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High-affinity DNA-binding domains of replication protein A (RPA) direct SMARCAL1-dependent replication fork remodeling.
Bhat KP, Bétous R, Cortez D
(2015) J Biol Chem 290: 4110-7
MeSH Terms: Amino Acid Motifs, Bone Neoplasms, DNA Damage, DNA Helicases, DNA Replication, DNA, Single-Stranded, Electrophoretic Mobility Shift Assay, Humans, Osteosarcoma, Protein Binding, Replication Protein A, Substrate Specificity, Tumor Cells, Cultured
Show Abstract · Added January 20, 2015
SMARCAL1 catalyzes replication fork remodeling to maintain genome stability. It is recruited to replication forks via an interaction with replication protein A (RPA), the major ssDNA-binding protein in eukaryotic cells. In addition to directing its localization, RPA also activates SMARCAL1 on some fork substrates but inhibits it on others, thereby conferring substrate specificity to SMARCAL1 fork-remodeling reactions. We investigated the mechanism by which RPA regulates SMARCAL1. Our results indicate that although an interaction between SMARCAL1 and RPA is essential for SMARCAL1 activation, the location of the interacting surface on RPA is not. Counterintuitively, high-affinity DNA binding of RPA DNA-binding domain (DBD) A and DBD-B near the fork junction makes it easier for SMARCAL1 to remodel the fork, which requires removing RPA. We also found that RPA DBD-C and DBD-D are not required for SMARCAL1 regulation. Thus, the orientation of the high-affinity RPA DBDs at forks dictates SMARCAL1 substrate specificity.
© 2015 by The American Society for Biochemistry and Molecular Biology, Inc.
0 Communities
1 Members
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13 MeSH Terms
Micro-computed tomography derived anisotropy detects tumor provoked deviations in bone in an orthotopic osteosarcoma murine model.
Cole HA, Ohba T, Ichikawa J, Nyman JS, Cates JM, Haro H, Schwartz HS, Schoenecker JG
(2014) PLoS One 9: e97381
MeSH Terms: Animals, Anisotropy, Bone Neoplasms, Cell Proliferation, Disease Models, Animal, Mice, Inbred BALB C, Osteosarcoma, Tibia, X-Ray Microtomography
Show Abstract · Added July 28, 2014
Radiographic imaging plays a crucial role in the diagnosis of osteosarcoma. Currently, computed-tomography (CT) is used to measure tumor-induced osteolysis as a marker for tumor growth by monitoring the bone fractional volume. As most tumors primarily induce osteolysis, lower bone fractional volume has been found to correlate with tumor aggressiveness. However, osteosarcoma is an exception as it induces osteolysis and produces mineralized osteoid simultaneously. Given that competent bone is highly anisotropic (systematic variance in its architectural order renders its physical properties dependent on direction of load) and that tumor induced osteolysis and osteogenesis are structurally disorganized relative to competent bone, we hypothesized that μCT-derived measures of anisotropy could be used to qualitatively and quantitatively detect osteosarcoma provoked deviations in bone, both osteolysis and osteogenesis, in vivo. We tested this hypothesis in a murine model of osteosarcoma cells orthotopically injected into the tibia. We demonstrate that, in addition to bone fractional volume, μCT-derived measure of anisotropy is a complete and accurate method to monitor osteosarcoma-induced osteolysis. Additionally, we found that unlike bone fractional volume, anisotropy could also detect tumor-induced osteogenesis. These findings suggest that monitoring tumor-induced changes in the structural property isotropy of the invaded bone may represent a novel means of diagnosing primary and metastatic bone tumors.
1 Communities
3 Members
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9 MeSH Terms
Autocrine VEGF/VEGFR1 signaling in a subpopulation of cells associates with aggressive osteosarcoma.
