Hypoxia and TGF-β Drive Breast Cancer Bone Metastases through Parallel Signaling Pathways in Tumor Cells and the Bone Microenvironment
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{"title"=>"Hypoxia and TGF-β drive breast cancer bone metastases through parallel signaling pathways in tumor cells and the bone microenvironment", "type"=>"journal", "authors"=>[{"first_name"=>"Lauren K.", "last_name"=>"Dunn", "scopus_author_id"=>"35169156400"}, {"first_name"=>"Khalid S.", "last_name"=>"Mohammad", "scopus_author_id"=>"7003582867"}, {"first_name"=>"Pierrick G.J.", "last_name"=>"Fournier", "scopus_author_id"=>"14321733500"}, {"first_name"=>"C. Ryan", "last_name"=>"McKenna", "scopus_author_id"=>"16042921700"}, {"first_name"=>"Holly W.", "last_name"=>"Davis", "scopus_author_id"=>"26532707400"}, {"first_name"=>"Maria", "last_name"=>"Niewolna", "scopus_author_id"=>"6603454293"}, {"first_name"=>"Xiang Hong", "last_name"=>"Peng", "scopus_author_id"=>"56539131700"}, {"first_name"=>"John M.", "last_name"=>"Chirgwin", "scopus_author_id"=>"25941440400"}, {"first_name"=>"Theresa A.", "last_name"=>"Guise", "scopus_author_id"=>"7003535025"}], "year"=>2009, "source"=>"PLoS ONE", "identifiers"=>{"issn"=>"19326203", "scopus"=>"2-s2.0-70249108848", "sgr"=>"70249108848", "pui"=>"355250242", "isbn"=>"10.1371/journal.pone.0006896", "pmid"=>"19727403", "doi"=>"10.1371/journal.pone.0006896"}, "id"=>"5d7ba40d-ebfa-371a-a31e-1c7eaf566fcc", "abstract"=>"Background: Most patients with advanced breast cancer develop bone metastases, which cause pain, hypercalcemia, fractures, nerve compression and paralysis. Chemotherapy causes further bone loss, and bone-specific treatments are only palliative. Multiple tumor-secreted factors act on the bone microenvironment to drive a feed-forward cycle of tumor growth. Effective treatment requires inhibiting upstream regulators of groups of prometastatic factors. Two central regulators are hypoxia and transforming growth factor (TGF)- β. We asked whether hypoxia (via HIF-1α) and TGF-β signaling promote bone metastases independently or synergistically, and we tested molecular versus pharmacological inhibition strategies in an animal model. Methodology/Principal Findings: We analyzed interactions between HIF-1α and TGF-β pathways in MDA-MB-231 breast cancer cells. Only vascular endothelial growth factor (VEGF) and the CXC chemokine receptor 4 (CXCR4), of 16 genes tested, were additively increased by both TGF-β and hypoxia, with effects on the proximal promoters. We inhibited HIF-1α and TGF-β pathways in tumor cells by shRNA and dominant negative receptor approaches. Inhibition of either pathway decreased bone metastasis, with no further effect of double blockade. We tested pharmacologic inhibitors of the pathways, which target both the tumor and the bone microenvironment. Unlike molecular blockade, combined drug treatment decreased bone metastases more than either alone, with effects on bone to decrease osteoclastic bone resorption and increase osteoblast activity, in addition to actions on tumor cells. Conclusions/Significance: Hypoxia and TGF-β signaling in parallel drive tumor bone metastases and regulate a common set of tumor genes. In contrast, small molecule inhibitors, by acting on both tumor cells and the bone microenvironment, additively decrease tumor burden, while improving skeletal quality. Our studies suggest that inhibitors of HIF-1α and TGF-β may improve treatment of bone metastases and increase survival.", "link"=>"http://www.mendeley.com/research/hypoxia-tgf%CE%B2-drive-breast-cancer-bone-metastases-through-parallel-signaling-pathways-tumor-cells-bon", "reader_count"=>66, "reader_count_by_academic_status"=>{"Unspecified"=>2, "Professor > Associate Professor"=>1, "Researcher"=>16, "Student > Doctoral Student"=>3, "Student > Ph. D. Student"=>13, "Student > Postgraduate"=>1, "Student > Master"=>9, "Other"=>10, "Student > Bachelor"=>7, "Lecturer"=>1, "Professor"=>3}, "reader_count_by_user_role"=>{"Unspecified"=>2, "Professor > Associate Professor"=>1, "Researcher"=>16, "Student > Doctoral Student"=>3, "Student > Ph. D. Student"=>13, "Student > Postgraduate"=>1, "Student > Master"=>9, "Other"=>10, "Student > Bachelor"=>7, "Lecturer"=>1, "Professor"=>3}, "reader_count_by_subject_area"=>{"Engineering"=>1, "Unspecified"=>3, "Biochemistry, Genetics and Molecular Biology"=>11, "Mathematics"=>1, "Agricultural and Biological Sciences"=>30, "Medicine and Dentistry"=>19, "Immunology and Microbiology"=>1}, "reader_count_by_subdiscipline"=>{"Engineering"=>{"Engineering"=>1}, "Medicine and Dentistry"=>{"Medicine and Dentistry"=>19}, "Immunology and Microbiology"=>{"Immunology and Microbiology"=>1}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>30}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>11}, "Mathematics"=>{"Mathematics"=>1}, "Unspecified"=>{"Unspecified"=>3}}, "reader_count_by_country"=>{"United States"=>2, "Nigeria"=>1, "Germany"=>1}, "group_count"=>2}

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  • {"files"=>["https://ndownloader.figshare.com/files/885592"], "description"=>"<p>(A) Representative HIF-1α staining in demineralized bone sections from mice inoculated with MDA-MB-231 parental, shNT or shHIF cells. Arrows indicate HIF-1α positive nuclei. Scale bar equals 50 µm. Staining without primary antibody was used as negative control (Neg. Control). (B) The percentage of nuclei positive for HIF-1α was calculated in three non-overlapping fields at 400×magnification for each mouse (n = 3 per group). Results are the mean ± SEM number of HIF-1α positive nuclei per field.</p>", "links"=>[], "tags"=>["mda-mb-231", "cells"], "article_id"=>556045, "categories"=>["Medicine", "Plant Biology", "Biochemistry"], "users"=>["Lauren K. Dunn", "Khalid S. Mohammad", "Pierrick G. J. Fournier", "C. Ryan McKenna", "Holly W. Davis", "Maria Niewolna", "Xiang Hong Peng", "John M. Chirgwin", "Theresa A. Guise"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0006896.g006", "stats"=>{"downloads"=>3, "page_views"=>5, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Knockdown_of_HIF_1_in_MDA_MB_231_cells_is_stable_in_vivo_/556045", "title"=>"Knockdown of HIF-1α in MDA-MB-231 cells is stable <i>in vivo</i>.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2009-09-03 01:40:45"}
  • {"files"=>["https://ndownloader.figshare.com/files/438701", "https://ndownloader.figshare.com/files/438705"], "description"=>"<div><h3>Background</h3><p>Most patients with advanced breast cancer develop bone metastases, which cause pain, hypercalcemia, fractures, nerve compression and paralysis. Chemotherapy causes further bone loss, and bone-specific treatments are only palliative. Multiple tumor-secreted factors act on the bone microenvironment to drive a feed-forward cycle of tumor growth. Effective treatment requires inhibiting upstream regulators of groups of prometastatic factors. Two central regulators are hypoxia and transforming growth factor (TGF)- β. We asked whether hypoxia (via HIF-1α) and TGF-β signaling promote bone metastases independently or synergistically, and we tested molecular versus pharmacological inhibition strategies in an animal model.</p><h3>Methodology/Principal Findings</h3><p>We analyzed interactions between HIF-1α and TGF-β pathways in MDA-MB-231 breast cancer cells. Only vascular endothelial growth factor (VEGF) and the CXC chemokine receptor 4 (CXCR4), of 16 genes tested, were additively increased by both TGF-β and hypoxia, with effects on the proximal promoters. We inhibited HIF-1α and TGF-β pathways in tumor cells by shRNA and dominant negative receptor approaches. Inhibition of either pathway decreased bone metastasis, with no further effect of double blockade. We tested pharmacologic inhibitors of the pathways, which target both the tumor and the bone microenvironment. Unlike molecular blockade, combined drug treatment decreased bone metastases more than either alone, with effects on bone to decrease osteoclastic bone resorption and increase osteoblast activity, in addition to actions on tumor cells.</p><h3>Conclusions/Significance</h3><p>Hypoxia and TGF-β signaling in parallel drive tumor bone metastases and regulate a common set of tumor genes. In contrast, small molecule inhibitors, by acting on both tumor cells and the bone microenvironment, additively decrease tumor burden, while improving skeletal quality. Our studies suggest that inhibitors of HIF-1α and TGF-β may improve treatment of bone metastases and increase survival.