single representative structure of each group. Correlated mutations are found on IGHV in subset N1, no significant correlation is evident on the light chains. Two common mutations (M33I and A71V) are located in close proximity in the models and are likely to play a role in Abs specificity. Two similar mutations (S30BN and S34N) are found in loop H1 of both samples belonging to subset N3 and may influence the H3 position and the Abs shape. Several mutations on the heavy and light chains of both samples in subset N9 introduce polar and charged residues in the Abs. Sequence numbering follows the Kabat-Chothia scheme. Abs are colored according to their electrostatic potential, ranging from -5 kBT/e (red) to + 5 kBT/e (blue). (B) Hydrophobic areas of cases belonging to subset N1. Antigen binding sites of subset N1 immunoglobulins are depicted using the Kyte-Doolittle hydropaticity score. Note the large hydrophobic patch found in the H3 loops of all samples (dark-green region) that is often associated with an interaction area.Haematologica. ):.Publication TypesMeSH TermsSubstancesFull Text Sources
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