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Proteolysis of EphA2 Converts It from a Tumor Suppressor to an Oncoprotein.
Koshikawa N, Hoshino D, Taniguchi H, Minegishi T, Tomari T, Nam SO, Aoki M, Sueta T, Nakagawa T, Miyamoto S, Nabeshima K, Weaver AM, Seiki M
(2015) Cancer Res 75: 3327-39
MeSH Terms: Animals, Binding Sites, Blotting, Western, Cell Line, Tumor, Humans, Male, Matrix Metalloproteinase 14, Mice, Inbred BALB C, Microscopy, Fluorescence, Mutation, Neoplasm Metastasis, Neoplasms, Oncogene Proteins, Phosphorylation, Proteolysis, RNA Interference, Receptor, EphA2, Transplantation, Heterologous, Tumor Burden, Tumor Suppressor Proteins
Show Abstract · Added February 15, 2016
Eph receptor tyrosine kinases are considered candidate therapeutic targets in cancer, but they can exert opposing effects on cell growth. In the presence of its ligands, Eph receptor EphA2 suppresses signaling by other growth factor receptors, including ErbB, whereas ligand-independent activation of EphA2 augments ErbB signaling. To deploy EphA2-targeting drugs effectively in tumors, the anti-oncogenic ligand-dependent activation state of EphA2 must be discriminated from its oncogenic ligand-independent state. Because the molecular basis for the latter is little understood, we investigated how the activation state of EphA2 can be switched in tumor tissue. We found that ligand-binding domain of EphA2 is cleaved frequently by the membrane metalloproteinase MT1-MMP, a powerful modulator of the pericellular environment in tumor cells. EphA2 immunostaining revealed a significant loss of the N-terminal portion of EphA2 in areas of tumor tissue that expressed MT1-MMP. Moreover, EphA2 phosphorylation patterns that signify ligand-independent activation were observed specifically in these areas of tumor tissue. Mechanistic experiments revealed that processing of EphA2 by MT1-MMP promoted ErbB signaling, anchorage-independent growth, and cell migration. Conversely, expression of a proteolysis-resistant mutant of EphA2 prevented tumorigenesis and metastasis of human tumor xenografts in mice. Overall, our results showed how the proteolytic state of EphA2 in tumors determines its effector function and influences its status as a candidate biomarker for targeted therapy.
©2015 American Association for Cancer Research.
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20 MeSH Terms
Intrinsic TGF-β2-triggered SDF-1-CXCR4 signaling axis is crucial for drug resistance and a slow-cycling state in bone marrow-disseminated tumor cells.
Nakamura T, Shinriki S, Jono H, Guo J, Ueda M, Hayashi M, Yamashita S, Zijlstra A, Nakayama H, Hiraki A, Shinohara M, Ando Y
(2015) Oncotarget 6: 1008-19
MeSH Terms: Animals, Antineoplastic Agents, Bone Marrow, Cell Line, Tumor, Chemokine CXCL12, Cisplatin, Drug Resistance, Neoplasm, Gene Expression Regulation, Neoplastic, Heterocyclic Compounds, Humans, Immunoblotting, Mice, Neoplasms, RNA Interference, Receptors, CXCR4, Reverse Transcriptase Polymerase Chain Reaction, Signal Transduction, Transforming Growth Factor beta2, Transplantation, Heterologous
Show Abstract · Added January 20, 2015
Dormant or slow-cycling disseminated tumor cells (DTCs) in bone marrow (BM) are resistant to conventional therapy in various cancers including head and neck squamous cell carcinoma (HNSCC), although the molecular mechanisms remain largely unknown. This study aimed to identify the intrinsic molecular mechanisms underlying drug resistance in BM-DTCs. We used in vivo selection of the human HNSCC cell line HEp3, which mimics non-proliferative BM-DTCs in mice, to establish BM-DTC-derived (BM-HEp3) and lung metastases-derived (Lu-HEp3) sublines. Both sublines had higher migration activity and shortened survival in a murine xenograft model compared with parental (P-HEp3) cells. Slow-cycling BM-HEp3 cells had intrinsically enhanced cisplatin resistance compared with Lu-HEp3 cells, which also manifested this resistance but proliferated rapidly. The drug resistance and slow-cycling state of BM-HEp3 cells depended on enhanced positive feedback of the signaling axis of stromal cell-derived factor-1 (SDF-1)-C-X-C chemokine receptor-4 (CXCR4) via their overexpression. Interestingly, BM-DTCs highly expressed transforming growth factor-beta 2 (TGF-β2) to maintain SDF-1-CXCR4 overexpression. Inhibition of SDF-1-CXCR4 signaling by down-regulating TGF-β2 fully reversed the drug resistance of BM-HEp3 cells via reactivation of cell proliferation. These data suggest that the intrinsic TGF-β2-triggered SDF-1-CXCR4 signaling axis is crucial for drug resistance dependent on a slow-cycling state in BM-DTCs.