</p></div>", "links"=>[], "tags"=>["hypoxia", "cancer", "metastases", "parallel", "signaling", "pathways", "cells", "microenvironment"], "article_id"=>146505, "categories"=>["Medicine", "Cell Biology", "Biochemistry"], "users"=>["Lauren K. Dunn", "Khalid S. Mohammad", "Pierrick G. J. Fournier", "C. Ryan McKenna", "Holly W. Davis", "Maria Niewolna", "Xiang Hong Peng", "John M. Chirgwin", "Theresa A. Guise"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0006896.s001", "https://dx.doi.org/10.1371/journal.pone.0006896.s002"], "stats"=>{"downloads"=>6, "page_views"=>8, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/Hypoxia_and_TGF_Drive_Breast_Cancer_Bone_Metastases_through_Parallel_Signaling_Pathways_in_Tumor_Cells_and_the_Bone_Microenvironment/146505", "title"=>"Hypoxia and TGF-β Drive Breast Cancer Bone Metastases through Parallel Signaling Pathways in Tumor Cells and the Bone Microenvironment", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2009-09-03 01:48:25"}
  • {"files"=>["https://ndownloader.figshare.com/files/886361"], "description"=>"<p>(A) Bone mineral density of the femur, tibia, and spine measured by DXA in mice treated ± 2ME2 (150 mg/kg). Results are expressed as the mean ± SEM % change in BMD (n = 10 per group). Statistical analysis by two-way ANOVA with a Bonferroni post-test at week 4. (B) Representative histology of tibias from mice ± 2ME2 (150 mg/kg) for 4 weeks. Trabecular bone is indicated by arrows. Scale bar equal to 500 µm. (C) Representative TRAP staining of bone histology of the proximal tibias from the mice. TRAP+ osteoclasts (OC) are indicated by arrows. Scale bar is equal to 50 µm. (D) Osteoclast number was measured in the distal femur and proximal tibia at 200×magnification on TRAP stained slides. Results are expressed as the number of osteoclasts (OC) per mm<sup>2</sup> bone surface (BS). (E) Representative H&E stained bone histology of the proximal tibias from mice treated ± 2ME2 (150 mg/kg). Osteoblasts (OB) indicated by arrows. Scale bar is equal to 50 µm. (F) Osteoblast number was measured below the primary spongiosa in the distal femur and proximal tibia at 200×magnification on H&E stained slides. Results are expressed as the number of osteoblasts (OB) per mm<sup>2</sup> bone surface (BS).</p>", "links"=>[], "tags"=>["increases", "inhibits", "osteoclasts", "osteoblasts", "unaffected"], "article_id"=>556806, "categories"=>["Medicine", "Plant Biology", "Biochemistry"], "users"=>["Lauren K. Dunn", "Khalid S. Mohammad", "Pierrick G. J. Fournier", "C. Ryan McKenna", "Holly W. Davis", "Maria Niewolna", "Xiang Hong Peng", "John M. Chirgwin", "Theresa A. Guise"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0006896.g011", "stats"=>{"downloads"=>1, "page_views"=>9, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_2ME2_increases_bone_density_inhibits_osteoclasts_and_increases_osteoblasts_in_normal_bone_unaffected_by_tumor_/556806", "title"=>"2ME2 increases bone density, inhibits osteoclasts and increases osteoblasts in normal bone unaffected by tumor.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2009-09-03 01:53:26"}
  • {"files"=>["https://ndownloader.figshare.com/files/886512"], "description"=>"<p>(A) Representative x-ray images from hindlimbs of mice inoculated with MDA-MB-231 cells and treated ± SD-208 (0.3 mg/mL or 1.0 mg/mL), arrows indicate osteolytic bone lesions. (B) Osteolytic lesion area measured on radiographs of hindlimbs and forelimbs from mice with bone metastases. Results are expressed as the mean area ± SEM per mouse. **** <i>P<</i>0.0001 0.3 mg/mL and 1.0 mg/mL SD-208 compared to vehicle, using a two-way ANOVA with a Bonferroni post-test at 4 weeks. (C) Representative histology of femurs with tumor indicated by arrows. Scale bar equal to 500 µm. (D) Tumor burden in hindlimbs and humeri was measured by quantitative histomorphometry. Results are expressed as the mean ± SEM area per bone. Statistical analysis by one-way ANOVA with a Newman-Keuls multiple comparison test. (E) Kaplan-Meyer analysis of mouse survival analyzed using a Logrank test.</p>", "links"=>[], "tags"=>["sd-208", "osteolytic", "lesions", "increases"], "article_id"=>556963, "categories"=>["Medicine", "Plant Biology", "Biochemistry"], "users"=>["Lauren K. Dunn", "Khalid S. Mohammad", "Pierrick G. J. Fournier", "C. Ryan McKenna", "Holly W. Davis", "Maria Niewolna", "Xiang Hong Peng", "John M. Chirgwin", "Theresa A. Guise"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0006896.g012", "stats"=>{"downloads"=>0, "page_views"=>2, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Preventive_treatment_with_SD_208_reduces_osteolytic_bone_lesions_and_increases_survival_/556963", "title"=>"Preventive treatment with SD-208 reduces osteolytic bone lesions and increases survival.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2009-09-03 01:56:03"}
