In Vivo “MRI Phenotyping” Reveals Changes in Extracellular Matrix Transport and Vascularization That Mediate VEGF-Driven Increase in Breast Cancer Metastasis
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{"title"=>"In Vivo \"MRI Phenotyping\" Reveals Changes in Extracellular Matrix Transport and Vascularization That Mediate VEGF-Driven Increase in Breast Cancer Metastasis", "type"=>"journal", "authors"=>[{"first_name"=>"Arvind P.", "last_name"=>"Pathak", "scopus_author_id"=>"7103002119"}, {"first_name"=>"Stephen", "last_name"=>"McNutt", "scopus_author_id"=>"36815161900"}, {"first_name"=>"Tariq", "last_name"=>"Shah", "scopus_author_id"=>"15756552000"}, {"first_name"=>"Flonne", "last_name"=>"Wildes", "scopus_author_id"=>"8613546800"}, {"first_name"=>"Venu", "last_name"=>"Raman", "scopus_author_id"=>"7101864763"}, {"first_name"=>"Zaver M.", "last_name"=>"Bhujwalla", "scopus_author_id"=>"7005605195"}], "year"=>2013, "source"=>"PLoS ONE", "identifiers"=>{"pmid"=>"23650550", "doi"=>"10.1371/journal.pone.0063146", "pui"=>"368847413", "issn"=>"19326203", "sgr"=>"84877079040", "scopus"=>"2-s2.0-84877079040"}, "id"=>"d95e8674-eee7-3598-b288-4baf673768c0", "abstract"=>"PURPOSE: To gain new insights into the relationship between angiogenic factors in breast cancer and their effect on extracellular matrix (ECM) remodeling and metastasis, we characterized and validated the \"metastatic signature\" of human breast cancer cell lines engineered to overexpress VEGF in terms of in vivo MRI-derived angiogenesis and ECM transport parameters. METHODOLOGY: MRI was used to evaluate the effects of overexpressing VEGF-A (VEGF165) on tumor angiogenesis and ECM remodeling in vivo, for two differentially metastatic human breast cancer cell lines: MCF-7 and MDA-MB-231. PRINCIPAL FINDINGS: Overexpression of VEGF elevated vascular volume in both MCF-7-VEGF and MDA-MB-231-VEGF tumors relative to their wild-type counterparts, but vascular permeability was elevated only in MCF-7-VEGF tumors. A significant increase in the volume of extravascular fluid drained as well as the number of ECM drainage voxels was detected in MCF-7-VEGF tumors relative to MCF-7 tumors, but not in MDA-MB-231-VEGF versus MDA-MB-231 tumors. The angiogenic effects of VEGF overexpression in both MCF-7-VEGF and MDA-MB-231-VEGF tumors were validated histologically. MCF-7-VEGF tumors exhibited enhanced invasion and a greater fraction of cancer positive lungs and lymph nodes relative to MCF-7 tumors. CONCLUSIONS AND SIGNIFICANCE: In vivo MRI and histological data demonstrate that VEGF overexpression results in the progression of noninvasive MCF-7 and invasive MDA-MB-321 tumors to a more angiogenic phenotype. However, VEGF overexpression significantly altered ECM integrity only in MCF-7 tumors, causing them to progress to an invasive and metastatic phenotype. This study for the first time demonstrates the concurrent effects of VEGF overexpression and ECM remodeling on metastasis in vivo. Collectively, these findings demonstrate that in vivo MRI can non-invasively monitor changes in the tumor microenvironment that can potentially predict a cancer's ability to metastasize.", "link"=>"http://www.mendeley.com/research/vivo-mri-phenotyping-reveals-changes-extracellular-matrix-transport-vascularization-mediate-vegfdriv", "reader_count"=>18, "reader_count_by_academic_status"=>{"Professor > Associate Professor"=>1, "Researcher"=>5, "Student > Ph. D. Student"=>5, "Student > Postgraduate"=>1, "Student > Master"=>3, "Professor"=>1, "Unspecified"=>2}, "reader_count_by_user_role"=>{"Professor > Associate Professor"=>1, "Researcher"=>5, "Student > Ph. D. Student"=>5, "Student > Postgraduate"=>1, "Student > Master"=>3, "Professor"=>1, "Unspecified"=>2}, "reader_count_by_subject_area"=>{"Engineering"=>3, "Biochemistry, Genetics and Molecular Biology"=>2, "Medicine and Dentistry"=>2, "Agricultural and Biological Sciences"=>6, "Physics and Astronomy"=>1, "Computer Science"=>1, "Neuroscience"=>1, "Unspecified"=>2}, "reader_count_by_subdiscipline"=>{"Engineering"=>{"Engineering"=>3}, "Medicine and Dentistry"=>{"Medicine and Dentistry"=>2}, "Neuroscience"=>{"Neuroscience"=>1}, "Physics and Astronomy"=>{"Physics and Astronomy"=>1}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>6}, "Computer Science"=>{"Computer Science"=>1}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>2}, "Unspecified"=>{"Unspecified"=>2}}, "reader_count_by_country"=>{"United States"=>1, "Taiwan"=>1}, "group_count"=>1}