Ohba T, Cates JM, Cole HA, Slosky DA, Haro H, Ando T, Schwartz HS, Schoenecker JG
(2014) Mol Cancer Res 12: 1100-11
MeSH Terms: Animals, Autocrine Communication, Bone Neoplasms, Cell Line, Tumor, Cell Proliferation, Humans, Mice, Mice, Inbred BALB C, Neovascularization, Pathologic, Osteolysis, Osteosarcoma, Signal Transduction, Vascular Endothelial Growth Factor A, Vascular Endothelial Growth Factor Receptor-1
Show Abstract · Added May 28, 2014
UNLABELLED - Osteosarcoma is the most common primary bone malignancy and accounts for more than half of primary skeletal malignancies in children and young adults. Although vascular endothelial growth factor (VEGF) expression in osteosarcoma has been associated with poor outcome, its role in the pathogenesis of osteosarcoma remains controversial. Here, VEGF and VEGFR1 expression in both human and murine osteosarcoma cells associated with increasing malignant potential. Autocrine VEGF/VEGFR1 signaling resulted in constitutive activation of VEGFR1 in highly aggressive osteosarcoma cells. In addition, survival and proliferation of highly aggressive osteosarcoma cells was dependent on autocrine VEGF/R1 signaling in vitro. The effect of VEGFR1 expression on in vivo tumor growth and angiogenesis was evaluated by immunoselecting subpopulations of osteosarcoma cells that express high or low levels of VEGFR1. Cell enriched for high VEGFR1 expression showed increased VEGF production, tumor growth, tumor angiogenesis, and osteolysis in vivo. In addition, it was demonstrated that VEGF and VEGFR1 are coexpressed by a subset of tumor cells in human osteosarcoma, similar to what was observed in the murine osteosarcoma cells. These results suggest that autocrine VEGF/VEGFR1 signaling in a subpopulation of tumor cells plays a pivotal role in osteosarcoma progression.
IMPLICATIONS - Aggressive osteosarcoma phenotypes are mediated by autocrine VEGF/VEGFR1 signaling and improved stratification measures and novel anti-angiogenic strategies may benefit this specific tumor type.
©2014 American Association for Cancer Research.
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2 Members
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14 MeSH Terms
Pleiotropic effects of bisphosphonates on osteosarcoma.
Ohba T, Cates JM, Cole HA, Slosky DA, Haro H, Ichikawa J, Ando T, Schwartz HS, Schoenecker JG
(2014) Bone 63: 110-20
MeSH Terms: Animals, Apoptosis, Cell Line, Tumor, Cell Movement, Cell Proliferation, Cell Survival, Diphosphonates, Humans, Mice, Mice, Inbred BALB C, Osteosarcoma, Vascular Endothelial Growth Factor A
Show Abstract · Added March 20, 2014
Osteosarcoma is the most common primary malignant tumor of bone and accounts for half of all primary skeletal malignancies in children and teenagers. The prognosis for patients who fail or progress on first-line chemotherapy protocols is poor, therefore, additional adjuvant therapeutic strategies are needed. A recent feasibility study has demonstrated that the nitrogen-containing bisphosphonate zoledronic acid (ZOL) can be combined safely with conventional chemotherapy. However, the pharmacodynamics of bisphosphonate therapy is not well characterized. Osteosarcoma is a highly angiogenic tumor. Recent reports of the anti-angiogenic effects of bisphosphonates prompted us to determine whether nitrogen-containing bisphosphonate (ZOL and alendronate) treatment attenuates osteosarcoma growth by inhibition of osteoclast activity, tumor-mediated angiogenesis, or direct inhibitory effects on osteosarcoma. Here, we demonstrate that bisphosphonates directly inhibit VEGFR2 expression in endothelial cells, as well as endothelial cell proliferation and migration. Additionally, bisphosphonates also decrease VEGF-A expression in osteosarcoma (K7M3) cells, resulting in reduced stimulation of endothelial cell migration in co-culture assays. ZOL also decreases VEGFR1 expression in aggressive osteosarcoma cell lines (K7M3, 143B) and induces apoptosis of these cells, but has negligible effects on less aggressive osteosarcoma cell lines (K12 and TE85). In vivo ZOL treatment results in significant reduction in osteosarcoma-initiated angiogenesis and tumor growth in a murine model of osteosarcoma. In conclusion, bisphosphonates have diverse growth inhibitory effects on osteosarcoma through: (1) activation of apoptosis and inhibition of cell proliferation, (2) inhibition of VEGF-A and VEGFR1 expression by tumor cells, (3) inhibition of tumor-induced angiogenesis, and (4) direct inhibitory actions on endothelial cells.