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19 MeSH Terms
An immunosufficient murine model for the study of human islets.
Zhao G, Moore DJ, Kim JI, Lee KM, O'Connor M, Yang M, Marshall AF, Lei J, Schuetz C, Markmann JF, Deng S
(2014) Xenotransplantation 21: 567-73
MeSH Terms: Animals, Antibodies, Diabetes Mellitus, Experimental, Graft Rejection, Graft Survival, Humans, Islets of Langerhans Transplantation, Mice, Inbred C57BL, Transplantation Tolerance, Transplantation, Heterologous
Show Abstract · Added October 15, 2014
For the sake of therapy of diabetes, it is critical to understand human beta cell function in detail in health and disease. Current studies of human beta cell physiology in vivo are mostly limited to immunodeficient mouse models, which possess significant technical limitations. This study aimed to create a new model for the study of human islets through induction of transplant tolerance in immunosufficient mice. B6 diabetic mice were transplanted with human islets and treated with anti-CD45RB. To assess whether anti-CD45RB-induced transplant tolerance requires B cells, B6 recipients received additional anti-CD20 or B6μMT-/- mice were used. For some anti-CD45RB-treated B6μMT-/- mice, additional anti-CD25 mAb was applied at the early or late stage post-transplant. Immunohistology was performed to show the Foxp3 cells in grafted anti-CD45RB/anti-CD20-treated Foxp3-GFP B6 mice. The results showed that anti-CD45RB alone allowed indefinite graft survival in 26.6% of B6 mice, however 100% of xenografts were accepted in mice treated simultaneously with anti-CD20, and 88.9% of xenografts accepted in anti-CD45RB-treated μMT-/- mice. These μMT-/- mice accepted the islets from another human donor but rejected the islets from baboon. Additional administration of anti-CD25 mAb at the time of transplantation resulted in 100% rejection, whereas 40% of grafts were rejected while the antibody was administrated at days 60 post-transplant. Immunohistologic examination showed Foxp3+ cells accumulated around grafts. We conclude that induction of tolerance to human islets in an immunosufficient mouse model could be generated by targeting murine CD45RB and CD20. This new system will facilitate study of human islets and accelerate the dissection of the critical mechanisms underlying islet health in human disease.
© 2014 John Wiley & Sons A/S Published by John Wiley & Sons Ltd.
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10 MeSH Terms
Ischemia in tumors induces early and sustained phosphorylation changes in stress kinase pathways but does not affect global protein levels.
Mertins P, Yang F, Liu T, Mani DR, Petyuk VA, Gillette MA, Clauser KR, Qiao JW, Gritsenko MA, Moore RJ, Levine DA, Townsend R, Erdmann-Gilmore P, Snider JE, Davies SR, Ruggles KV, Fenyo D, Kitchens RT, Li S, Olvera N, Dao F, Rodriguez H, Chan DW, Liebler D, White F, Rodland KD, Mills GB, Smith RD, Paulovich AG, Ellis M, Carr SA
(2014) Mol Cell Proteomics 13: 1690-704
MeSH Terms: Animals, Breast Neoplasms, Cold Ischemia, Female, Gene Expression Profiling, Humans, Mice, Mice, Inbred NOD, Neoplasm Transplantation, Ovarian Neoplasms, Phosphoproteins, Phosphorylation, Proteome, Proteomics, Transplantation, Heterologous
Show Abstract · Added May 20, 2014
Protein abundance and phosphorylation convey important information about pathway activity and molecular pathophysiology in diseases including cancer, providing biological insight, informing drug and diagnostic development, and guiding therapeutic intervention. Analyzed tissues are usually collected without tight regulation or documentation of ischemic time. To evaluate the impact of ischemia, we collected human ovarian tumor and breast cancer xenograft tissue without vascular interruption and performed quantitative proteomics and phosphoproteomics after defined ischemic intervals. Although the global expressed proteome and most of the >25,000 quantified phosphosites were unchanged after 60 min, rapid phosphorylation changes were observed in up to 24% of the phosphoproteome, representing activation of critical cancer pathways related to stress response, transcriptional regulation, and cell death. Both pan-tumor and tissue-specific changes were observed. The demonstrated impact of pre-analytical tissue ischemia on tumor biology mandates caution in interpreting stress-pathway activation in such samples and motivates reexamination of collection protocols for phosphoprotein analysis.