Scopus | Further Information

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/1050164"], "description"=>"<p>Representative functional MRI maps of the vascular volume from: (a) MDA-MB-231 and (b) MDA-MB-231 VEGF overexpressing tumor bearing animals. (c) Box-and-whisker plot comparing the vascular volume between MDA-MB-231 (n = 5) and MDA-MB-231-VEGF (n = 4) xenografts (*p = 0.0159 with the two-tailed Mann-Whitney U Test). Representative functional MRI maps of the permeability-surface area product from: (d) MDA-MB-231 and (e) MDA-MB-231 VEGF overexpressing tumor-bearing animals. (f) Box-and-whisker plot comparing the permeability-surface area product between MDA-MB-231 (n = 5) and MDA-MB-231-VEGF (n = 4) xenografts.</p>", "links"=>[], "tags"=>["Molecular cell biology", "Cellular types", "Endothelial cells", "Extracellular matrix", "Extracellular matrix composition", "cardiovascular", "Vascular biology", "Obstetrics and gynecology", "breast cancer", "oncology", "Basic cancer research", "metastasis", "Cancer detection and diagnosis", "radiology", "Diagnostic radiology", "Magnetic resonance imaging", "mri", "reveals", "vegf", "overexpression", "alters", "angiogenic", "phenotype", "mda-mb-231"], "article_id"=>695136, "categories"=>["Medicine", "Biological Sciences"], "users"=>["Arvind P. Pathak", "Stephen McNutt", "Tariq Shah", "Flonne Wildes", "Venu Raman", "Zaver M. Bhujwalla"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0063146.g004", "stats"=>{"downloads"=>1, "page_views"=>6, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_In_vivo_MRI_reveals_VEGF_overexpression_alters_the_angiogenic_phenotype_of_MDA_MB_231_tumors_/695136", "title"=>"<i>In vivo</i> MRI reveals VEGF overexpression alters the angiogenic phenotype of MDA-MB-231 tumors.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-05-01 01:25:36"}
  • {"files"=>["https://ndownloader.figshare.com/files/1050168"], "description"=>"<p>Representative (40×) images of H&E stained lung sections from: (a) MCF-7, (b) MCF-7-VEGF, (c) MDA-MB-231 and (d) MDA-MB-231-VEGF tumor bearing animals. Cancer cells are indicated by solid arrows in each panel. (e) Comparison of the number of animals with cancer positive (CA <i>+ve</i>) and cancer negative (CA <i>-ve</i>) lungs for each type of breast cancer xenograft. Representative (40×) images of H&E stained lymph node sections from: (f) MCF-7, (g) MCF-7-VEGF, (h) MDA-MB-231 and (i) MDA-MB-231-VEGF tumor bearing animals. Cancer cells are indicated by solid arrows in each panel. (j) Comparison of the number of animals with cancer positive (CA <i>+ve</i>) and cancer negative (CA <i>-ve</i>) lymph nodes for each type of breast cancer xenograft.</p>", "links"=>[], "tags"=>["Molecular cell biology", "Cellular types", "Endothelial cells", "Extracellular matrix", "Extracellular matrix composition", "cardiovascular", "Vascular biology", "Obstetrics and gynecology", "breast cancer", "oncology", "Basic cancer research", "metastasis", "Cancer detection and diagnosis", "radiology", "Diagnostic radiology", "Magnetic resonance imaging", "validation", "non-invasive", "mcf-7", "tumors", "metastatic", "phenotype", "vegf"], "article_id"=>695139, "categories"=>["Medicine", "Biological Sciences"], "users"=>["Arvind P. Pathak", "Stephen McNutt", "Tariq Shah", "Flonne Wildes", "Venu Raman", "Zaver M. Bhujwalla"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0063146.g007", "stats"=>{"downloads"=>0, "page_views"=>5, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Histological_validation_of_the_transformation_of_non_invasive_MCF_7_tumors_to_the_metastatic_phenotype_following_VEGF_overexpression_/695139", "title"=>"Histological validation of the transformation of non-invasive MCF-7 tumors to the metastatic phenotype following VEGF overexpression.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-05-01 01:25:39"}