Published by Elsevier Inc.
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2 Members
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12 MeSH Terms
Bisphosphonates inhibit osteosarcoma-mediated osteolysis via attenuation of tumor expression of MCP-1 and RANKL.
Ohba T, Cole HA, Cates JM, Slosky DA, Haro H, Ando T, Schwartz HS, Schoenecker JG
(2014) J Bone Miner Res 29: 1431-45
MeSH Terms: Animals, Bone Resorption, Cell Differentiation, Cell Line, Tumor, Cell Proliferation, Chemokine CCL2, Diphosphonates, Humans, Imidazoles, Mice, Monocytes, Neoplasm Invasiveness, Osteoclasts, Osteogenesis, Osteolysis, Osteoprotegerin, Osteosarcoma, RANK Ligand, Zoledronic Acid
Show Abstract · Added March 20, 2014
Osteosarcoma is the most common primary malignant tumor of bone and accounts for around 50% of all primary skeletal malignancies. In addition to novel chemotherapies, there is a need for adjuvant therapies designed to inhibit osteosarcoma proliferation and tumor-induced osteolysis to attenuate tumor expansion and metastasis. As such, studies on the efficacy of bisphosphonates on human osteosarcoma are planned after feasibility studies determined that the bisphosphonate zoledronic acid (ZOL) can be safely combined with conventional chemotherapy. However, the molecular mechanisms responsible for, and means of inhibiting, osteosarcoma-induced osteolysis are largely unknown. We establish that osteosarcoma growth directly correlates with tumor-induced osteolysis and activation of osteoclasts in vivo. In vitro, tumor cells were determined to expresses surface, but not soluble, receptor activator of NF-κB ligand (RANKL) and stimulated osteoclastogenesis in a manner directly proportional to their malignant potential. In addition, an aggressive osteosarcoma cell line was shown to secrete monocyte chemoattractant protein-1 (MCP-1), resulting in robust monocyte migration. Because MCP-1 is a key cytokine for monocyte recruitment and surface-bound RANKL strongly supports local osteoclastogenesis, we suggest that high levels of these signaling molecules are associated with the aggressive potential of osteosarcoma. Consistent with these findings, abundant expression of RANKL/MCP-1 was observed in tumor in vivo, and MCP-1 plasma levels strongly correlated with tumor progression and osteolysis. ZOL administration directly attenuates osteosarcoma production of RANKL/MCP-1, reducing tumor-induced bone destruction. In vivo, these findings also correlated with significant reduction in osteosarcoma growth. ZOL attenuates tumor-induced osteolysis, not only through direct inhibition of osteoclasts, but also through direct actions on tumor expression of osteoclast activators. These data provide insight regarding the effect of ZOL on osteosarcoma essential for designing the planned upcoming prospective randomized trials to determine the efficacy of bisphosphonates on osteosarcoma in humans.
© 2014 American Society for Bone and Mineral Research.
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2 Members
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19 MeSH Terms
Analysis of serum insulin growth factor-1 concentrations in localized osteosarcoma: a children's oncology group study.
Borinstein SC, Barkauskas DA, Bernstein M, Goorin A, Gorlick R, Krailo M, Schwartz CL, Wexler LH, Toretsky JA
(2014) Pediatr Blood Cancer 61: 749-52
MeSH Terms: Adolescent, Age Factors, Antineoplastic Combined Chemotherapy Protocols, Biomarkers, Tumor, Bone Neoplasms, Child, Child, Preschool, Female, Follow-Up Studies, Humans, Infant, Infant, Newborn, Insulin-Like Growth Factor Binding Protein 2, Insulin-Like Growth Factor Binding Protein 3, Insulin-Like Growth Factor I, Male, Osteosarcoma, Prognosis, Prospective Studies, Survival Rate
Show Abstract · Added March 7, 2014
To investigate the role of insulin-like growth factor-1 (IGF-1), in localized osteosarcoma, serum levels of IGF-1, IGFBP-2, and IGFBP-3 were measured in 224 similarly treated, newly diagnosed patients. We demonstrated that younger patients had lower concentrations of IGF-1 and IGFBP-3 compared to older (P < 0.001) along with lower IGFBP-3:IGF-1 and IGFBP-2:IGF-1 ratios (P < 0.001). IGFBP-2 did not correlate with age (P = 0.16), yet IGFBP-2:IGF-1 ratios were higher in the younger population (P < 0.001). These findings show that older patients have higher concentrations of free IGF-1. None of IGF-1, IGFBP-2, nor IGFBP-3 concentrations were associated with event-free nor overall survival.