  • {"files"=>["https://ndownloader.figshare.com/files/885190"], "description"=>"<p>(A) HepG2 cells were transfected with pGL3 plasmids containing full-length for 5′-deleted fragments of the human VEGF or CXCR4 promoter and the phRL-CMV plasmid. Cells were treated ± TGF-β (5 ng/mL) ± 1% O<sub>2</sub> during 24 h before measuring dual-luciferase activity. Results are expressed as the mean ± SEM (n = 3) of the relative luciferase activity, analyzed using an unpaired Student's t test. (B) Schematic representation of wild-type (WT), HRE-mutant (mH1) and SBE-mutant (mS1 or mS2) VEGF and CXCR4 promoters. One to three nucleotides (underlined, bold letters) within HRE and SBEs were substituted as indicated. (C) HepG2 cells were transfected with pGL3 plasmids containing a wild-type VEGF or CXCR4 promoter or promoters with mutations to the HRE or SBE and the phRL-CMV plasmid. Cells were treated ± TGF-β (5 ng/mL) ± 1% O<sub>2</sub> during 24 h before measuring dual-luciferase activity. Results are expressed as the mean ± SEM (n = 3) of the relative luciferase activity, analyzed using an unpaired Student's t test. * <i>P</i><0.05, ** <i>P</i><0.01, *** <i>P</i><0.005, **** <i>P</i><0.001.</p>", "links"=>[], "tags"=>["vegf", "cxcr4", "transcription", "proximal", "promoter"], "article_id"=>555636, "categories"=>["Medicine", "Plant Biology", "Biochemistry"], "users"=>["Lauren K. Dunn", "Khalid S. Mohammad", "Pierrick G. J. Fournier", "C. Ryan McKenna", "Holly W. Davis", "Maria Niewolna", "Xiang Hong Peng", "John M. Chirgwin", "Theresa A. Guise"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0006896.g003", "stats"=>{"downloads"=>1, "page_views"=>17, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Hypoxia_and_TGF_946_increase_VEGF_and_CXCR4_transcription_through_proximal_promoter_response_elements_/555636", "title"=>"Hypoxia and TGF-β increase VEGF and CXCR4 transcription through proximal promoter response elements.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2009-09-03 01:33:56"}
  • {"files"=>["https://ndownloader.figshare.com/files/886711"], "description"=>"<p>(A) Representative x-ray images from hindlimbs of mice inoculated with MDA-MB-231 cells and therapeutically treated ± 2ME2 (150 mg/kg) and ± SD-208 (60 mg/kg), arrows indicate osteolytic lesions and osteolytic lesion area measured on radiographs of hindlimbs and forelimbs from mice with bone metastases. Results are expressed as the mean area ± SEM per mouse (n = 12–14 per group). * <i>P<</i>0.01 SD-208 and ** <i>P<</i>0.001 2ME2 compared to vehicle, † <i>P<</i>0.01 SD-208 and ‡ <i>P<</i>0.05 2ME2 compared to SD-208 + 2ME2, using a two-way ANOVA with a Bonferroni post-test at 3 weeks. (B) Representative histology of femurs with tumor indicated by arrows. Scale bar equal to 500 µm. (C) Tumor burden in hindlimbs and humeri was measured by quantitative histomorphometry. Results are expressed as the mean ± SEM area per bone. * <i>P<</i>0.05, **** <i>P<</i>0.001, using a one-way ANOVA with a Newman-Keuls multiple comparison test. (D) Osteoclast number per mm bone surface (BS) was counted in TRAP stained bone metastases sections. Results are expressed as mean ± SEM OC number per millimeter BS per bone. ** <i>P<</i>0.01, **** <i>P<</i>0.001, using a one-way ANOVA with a Newman-Keuls multiple comparison test.</p>", "links"=>[], "tags"=>["therapeutic", "2me2", "sd-208", "additively", "decreases", "metastases"], "article_id"=>557154, "categories"=>["Medicine", "Plant Biology", "Biochemistry"], "users"=>["Lauren K. Dunn", "Khalid S. Mohammad", "Pierrick G. J. Fournier", "C. Ryan McKenna", "Holly W. Davis", "Maria Niewolna", "Xiang Hong Peng", "John M. Chirgwin", "Theresa A. Guise"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0006896.g013", "stats"=>{"downloads"=>1, "page_views"=>9, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Combined_therapeutic_treatment_with_2ME2_and_SD_208_additively_decreases_bone_metastases_in_mice_/557154", "title"=>"Combined therapeutic treatment with 2ME2 and SD-208 additively decreases bone metastases in mice.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2009-09-03 01:59:14"}