  • {"files"=>["https://ndownloader.figshare.com/files/1050166"], "description"=>"<p>Representative functional MRI maps of the volume of extravascular fluid drained from: (a) MCF-7 and (b) MCF-7-VEGF overexpressing tumor xenografts. (c) Box-and-whisker plot comparing the volume drained between MCF-7 (n = 5) and MCF-7-VEGF (n = 5) xenografts (*p = 0.0277 with the one-tailed Mann-Whitney U Test). Representative functional MRI maps of the volume of extravascular fluid drained from: (d) MDA-MB-231 and (e) MDA-MB-231-VEGF overexpressing tumor xenografts. (f) Box-and-whisker plot comparing the volume drained between MDA-MB-231 (n = 5) and MDA-MB-23-VEGF (n = 4) xenografts.</p>", "links"=>[], "tags"=>["Molecular cell biology", "Cellular types", "Endothelial cells", "Extracellular matrix", "Extracellular matrix composition", "cardiovascular", "Vascular biology", "Obstetrics and gynecology", "breast cancer", "oncology", "Basic cancer research", "metastasis", "Cancer detection and diagnosis", "radiology", "Diagnostic radiology", "Magnetic resonance imaging", "mri", "reveals", "vegf", "overexpression", "alters", "ecm", "mcf-7"], "article_id"=>695138, "categories"=>["Medicine", "Biological Sciences"], "users"=>["Arvind P. Pathak", "Stephen McNutt", "Tariq Shah", "Flonne Wildes", "Venu Raman", "Zaver M. Bhujwalla"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0063146.g006", "stats"=>{"downloads"=>0, "page_views"=>4, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_In_vivo_MRI_reveals_VEGF_overexpression_alters_the_ECM_of_MCF_7_tumors_/695138", "title"=>"<i>In vivo</i> MRI reveals VEGF overexpression alters the ECM of MCF-7 tumors.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-05-01 01:25:38"}
  • {"files"=>["https://ndownloader.figshare.com/files/1050161"], "description"=>"<p>(a) Representative MR images of Matrigel® acquired from a MR compatible perfusion chamber over 48 h, which demonstrate significant Matrigel® degradation by MCF-7-VEGF (lower panel) cells in contrast to MCF-7 cells. (b) The time-dependent invasion indices showed a significant (*p = 0.024, p = 0.026 and p = 0.025, respectively with the two-tailed Aspin-Welch Unequal-Variance Test) increase in invasion by MCF-7-VEGF cells compared to MCF-7cells, at 1, 1.5 and 2 days.</p>", "links"=>[], "tags"=>["Molecular cell biology", "Cellular types", "Endothelial cells", "Extracellular matrix", "Extracellular matrix composition", "cardiovascular", "Vascular biology", "Obstetrics and gynecology", "breast cancer", "oncology", "Basic cancer research", "metastasis", "Cancer detection and diagnosis", "radiology", "Diagnostic radiology", "Magnetic resonance imaging", "overexpression", "invasiveness", "mcf-7"], "article_id"=>695133, "categories"=>["Medicine", "Biological Sciences"], "users"=>["Arvind P. Pathak", "Stephen McNutt", "Tariq Shah", "Flonne Wildes", "Venu Raman", "Zaver M. Bhujwalla"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0063146.g002", "stats"=>{"downloads"=>0, "page_views"=>3, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_VEGF_overexpression_increases_the_invasiveness_of_MCF_7_cells_/695133", "title"=>"VEGF overexpression increases the invasiveness of MCF-7 cells.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-05-01 01:25:33"}
  • {"files"=>["https://ndownloader.figshare.com/files/1050160"], "description"=>"<p>(a) Box-and-whisker plot comparing the VEGF expression levels (expressed on a logarithmic scale) assessed in lysates from MCF-7 and MCF-7-VEGF overexpressing tumors (*p = 0.007 with the one-tailed Mann-Whitney U Test), and from MDA-MB-231 and MDA-MB-231-VEGF overexpressing tumors (*p = 0.0476 with the one-tailed Mann-Whitney U Test), respectively.