© 2013 Wiley Periodicals, Inc.
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1 Members
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20 MeSH Terms
Analytical methods for measuring collagen XIX in human cell cultures, tissue extracts, and biological fluids.
Oudart JB, Brassart-Pasco S, Luczka E, Dupont-Deshorgue A, Bellon G, Boudko SP, Bächinger HP, Monboisse JC, Maquart FX, Ramont L
(2013) Anal Biochem 437: 111-7
MeSH Terms: Body Fluids, Cell Line, Collagen, Enzyme-Linked Immunosorbent Assay, Epithelial Cells, Fibroblasts, Gene Expression Regulation, Humans, Osteosarcoma, Tissue Extracts
Show Abstract · Added November 2, 2017
Type XIX collagen is a minor collagen associated with basement membranes in vascular, neuronal, mesenchymal, and epithelial tissues. We demonstrated that the NC1, C-terminal, domain of collagen XIX inhibits the migration capacities of tumor cells and exerts a strong inhibition of tumor growth. Other basement membrane collagens or derived fragments were measured in biological fluids such as blood and urine of patients and appeared to be useful for diagnosis, prognosis, or treatment monitoring. The aim of this study was to develop and validate methods to measure collagen XIX and its fragments in human cell cultures, tissue extracts, and human biological fluids. For that purpose, we developed real-time PCR, Western blot, and competitive enzyme-linked immunosorbent assays. We demonstrated that the methods developed in this paper are specific for collagen XIX. We showed that it is expressed in human cell cultures, tissue extracts, and various biological fluids. These methods may be used in various human tissue extracts and biological fluids such as serum, amniotic fluid, cord blood, and many other fluids. Collagen XIX or its fragments could constitute new biomarkers for human diseases as well as for diagnosis and/or prognosis.
Copyright © 2013 Elsevier Inc. All rights reserved.
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1 Members
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10 MeSH Terms
Nuclear p63 expression in osteoblastic tumors.
Kallen ME, Sanders ME, Gonzalez AL, Black JO, Keedy VL, Hande KR, Homlar KC, Halpern JL, Holt GE, Schwartz HS, Coffin CM, Cates JM
(2012) Tumour Biol 33: 1639-44
MeSH Terms: Adolescent, Adult, Biomarkers, Tumor, Bone Neoplasms, Child, Female, Humans, Male, Middle Aged, Osteoblastoma, Osteosarcoma, Transcription Factors, Tumor Suppressor Proteins, Young Adult
Show Abstract · Added March 15, 2013
Expression of the p63 tumor suppressor protein has been reported in the mononuclear stromal cells of giant cell tumor of the bone, which may represent osteoblast-precursor cells. Only a limited number of osteoblastic tumors have been studied for p63 expression thus far. We therefore examined whether p63 may serve as a marker for osteoblastic differentiation in osteosarcomas or as a differential diagnostic marker to distinguish osteoblastoma from osteosarcoma. Immunohistochemical stains for p63 were performed on a tissue microarray containing 71 chemotherapy naïve biopsy samples of osteosarcoma, 21 whole sections of osteosarcoma, and 8 osteoblastomas. Nuclear p63 was detected in seven of eight osteoblastomas but was restricted to stromal cells within primitive, immature-appearing areas of osteoid deposition. Although only 7 of 71 (10 %) biopsy samples of osteosarcoma represented on the tissue microarray were positive for p63, 7 of 21 (33 %) osteosarcomas were positive when whole tissue sections were evaluated. Although p63 is detected in most osteoblastomas, it is also observed in a significant subset of osteosarcomas, severely limiting its utility in distinguishing between benign and malignant osteoblastic tumors. The relatively low prevalence of p63 expression in osteosarcoma would also seem to preclude its use as a marker of osteoblastic differentiation in skeletal sarcomas.