  • {"files"=>["https://ndownloader.figshare.com/files/885467"], "description"=>"<p>(A) Representative x-ray images from hindlimbs of mice 4 weeks post inoculation with MDA-MB-231 parental, shNT and shHIF cells. Arrows indicate osteolytic lesions. (B) Osteolytic lesion area measured on radiographs of hindlimbs and forelimbs of mice with bone metastases. Results are expressed as the mean area ± SEM per mouse (n = 5–10 per group). † <i>P<</i>0.01 and * <i>P<</i>0.001 compared to parental or shNT clones using a two-way ANOVA with a Bonferroni post-test at 4 weeks. (C) Kaplan-Meyer analysis of mouse survival. * <i>P<</i>0.05 shHIF#3 compared to Parental or shNT clones, † <i>P<</i>0.005 and ‡ <i>P = </i>0.089 shHIF#11 respectively compared to Parental and shNT#7 using a Logrank test. (D) Representative histology of femurs with tumor indicated by arrows. Scale bar equal to 500 µm. (E) Tumor burden in hindlimbs was measured by quantitative histomorphometry. Results are expressed as the mean ± SEM area per bone. A one-way ANOVA with a Newman-Keuls multiple comparison test showed no significant differences (<i>N.S.</i>) between groups.</p>", "links"=>[], "tags"=>["decreases", "osteolytic", "lesions", "improves", "mice"], "article_id"=>555905, "categories"=>["Medicine", "Plant Biology", "Biochemistry"], "users"=>["Lauren K. Dunn", "Khalid S. Mohammad", "Pierrick G. J. Fournier", "C. Ryan McKenna", "Holly W. Davis", "Maria Niewolna", "Xiang Hong Peng", "John M. Chirgwin", "Theresa A. Guise"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0006896.g005", "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Knockdown_of_HIF_1_decreases_osteolytic_lesions_and_improves_survival_of_mice_in_vivo_/555905", "title"=>"Knockdown of HIF-1α decreases osteolytic lesions and improves survival of mice <i>in vivo</i>.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2009-09-03 01:38:25"}
  • {"files"=>["https://ndownloader.figshare.com/files/886822"], "description"=>"<p>Number of hits returned from a Pubmed literature search conducted in February 2009 for the name of each gene with the keywords TGF-β and/or hypoxia. Asterisk (<sup>*</sup>) indicates genes for which regulation by these pathways has been published.</p>", "links"=>[], "tags"=>["metastases", "genes", "hypoxia"], "article_id"=>557266, "categories"=>["Medicine", "Plant Biology", "Biochemistry"], "users"=>["Lauren K. Dunn", "Khalid S. Mohammad", "Pierrick G. J. Fournier", "C. Ryan McKenna", "Holly W. Davis", "Maria Niewolna", "Xiang Hong Peng", "John M. Chirgwin", "Theresa A. Guise"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0006896.t001", "stats"=>{"downloads"=>0, "page_views"=>1, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Regulation_of_bone_metastases_genes_by_hypoxia_and_TGF_946_/557266", "title"=>"Regulation of bone metastases genes by hypoxia and TGF-β.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2009-09-03 02:01:06"}
  • {"files"=>["https://ndownloader.figshare.com/files/885716"], "description"=>"<p>(A) Representative sections from mice with bone metastases stained for the endothelial cell marker CD31. Arrows indicate CD31+ vessels. Scale bar equals 50 µm (B) The number of vessels in bone metastases was counted in three non-overlapping fields at 200×magnification per mouse (n = 3 per group). Results are expressed as the mean ± SEM number of vessel per tumor area. * <i>P<</i>0.05, ** <i>P<</i>0.01, **** <i>P<</i>0.001, using a one-way ANOVA with a Newman-Keuls multiple comparison test.</p>", "links"=>[], "tags"=>["knockdown", "decreases", "angiogenesis", "sites", "metastases"], "article_id"=>556162, "categories"=>["Medicine", "Plant Biology", "Biochemistry"], "users"=>["Lauren K. Dunn", "Khalid S. Mohammad", "Pierrick G. J. Fournier", "C. Ryan McKenna", "Holly W. Davis", "Maria Niewolna", "Xiang Hong Peng", "John M. Chirgwin", "Theresa A. Guise"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0006896.g007", "stats"=>{"downloads"=>0, "page_views"=>2, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_HIF_1_945_knockdown_decreases_tumor_angiogenesis_at_sites_of_bone_metastases_in_mice_/556162", "title"=>"HIF-1α knockdown decreases tumor angiogenesis at sites of bone metastases in mice.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2009-09-03 01:42:42"}