</p>", "links"=>[], "tags"=>["Molecular cell biology", "Cellular types", "Endothelial cells", "Extracellular matrix", "Extracellular matrix composition", "cardiovascular", "Vascular biology", "Obstetrics and gynecology", "breast cancer", "oncology", "Basic cancer research", "metastasis", "Cancer detection and diagnosis", "radiology", "Diagnostic radiology", "Magnetic resonance imaging", "cancer", "lines", "overexpressing"], "article_id"=>695132, "categories"=>["Medicine", "Biological Sciences"], "users"=>["Arvind P. Pathak", "Stephen McNutt", "Tariq Shah", "Flonne Wildes", "Venu Raman", "Zaver M. Bhujwalla"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0063146.g001", "stats"=>{"downloads"=>0, "page_views"=>2, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Generation_of_human_breast_cancer_cell_lines_overexpressing_VEGF_/695132", "title"=>"Generation of human breast cancer cell lines overexpressing VEGF.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-05-01 01:25:32"}
  • {"files"=>["https://ndownloader.figshare.com/files/1050169"], "description"=>"<p>Scatter plots of permeability-surface area (PS) product <i>versus</i> vascular volume (VV) for each tumor type, in which each symbol is scaled according to the volume of extravascular fluid drained. The vertical lines represent the mean value of VV for each tumor type, while the horizontal lines represent the mean value of PS for each tumor type. (a) Scatter plot of parameters measured <i>in vivo</i> from MCF-7 (n = 5) and MCF-7-VEGF (n = 5) tumors reveal a trend in the MCF-7-VEGF group towards elevated PS and VV values (gray crosshairs) in conjunction with greater extravascular fluid drainage (larger symbol size) – which collectively indicate the progression of the original MCF-7 phenotype to a metastatic one. In contrast, (b) a scatter plot of parameters measured <i>in vivo</i> from MDA-MB-231 (n = 5) and MDA-MB-231-VEGF (n = 4) tumors does not show this trend, but shows the elevation of VV in the MDA-MB-231-VEGF tumors.</p>", "links"=>[], "tags"=>["Molecular cell biology", "Cellular types", "Endothelial cells", "Extracellular matrix", "Extracellular matrix composition", "cardiovascular", "Vascular biology", "Obstetrics and gynecology", "breast cancer", "oncology", "Basic cancer research", "metastasis", "Cancer detection and diagnosis", "radiology", "Diagnostic radiology", "Magnetic resonance imaging", "reveals", "progression", "non-invasive", "mcf-7", "cancer", "metastatic", "phenotype", "driven", "vegf"], "article_id"=>695140, "categories"=>["Medicine", "Biological Sciences"], "users"=>["Arvind P. Pathak", "Stephen McNutt", "Tariq Shah", "Flonne Wildes", "Venu Raman", "Zaver M. Bhujwalla"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0063146.g008", "stats"=>{"downloads"=>0, "page_views"=>1, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_8220_MRI_phenotyping_8221_reveals_progression_of_the_non_invasive_MCF_7_human_breast_cancer_model_to_the_metastatic_phenotype_is_driven_by_VEGF_overexpression_/695140", "title"=>"“MRI phenotyping” reveals progression of the non-invasive MCF-7 human breast cancer model to the metastatic phenotype is driven by VEGF overexpression.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-05-01 01:25:40"}
  • {"files"=>["https://ndownloader.figshare.com/files/1050165"], "description"=>"<p>(a) Box-and-whisker plot comparing the stereologically assessed fractional blood vessel area between MCF-7 and MCF-7-VEGF xenografts (*p = 0.0476 with the one-tailed Mann-Whitney U Test). Representative fluorescence (CD34-red, DAPI-blue) photomicrographs (20×) from: (b) MCF-7, and (c) MCF-7-VEGF tumor sections illustrating the difference in the fractional area of CD34 stained blood vessels. (d) Box-and-whisker plot comparing the stereologically assessed fractional vessel area between MDA-MB-231 and MDA-MB-231-VEGF xenografts (*p = 0.0012 with the one-tailed Mann-Whitney U Test). Representative fluorescence (CD34-red, DAPI-blue) photomicrographs (20×) from: (b) MDA-MB-231, and (c) MDA-MB-231-VEGF tumor sections illustrating the difference in the fractional area of CD34 stained blood vessels.