© 2014 by The American Society for Biochemistry and Molecular Biology, Inc.
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15 MeSH Terms
Primary orthotopic glioma xenografts recapitulate infiltrative growth and isocitrate dehydrogenase I mutation.
Valadez JG, Sarangi A, Lundberg CJ, Cooper MK
(2014) J Vis Exp : e50865
MeSH Terms: Animals, Brain Neoplasms, Glioma, Heterografts, Humans, Isocitrate Dehydrogenase, Mice, Mutation, Neoplasm Transplantation, Transplantation, Heterologous
Show Abstract · Added March 21, 2014
Malignant gliomas constitute a heterogeneous group of highly infiltrative glial neoplasms with distinct clinical and molecular features. Primary orthotopic xenografts recapitulate the histopathological and molecular features of malignant glioma subtypes in preclinical animal models. To model WHO grades III and IV malignant gliomas in transplantation assays, human tumor cells are xenografted into an orthotopic site, the brain, of immunocompromised mice. In contrast to secondary xenografts that utilize cultured tumor cells, human glioma cells are dissociated from resected specimens and transplanted without prior passage in tissue culture to generate primary xenografts. The procedure in this report details tumor sample preparation, intracranial transplantation into immunocompromised mice, monitoring for tumor engraftment and tumor harvesting for subsequent passage into recipient animals or analysis. Tumor cell preparation requires 2 hr and surgical procedure requires 20 min/animal.
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10 MeSH Terms
Passage-dependent cancerous transformation of human mesenchymal stem cells under carcinogenic hypoxia.
Crowder SW, Horton LW, Lee SH, McClain CM, Hawkins OE, Palmer AM, Bae H, Richmond A, Sung HJ
(2013) FASEB J 27: 2788-98
MeSH Terms: Animals, Blotting, Western, Cell Differentiation, Cell Hypoxia, Cell Proliferation, Cell Transformation, Neoplastic, Cells, Cultured, DNA-Binding Proteins, Female, Forkhead Transcription Factors, Gene Expression, Humans, Hypoxia-Inducible Factor 1, alpha Subunit, Mesenchymal Stem Cells, Mice, Mice, Knockout, Mice, Nude, Neoplasms, Experimental, Nickel, Reactive Oxygen Species, Reverse Transcriptase Polymerase Chain Reaction, Time Factors, Transcription Factors, Transplantation, Heterologous, Tumor Burden, Tumor Suppressor Protein p53
Show Abstract · Added June 14, 2013
Bone marrow-derived human mesenchymal stem cells (hMSCs) either promote or inhibit cancer progression, depending on factors that heretofore have been undefined. Here we have utilized extreme hypoxia (0.5% O2) and concurrent treatment with metal carcinogen (nickel) to evaluate the passage-dependent response of hMSCs toward cancerous transformation. Effects of hypoxia and nickel treatment on hMSC proliferation, apoptosis, gene and protein expression, replicative senescence, reactive oxygen species (ROS), redox mechanisms, and in vivo tumor growth were analyzed. The behavior of late passage hMSCs in a carcinogenic hypoxia environment follows a profile similar to that of transformed cancer cells (i.e., increased expression of oncogenic proteins, decreased expression of tumor suppressor protein, increased proliferation, decreased apoptosis, and aberrant redox mechanisms), but this effect was not observed in earlier passage control cells. These events resulted in accumulated intracellular ROS in vitro and excessive proliferation in vivo. We suggest a mechanism by which carcinogenic hypoxia modulates the activity of three critical transcription factors (c-MYC, p53, and HIF1), resulting in accumulated ROS and causing hMSCs to undergo cancer-like behavioral changes. This is the first study to utilize carcinogenic hypoxia as an environmentally relevant experimental model for studying the age-dependent cancerous transformation of hMSCs.
2 Communities
4 Members
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26 MeSH Terms
Limits of [18F]-FLT PET as a biomarker of proliferation in oncology.