  • {"files"=>["https://ndownloader.figshare.com/files/885824"], "description"=>"<p>(A) MDA-MB-231 dominant-negative TβRII expressing cells (DNRII) were transfected with a pLKO.1 vector expressing a non-target shRNA (DNRII/shNT#2 and #4) or an shRNA against HIF-1α (DNRII/shHIF#22 and #26) were cultured ± 1% O<sub>2</sub> during 6 h. Total RNA was extracted and mean ± SEM expression of HIF-1α was measured using semi-quantitative RT-PCR (n = 3). * <i>P</i><0.05 compared to parental (P), using an unpaired Student's t test. (B) Proteins were extracted from treated cells and HIF-1α level was assayed by Western-blotting. α-tubulin was used as loading control. (C) MDA-MB-231 parental cells (P) and DNRII clones were treated ± TGF-β (5 ng/mL) for 2 h. Proteins were extracted and analyzed for phosphorylated Smad2 (pSmad2) and total Smad2 by Western-blotting. (D) MDA-MB-231 parental cells (P) and DNRII clones transfected with pGL3-(CAGA)<sub>9</sub> and phRL-CMV plasmids were treated ± TGF-β (5 ng/mL) during 24 h before measuring dual-luciferase activity. Results are expressed as the mean ± SEM of the relative luciferase activity (n = 3). **** <i>P</i><0.001, using an unpaired Student's t test. (E) Total RNA was extracted from MDA-MB-231 parental (P) and DNRII clones treated ± TGF-β (5 ng/mL) and ± 1% O<sub>2</sub> during 24 h. Mean ± SEM VEGF and CXCR4 expression was measured using semi-quantitative RT-PCR (n = 3). * <i>P</i><0.05, ** <i>P</i><0.01, *** <i>P</i><0.005, using an unpaired Student's t test.</p>", "links"=>[], "tags"=>["knockdown", "blockade", "decreases", "vegf", "cxcr4", "mrna"], "article_id"=>556266, "categories"=>["Medicine", "Plant Biology", "Biochemistry"], "users"=>["Lauren K. Dunn", "Khalid S. Mohammad", "Pierrick G. J. Fournier", "C. Ryan McKenna", "Holly W. Davis", "Maria Niewolna", "Xiang Hong Peng", "John M. Chirgwin", "Theresa A. Guise"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0006896.g008", "stats"=>{"downloads"=>0, "page_views"=>1, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_HIF_1_knockdown_and_TGF_blockade_decreases_VEGF_and_CXCR4_mRNA_expression_in_vitro_/556266", "title"=>"HIF-1α knockdown and TGF-β blockade decreases VEGF and CXCR4 mRNA expression <i>in vitro</i>.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2009-09-03 01:44:26"}
  • {"files"=>["https://ndownloader.figshare.com/files/884908"], "description"=>"<p>(A) MDA-MB-231, PC-3 and 1205Lu cells were treated with 2ME2 and cultured ± 1% O<sub>2</sub> during 6 h. Protein lysates from the treated cells were analyzed for HIF-1α protein expression by Western blotting. α-tubulin was used as loading control. (B) Representative demineralized bone sections from mice with MDA-MB-231 bone metastases stained for tumor hypoxia with Hypoxyprobe<sup>TM</sup>-1 (HP), with an antibody against HIF-1α, or with hematoxylin and eosin (H&E). Arrows indicate HIF-1α positive nuclei. Images are at 200×magnification with scale bar equal to 100 µm, inset is at 630×magnification with scale bar equal to 50 µm. Staining without primary antibody was used as negative control.</p>", "links"=>[], "tags"=>["induces", "bone-metastatic", "cancer", "cells", "metastases"], "article_id"=>555351, "categories"=>["Medicine", "Plant Biology", "Biochemistry"], "users"=>["Lauren K. Dunn", "Khalid S. Mohammad", "Pierrick G. J. Fournier", "C. Ryan McKenna", "Holly W. Davis", "Maria Niewolna", "Xiang Hong Peng", "John M. Chirgwin", "Theresa A. Guise"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0006896.g001", "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Hypoxia_induces_HIF_1_in_bone_metastatic_cancer_cells_in_vitro_and_in_bone_metastases_in_vivo_/555351", "title"=>"Hypoxia induces HIF-1α in bone-metastatic cancer cells <i>in vitro</i> and in bone metastases <i>in vivo</i>.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2009-09-03 01:29:11"}