</p>", "links"=>[], "tags"=>["Molecular cell biology", "Cellular types", "Endothelial cells", "Extracellular matrix", "Extracellular matrix composition", "cardiovascular", "Vascular biology", "Obstetrics and gynecology", "breast cancer", "oncology", "Basic cancer research", "metastasis", "Cancer detection and diagnosis", "radiology", "Diagnostic radiology", "Magnetic resonance imaging", "validation", "vegf-induced", "alterations", "angiogenic"], "article_id"=>695137, "categories"=>["Medicine", "Biological Sciences"], "users"=>["Arvind P. Pathak", "Stephen McNutt", "Tariq Shah", "Flonne Wildes", "Venu Raman", "Zaver M. Bhujwalla"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0063146.g005", "stats"=>{"downloads"=>0, "page_views"=>3, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Immunofluorescent_validation_of_VEGF_induced_alterations_in_the_angiogenic_phenotype_/695137", "title"=>"Immunofluorescent validation of VEGF-induced alterations in the angiogenic phenotype.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-05-01 01:25:37"}
  • {"files"=>["https://ndownloader.figshare.com/files/1050163"], "description"=>"<p>Representative functional MRI maps of the vascular volume from: (a) MCF-7 and (b) MCF-7 VEGF overexpressing tumor bearing animals. (c) Box-and-whisker plot comparing the vascular volume between MCF-7 (n = 10) and MCF-7-VEGF (n = 12) xenografts. The length of each box is the interquartile range (IQR), while the line through the middle of each box is the median value. The T-shaped lines extending from each end of the box represent the upper adjacent value (i.e. the largest observation ≤ 75th percentile+1.5×IQR) and the lower adjacent value (i.e. the smallest observation ≤ 25th percentile–1.5×IQR), and gray dots denote values outside this range (*p = 0.000059 with the two-tailed Mann-Whitney U Test). Representative functional MRI maps of the permeability-surface area product from: (d) MCF-7 and (e) MCF-7 VEGF overexpressing tumor-bearing animals. (f) Box-and-whisker plot comparing the permeability-surface area product between MCF-7 (n = 10) and MCF-7-VEGF (n = 12) xenografts (*p = 0.0026 with the two-tailed Mann-Whitney U Test).</p>", "links"=>[], "tags"=>["Molecular cell biology", "Cellular types", "Endothelial cells", "Extracellular matrix", "Extracellular matrix composition", "cardiovascular", "Vascular biology", "Obstetrics and gynecology", "breast cancer", "oncology", "Basic cancer research", "metastasis", "Cancer detection and diagnosis", "radiology", "Diagnostic radiology", "Magnetic resonance imaging", "mri", "reveals", "vegf", "overexpression", "alters", "angiogenic", "phenotype", "mcf-7"], "article_id"=>695135, "categories"=>["Medicine", "Biological Sciences"], "users"=>["Arvind P. Pathak", "Stephen McNutt", "Tariq Shah", "Flonne Wildes", "Venu Raman", "Zaver M. Bhujwalla"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0063146.g003", "stats"=>{"downloads"=>0, "page_views"=>15, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_In_vivo_MRI_reveals_VEGF_overexpression_alters_the_angiogenic_phenotype_of_MCF_7_tumors_/695135", "title"=>"<i>In vivo</i> MRI reveals VEGF overexpression alters the angiogenic phenotype of MCF-7 tumors.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-05-01 01:25:35"}

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Relative Metric

{"start_date"=>"2013-01-01T00:00:00Z", "end_date"=>"2013-12-31T00:00:00Z", "subject_areas"=>[{"subject_area"=>"/Biology and life sciences/Anatomy", "average_usage"=>[248, 440, 562, 666, 765, 856, 944, 1028, 1112, 1198, 1282, 1362, 1430]}, {"subject_area"=>"/Medicine and health sciences/Anatomy", "average_usage"=>[248, 441, 564, 668, 769, 859, 948, 1034, 1117, 1202, 1290, 1368, 1437]}, {"subject_area"=>"/Medicine and health sciences/Diagnostic medicine", "average_usage"=>[244, 425, 535, 636, 728, 814, 900, 982, 1063, 1139, 1221, 1296, 1361]}, {"subject_area"=>"/Medicine and health sciences/Radiology and imaging", "average_usage"=>[230, 403, 513, 618, 711, 806, 896, 985, 1065, 1141, 1225, 1296, 1360]}, {"subject_area"=>"/Medicine and health sciences/Vascular medicine", "average_usage"=>[222, 394, 496, 593, 683, 762, 835, 910, 980, 1047, 1116, 1184, 1244]}]}
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