McKinley ET, Ayers GD, Smith RA, Saleh SA, Zhao P, Washington MK, Coffey RJ, Manning HC
(2013) PLoS One 8: e58938
MeSH Terms: Animals, Biomarkers, Cell Line, Tumor, Cell Proliferation, Dideoxynucleosides, Disease Models, Animal, HCT116 Cells, Humans, Immunohistochemistry, Mice, Mutation, Neoplasms, Positron-Emission Tomography, Thymidine, Transplantation, Heterologous
Show Abstract · Added March 5, 2014
BACKGROUND - Non-invasive imaging biomarkers of cellular proliferation hold great promise for quantifying response to personalized medicine in oncology. An emerging approach to assess tumor proliferation utilizes the positron emission tomography (PET) tracer 3'-deoxy-3'[(18)F]-fluorothymidine, [(18)F]-FLT. Though several studies have associated serial changes in [(18)F]-FLT-PET with elements of therapeutic response, the degree to which [(18)F]-FLT-PET quantitatively reflects proliferative index has been continuously debated for more that a decade. The goal of this study was to elucidate quantitative relationships between [(18)F]-FLT-PET and cellular metrics of proliferation in treatment naïve human cell line xenografts commonly employed in cancer research.
METHODS AND FINDINGS - [(18)F]-FLT-PET was conducted in human cancer xenograft-bearing mice. Quantitative relationships between PET, thymidine kinase 1 (TK1) protein levels and immunostaining for proliferation markers (Ki67, TK1, PCNA) were evaluated using imaging-matched tumor specimens. Overall, we determined that [(18)F]-FLT-PET reflects TK1 protein levels, yet the cell cycle specificity of TK1 expression and the extent to which tumors utilize thymidine salvage for DNA synthesis decouple [(18)F]-FLT-PET data from standard estimates of proliferative index.
CONCLUSIONS - Our findings illustrate that [(18)F]-FLT-PET reflects tumor proliferation as a function of thymidine salvage pathway utilization. Unlike more general proliferation markers, such as Ki67, [(18)F]-FLT PET reflects proliferative indices to variable and potentially unreliable extents. [(18)F]-FLT-PET cannot discriminate moderately proliferative, thymidine salvage-driven tumors from those of high proliferative index that rely primarily upon de novo thymidine synthesis. Accordingly, the magnitude of [(18)F]-FLT uptake should not be considered a surrogate of proliferative index. These data rationalize the diversity of [(18)F]-FLT-PET correlative results previously reported and suggest future best-practices when [(18)F]-FLT-PET is employed in oncology.
1 Communities
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15 MeSH Terms
Viable biobanking of primary head and neck squamous cell carcinoma.
Godoy JM, Sewell A, Johnston B, Brown BT, Lu X, Sinard RJ, Rohde S, Mannion K, Netterville JL, Yarbrough WG
(2013) Laryngoscope 123: 641-5
MeSH Terms: Carcinoma, Squamous Cell, Cryopreservation, Feasibility Studies, Head and Neck Neoplasms, Humans, Immunohistochemistry, Keratins, Laryngeal Neoplasms, Mouth Neoplasms, Oropharyngeal Neoplasms, Squamous Cell Carcinoma of Head and Neck, Tissue Banks, Transplantation, Heterologous, Tumor Cells, Cultured
Show Abstract · Added March 7, 2014
OBJECTIVES/HYPOTHESIS - To determine the feasibility of viable storage of head and neck squamous cell carcinoma (HNSCC) for regrowth of cells in culture.
STUDY DESIGN - Laboratory-based translational study.
METHODS - Methods for intermediate-term frozen storage of viable HNSCC were explored using small pieces of primary tumor and dissociated HNSCC cells after short-term culture. Viable cells after freezing were confirmed by adherence to tissue culture plates, cell morphology, and increased cell or colony density. Two cultures were immunostained for cytokeratin to confirm epithelial origin of viable cultured cells after freezing.
RESULTS - Six primary HNSCCs (two oral cavity, three larynx, one oropharynx) and two HNSCCs that had been passaged through a xenograft (two oral cavity) were dissociated to single cells and grown in short-term cell culture for 0 to 12 passages. After short-term culture, cells were frozen for up to 8 months, thawed, and replated. Frozen cells derived from all tumors (six primary and two xenografts) were successfully replated with cultures lasting >7 days with seven of eight tumors presenting increased colony or cell density over 1 week of growth after freezing. In total, 15 of 15 tested samples derived from six primary and two xenografted HNSCCs were viable after freezing.
CONCLUSIONS - In the current study, we show that biopreservation of primary or xenografted HNSCC using short-term cell culture is feasible. Initial short-term cell culture was required for successful storage and viability of frozen cells. These proof-of-principle studies, if more widely implemented, could improve preclinical testing of new therapies for HNSCC.