  • {"files"=>["https://ndownloader.figshare.com/files/885363"], "description"=>"<p>(A) MDA-MB-231 parental cells (P) or cells transfected with a pLKO.1 vector expressing a non-target shRNA (shNT#3 and #7) or an shRNA against HIF-1α (shHIF#3 and #11) were cultured ± 1% O<sub>2</sub> during 6 h. Total RNA was extracted and mean ± SEM expression of HIF-1α was measured using semi-quantitative RT-PCR (n = 3). Proteins were extracted from treated cells and HIF-1α level was assayed by Western-blotting, α-tubulin was used as loading control. * <i>P</i><0.05, using an unpaired Student's t test. (B) Parental (P) cells and shNT and shHIF clones were treated ± TGF-β (5 ng/mL) ± 1% O<sub>2</sub> for 24 h. Total RNA was extracted and mean ± SEM VEGF and CXCR4 expression was measured using semi-quantitative RT-PCR (n = 3). * <i>P<</i>0.05, ** <i>P<</i>0.01, **** <i>P<</i>0.001, using an unpaired Student's t test. (C) MDA-MB-231 parental (P) cells and clones were treated ± TGF-β (5 ng/mL) ± 1% O<sub>2</sub> and conditioned media were collected 24 h later. VEGF-A levels were measured by ELISA assay. Results are expressed as mean ± SEM nanograms VEGF-A per 10<sup>6</sup> cells. **** <i>P<</i>0.001, using an unpaired Student's t test. (D) MDA-MB-231 parental (P) cells and clones were treated ± 1% O<sub>2</sub> for 24 h and then analyzed by flow cytometry for CXCR4 protein expression. Results are reported as the percentage of maximal CXCR4 expression.</p>", "links"=>[], "tags"=>["inhibits", "vegf", "cxcr4", "mrna"], "article_id"=>555800, "categories"=>["Medicine", "Plant Biology", "Biochemistry"], "users"=>["Lauren K. Dunn", "Khalid S. Mohammad", "Pierrick G. J. Fournier", "C. Ryan McKenna", "Holly W. Davis", "Maria Niewolna", "Xiang Hong Peng", "John M. Chirgwin", "Theresa A. Guise"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0006896.g004", "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Knockdown_of_HIF_1_inhibits_VEGF_and_CXCR4_mRNA_and_protein_expression_in_vitro_/555800", "title"=>"Knockdown of HIF-1α inhibits VEGF and CXCR4 mRNA and protein expression <i>in vitro</i>.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2009-09-03 01:36:40"}
  • {"files"=>["https://ndownloader.figshare.com/files/885056"], "description"=>"<p>(A) MDA-MB-231 cells were cultured ± TGF-β (5 ng/mL) ± 1% O<sub>2</sub> during 24 h and total RNA was extracted. VEGF and CXCR4 mRNA expression (mean ± SEM) was measured by semi-quantitative RT-PCR (n = 3). * <i>P<</i>0.05, *** <i>P<</i>0.005, **** <i>P<</i>0.001, using an unpaired Student's t test. (B) HepG2 hepatocarcinoma cells co-transfected with a renilla luciferase plasmid (phRL-CMV) and a pGL3 plasmid containing a fragment of the human VEGF (3.3 kb) or CXCR4 (2.6 kb) promoter, or the TGF-β-sensitive (CAGA)<sub>9</sub> promoter were treated ± TGF-β (5 ng/mL) and ± 1% O<sub>2</sub> during 24 h before measuring dual-luciferase activity. (C) MDA-MB-231 breast cancer cells were transfected with a pGL3 plasmid containing the human VEGF or CXCR4 promoter and the phRL-CMV plasmid, as well as plasmids to overexpress HIF-1α and/or Smad2, 3 and 4. Cells were treated ± TGF-β (5 ng/mL) ± 1% O<sub>2</sub> during 24 h before measuring dual-luciferase activity. Results are expressed as the mean ± SEM (n = 3) of the relative luciferase activity. * <i>P</i><0.05, ** <i>P</i><0.01, *** <i>P</i><0.005, **** <i>P</i><0.001, using an unpaired Student's t test.</p>", "links"=>[], "tags"=>["vegf", "cxcr4", "mrna", "promoter"], "article_id"=>555507, "categories"=>["Medicine", "Plant Biology", "Biochemistry"], "users"=>["Lauren K. Dunn", "Khalid S. Mohammad", "Pierrick G. J. Fournier", "C. Ryan McKenna", "Holly W. Davis", "Maria Niewolna", "Xiang Hong Peng", "John M. Chirgwin", "Theresa A. Guise"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0006896.g002", "stats"=>{"downloads"=>0, "page_views"=>1, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Hypoxia_and_TGF_946_increase_VEGF_and_CXCR4_mRNA_expression_and_promoter_activity_/555507", "title"=>"Hypoxia and TGF-β increase VEGF and CXCR4 mRNA expression and promoter activity.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2009-09-03 01:31:47"}