0 Communities
3 Members
0 Resources
14 MeSH Terms
Human DNA helicase B (HDHB) binds to replication protein A and facilitates cellular recovery from replication stress.
Guler GD, Liu H, Vaithiyalingam S, Arnett DR, Kremmer E, Chazin WJ, Fanning E
(2012) J Biol Chem 287: 6469-81
MeSH Terms: Amino Acid Sequence, Chromosomes, DNA Damage, DNA Helicases, DNA Replication, HCT116 Cells, HeLa Cells, Humans, Molecular Sequence Data, Mutagenesis, Site-Directed, Osteosarcoma, Protein Folding, Protein Interaction Domains and Motifs, Replication Protein A, S Phase Cell Cycle Checkpoints, Stress, Physiological
Show Abstract · Added March 7, 2014
Maintenance of genomic stability in proliferating cells depends on a network of proteins that coordinate chromosomal replication with DNA damage responses. Human DNA helicase B (HELB or HDHB) has been implicated in chromosomal replication, but its role in this coordinated network remains undefined. Here we report that cellular exposure to UV irradiation, camptothecin, or hydroxyurea induces accumulation of HDHB on chromatin in a dose- and time-dependent manner, preferentially in S phase cells. Replication stress-induced recruitment of HDHB to chromatin is independent of checkpoint signaling but correlates with the level of replication protein A (RPA) recruited to chromatin. We show using purified proteins that HDHB physically interacts with the N-terminal domain of the RPA 70-kDa subunit (RPA70N). NMR spectroscopy and site-directed mutagenesis reveal that HDHB docks on the same RPA70N surface that recruits S phase checkpoint signaling proteins to chromatin. Consistent with this pattern of recruitment, cells depleted of HDHB display reduced recovery from replication stress.
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1 Members
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16 MeSH Terms
Thrombin induces osteosarcoma growth, a function inhibited by low molecular weight heparin in vitro and in vivo: procoagulant nature of osteosarcoma.
Ichikawa J, Cole HA, Magnussen RA, Mignemi NA, Butler M, Holt GE, O'Rear L, Yuasa M, Pabla B, Haro H, Cates JM, Hamm HE, Schwartz HS, Schoenecker JG
(2012) Cancer 118: 2494-506
MeSH Terms: Adolescent, Adult, Animals, Blood Coagulation, Bone Neoplasms, Cell Line, Tumor, Cell Proliferation, Female, Heparin, Humans, Male, Mice, Middle Aged, Osteosarcoma, Thrombin, Venous Thrombosis, Young Adult
Show Abstract · Added December 10, 2013
BACKGROUND - Procoagulant states, leading to activation of the coagulation protease thrombin, are common in cancer and portend a poor clinical outcome. Although procoagulant states in osteosarcoma patients have been described, studies exploring osteosarcoma cells' ability to directly contribute to procoagulant activity have not been reported. This study explores the hypothesis that osteosarcoma can regulate thrombin generation and proliferate in response to thrombin, and that attenuating thrombin generation with anticoagulants can slow tumor growth.
METHODS - Pathologic analysis of osteosarcoma with adjacent venous thrombus was performed. In vitro proliferation assays, cell-based coagulant activity assays, and quantification of coagulation cofactor expression were performed on human and murine osteosarcoma cell lines with varying aggressiveness. The efficacy of low molecular weight heparin (LMWH) attenuation of tumor-dependent thrombin generation and growth in vitro and in vivo was determined.
RESULTS - Venous thrombi adjacent to osteosarcoma were found to harbor tumor surrounded by fibrin expressing coagulation cofactors, a finding associated with poor clinical outcome. More aggressive osteosarcoma cell lines had greater surface expression of procoagulant factors and generated more thrombin than less aggressive cell lines and were found to proliferate in response to thrombin. Treatment with LMWH reduced in vitro osteosarcoma proliferation and procoagulant activity as well as tumor growth in vivo.
CONCLUSIONS - These findings suggest that elements of the coagulation cascade may play a role in and represent a pharmaceutical target to disrupt osteosarcoma growth. They also have broader implications, as they suggest that, to be effective, dosing of anticoagulants must take into account an individual tumor's capacity to generate thrombin.
Copyright © 2011 American Cancer Society.
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4 Members
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17 MeSH Terms