Copyright © 2013 The American Laryngological, Rhinological, and Otological Society, Inc.
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14 MeSH Terms
Identification of Hedgehog pathway responsive glioblastomas by isocitrate dehydrogenase mutation.
Gerardo Valadez J, Grover VK, Carter MD, Calcutt MW, Abiria SA, Lundberg CJ, Williams TV, Cooper MK
(2013) Cancer Lett 328: 297-306
MeSH Terms: AC133 Antigen, Animals, Antigens, CD, Cell Line, Tumor, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Glioblastoma, Glycoproteins, Hedgehog Proteins, Humans, Isocitrate Dehydrogenase, Mice, Mutation, Neoplasm Grading, Patched Receptors, Patched-1 Receptor, Peptides, Receptors, Cell Surface, Signal Transduction, Transplantation, Heterologous
Show Abstract · Added March 7, 2014
The Hedgehog (Hh) pathway regulates the growth of a subset of adult gliomas and better definition of Hh-responsive subtypes could enhance the clinical utility of monitoring and targeting this pathway in patients. Somatic mutations of the isocitrate dehydrogenase (IDH) genes occur frequently in WHO grades II and III gliomas and WHO grade IV secondary glioblastomas. Hh pathway activation in WHO grades II and III gliomas suggests that it might also be operational in glioblastomas that developed from lower-grade lesions. To evaluate this possibility and to better define the molecular and histopathological glioma subtypes that are Hh-responsive, IDH genes were sequenced in adult glioma specimens assayed for an operant Hh pathway. The proportions of grades II-IV specimens with IDH mutations correlated with the proportions that expressed elevated levels of the Hh gene target PTCH1. Indices of an operational Hh pathway were measured in all primary cultures and xenografts derived from IDH-mutant glioma specimens, including IDH-mutant glioblastomas. In contrast, the Hh pathway was not operational in glioblastomas that lacked IDH mutation or history of antecedent lower-grade disease. IDH mutation is not required for an operant pathway however, as significant Hh pathway modulation was also measured in grade III gliomas with wild-type IDH sequences. These results indicate that the Hh pathway is operational in grades II and III gliomas and glioblastomas with molecular or histopathological evidence for evolvement from lower-grade gliomas. Lastly, these findings suggest that gliomas sharing this molecularly defined route of progression arise in Hh-responsive cell types.
Published by Elsevier Ireland Ltd.
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20 MeSH Terms
Targeting BRCA1 localization to augment breast tumor sensitivity to poly(ADP-Ribose) polymerase inhibition.
Yang ES, Nowsheen S, Rahman MA, Cook RS, Xia F
(2012) Cancer Res 72: 5547-55
MeSH Terms: Animals, Breast Neoplasms, Cell Nucleus, Cytoplasm, DNA Breaks, Double-Stranded, DNA Repair, Enzyme Inhibitors, Female, Fluorescent Antibody Technique, Humans, MCF-7 Cells, Mice, Poly(ADP-ribose) Polymerase Inhibitors, Protein Transport, Transplantation, Heterologous, Ubiquitin-Protein Ligases
Show Abstract · Added March 27, 2014
PARP inhibitors have gained recent attention due to their highly selective killing of BRCA1/2-mutated and DNA double-strand break (DSB) repair-deficient tumors. Unfortunately, the majority of sporadic breast cancers carry wild-type BRCA1/2 and are proficient in DSB repair. We and others have shown that BRCA1 is a nuclear/cytoplasm shuttling protein that is transiently exported from the nucleus to the cytosol upon various stimuli. Thus, we hypothesized that depletion of nuclear BRCA1 would compromise DSB repair and subsequently render sporadic tumors susceptible to PARP inhibition. Indeed, in human sporadic breast cancer cells with functional BRCA1 and proficient DSB repair, a transient nuclear depletion of BRCA1 and subsequent homologous recombination repair deficit was induced with either truncated BRCA1 or irradiation. This rendered these human sporadic breast cancer cells susceptible to PARP inhibition. These observations were confirmed genetically using mislocated BRCA1 mutants as well as in vivo in mice bearing breast tumor xenografts. These data support the potential strategy of targeting BRCA1 location to convert BRCA1-proficient sporadic tumors to be susceptible to the synthetic lethal combination with PARP inhibitors.
©2012 AACR.
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16 MeSH Terms