  • {"files"=>["https://ndownloader.figshare.com/files/886232"], "description"=>"<p>(A) Representative 4-week x-rays from mice inoculated with MDA-MB-231 cells and treated ± 2ME2 (150 mg/kg), arrows indicate osteolytic lesions. Osteolytic lesion area was measured on radiographs of hindlimbs and forelimbs of mice with bone metastases. Results are expressed as the mean ± SEM area per mouse (n = 10–12 per group). * <i>P<</i>0.01 using a two-way ANOVA with a Bonferroni post-test at 4 weeks. (B) Representative histology of tibias with tumor indicated by arrows. Scale bar equal to 500 µm. Tumor burden in hindlimbs and humeri was measured by quantitative histomorphometry. Results are expressed as the mean ± SEM area per bone, analysis by unpaired Student's t test. (C) Representative HIF-1α staining in demineralized bone metastases sections from mice treated ± 2ME2. Arrows indicate HIF-1α positive nuclei. Scale bar equals 25 µm. The percentage of nuclei positive for HIF-1α was calculated in three non-overlapping fields at 400×magnification for each mouse (n = 6 per group). Results are the mean ± SEM number of HIF-1α positive nuclei per field using an unpaired Student's t test. (D) Hypoxyprobe<sup>TM</sup>-1 staining for tumor hypoxia in bone metastases sections. Hypoxic regions indicated by asterisks. Staining was graded on a 1–4+ scale in three non-overlapping fields at 400×magnification per mouse (n = 3 per group). Results are the mean ± SEM staining per field using an unpaired Student's t test.</p>", "links"=>[], "tags"=>["inhibitor", "2me2", "inhibits", "metastases"], "article_id"=>556678, "categories"=>["Medicine", "Plant Biology", "Biochemistry"], "users"=>["Lauren K. Dunn", "Khalid S. Mohammad", "Pierrick G. J. Fournier", "C. Ryan McKenna", "Holly W. Davis", "Maria Niewolna", "Xiang Hong Peng", "John M. Chirgwin", "Theresa A. Guise"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0006896.g010", "stats"=>{"downloads"=>1, "page_views"=>13, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Preventive_treatment_with_the_HIF_1_945_inhibitor_2ME2_inhibits_bone_metastases_in_mice_/556678", "title"=>"Preventive treatment with the HIF-1α inhibitor 2ME2 inhibits bone metastases in mice.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2009-09-03 01:51:18"}
  • {"files"=>["https://ndownloader.figshare.com/files/886024"], "description"=>"<p>(A) Representative x-ray images from hindlimbs of mice 4 weeks post inoculation with MDA-MB-231 parental, shNT#3, shHIF#3, DNRII, DNRII/shNT#2 and DNRII/shHIF#22 cells. Arrows indicate osteolytic lesions. (B) Osteolytic lesion area measured on radiographs of hindlimbs and forelimbs of mice with bone metastases. Results are expressed as the mean area ± SEM per mouse (n = 6–11 per group). * <i>P<</i>0.001 compared to parental and † <i>P<</i>0.05 compared to shNT#3 using a two-way ANOVA with a Bonferroni post-test at 3 weeks. (C) Kaplan-Meyer analysis of mouse survival. * <i>P<</i>0.001 shHIF#3 and DNRII compared to Parental and † <i>P<</i>0.005 shHIF#3 compared to shNT#3 using a Logrank test. (D) Tumor burden in hindlimbs was measured by quantitative histomorphometry. Results are expressed as the mean ± SEM area per bone. A one-way ANOVA with a Newman-Keuls multiple comparison test showed no significant differences (<i>N.S.</i>) between groups.</p>", "links"=>[], "tags"=>["knockdown", "blockade", "provides", "further", "mice"], "article_id"=>556466, "categories"=>["Medicine", "Plant Biology", "Biochemistry"], "users"=>["Lauren K. Dunn", "Khalid S. Mohammad", "Pierrick G. J. Fournier", "C. Ryan McKenna", "Holly W. Davis", "Maria Niewolna", "Xiang Hong Peng", "John M. Chirgwin", "Theresa A. Guise"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0006896.g009", "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Combined_HIF_1_945_knockdown_and_TGF_946_blockade_provides_no_further_benefit_in_mice_with_bone_metastases_/556466", "title"=>"Combined HIF-1α knockdown and TGF-β blockade provides no further benefit in mice with bone metastases.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2009-09-03 01:47:46"}

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