The Rho Exchange Factors Vav2 and Vav3 Favor Skin Tumor Initiation and Promotion by Engaging Extracellular Signaling Loops
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{"title"=>"The Rho Exchange Factors Vav2 and Vav3 Favor Skin Tumor Initiation and Promotion by Engaging Extracellular Signaling Loops", "type"=>"journal", "authors"=>[{"first_name"=>"Mauricio", "last_name"=>"Menacho-Márquez", "scopus_author_id"=>"15064287500"}, {"first_name"=>"Ramón", "last_name"=>"García-Escudero", "scopus_author_id"=>"6602471179"}, {"first_name"=>"Virginia", "last_name"=>"Ojeda", "scopus_author_id"=>"53980269300"}, {"first_name"=>"Antonio", "last_name"=>"Abad", "scopus_author_id"=>"37116381400"}, {"first_name"=>"Pilar", "last_name"=>"Delgado", "scopus_author_id"=>"55321920300"}, {"first_name"=>"Clotilde", "last_name"=>"Costa", "scopus_author_id"=>"24748337800"}, {"first_name"=>"Sergio", "last_name"=>"Ruiz", "scopus_author_id"=>"57200253260"}, {"first_name"=>"Balbino", "last_name"=>"Alarcón", "scopus_author_id"=>"7007165708"}, {"first_name"=>"Jesús M.", "last_name"=>"Paramio", "scopus_author_id"=>"6701734556"}, {"first_name"=>"Xosé R.", "last_name"=>"Bustelo", "scopus_author_id"=>"7004908425"}], "year"=>2013, "source"=>"PLoS Biology", "identifiers"=>{"issn"=>"15449173", "scopus"=>"2-s2.0-84880960770", "sgr"=>"84880960770", "pui"=>"369463001", "isbn"=>"1545-7885", "pmid"=>"23935450", "doi"=>"10.1371/journal.pbio.1001615"}, "id"=>"966420e5-fe8b-3ea3-b345-2c68152bcbd5", "abstract"=>"The catalytic activity of GDP/GTP exchange factors (GEFs) is considered critical to maintain the typically high activity of Rho GTPases found in cancer cells. However, the large number of them has made it difficult to pinpoint those playing proactive, nonredundant roles in tumors. In this work, we have investigated whether GEFs of the Vav subfamily exert such specific roles in skin cancer. Using genetically engineered mice, we show here that Vav2 and Vav3 favor cooperatively the initiation and promotion phases of skin tumors. Transcriptomal profiling and signaling experiments indicate such function is linked to the engagement of, and subsequent participation in, keratinocyte-based autocrine/paracrine programs that promote epidermal proliferation and recruitment of pro-inflammatory cells. This is a pathology-restricted mechanism because the loss of Vav proteins does not cause alterations in epidermal homeostasis. These results reveal a previously unknown Rho GEF-dependent pro-tumorigenic mechanism that influences the biology of cancer cells and their microenvironment. They also suggest that anti-Vav therapies may be of potential interest in skin tumor prevention and/or treatment.", "link"=>"http://www.mendeley.com/research/rho-exchange-factors-vav2-vav3-favor-skin-tumor-initiation-promotion-engaging-extracellular-signalin", "reader_count"=>28, "reader_count_by_academic_status"=>{"Professor > Associate Professor"=>2, "Student > Doctoral Student"=>3, "Researcher"=>5, "Student > Ph. D. Student"=>7, "Student > Master"=>5, "Other"=>1, "Student > Bachelor"=>3, "Lecturer"=>1, "Professor"=>1}, "reader_count_by_user_role"=>{"Professor > Associate Professor"=>2, "Student > Doctoral Student"=>3, "Researcher"=>5, "Student > Ph. D. Student"=>7, "Student > Master"=>5, "Other"=>1, "Student > Bachelor"=>3, "Lecturer"=>1, "Professor"=>1}, "reader_count_by_subject_area"=>{"Biochemistry, Genetics and Molecular Biology"=>10, "Agricultural and Biological Sciences"=>8, "Medicine and Dentistry"=>4, "Chemistry"=>4, "Social Sciences"=>1, "Immunology and Microbiology"=>1}, "reader_count_by_subdiscipline"=>{"Medicine and Dentistry"=>{"Medicine and Dentistry"=>4}, "Chemistry"=>{"Chemistry"=>4}, "Social Sciences"=>{"Social Sciences"=>1}, "Immunology and Microbiology"=>{"Immunology and Microbiology"=>1}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>8}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>10}}, "reader_count_by_country"=>{"Monaco"=>1}, "group_count"=>2}

Scopus | Further Information

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/1126582"], "description"=>"<p>(A) Scheme of these experiments. (B, C) Example (B; scale bar, 100 µm) and quantification (C) of apoptotic cells found in the epidermis of mice of the indicated genotypes 24 h upon the application of DMBA (<i>n</i> = 4). In (B), sections were stained with antibodies to the cleaved fragment of caspase 3 (ID number: 12367) and 14, 4′,6-diamidino-2-phenylindole (DAPI) to reveal apoptotic cells (red color) and cell nuclei (blue color), respectively. (D, E) Example (D; scale bar, 100 µm) and quantification (E) of phospho-histone H2AX<sup>+</sup> keratinocytes (brown color) present in the epidermis of short-term DMBA-treated mice of indicated genotypes (<i>n</i> = 4). p-, phosphorylated. (F) Number of apoptotic (annexin V<sup>+</sup>) wild-type and <i>Vav2</i><sup>−/−</sup>;<i>Vav3</i><sup>−/−</sup> keratinocytes induced after 8 (left panel) and 12 (right panel) h in the indicated culture conditions (<i>n</i> = 4). Bleo, bleomycin; DTT, dithiothreitol; NS, no statistically significant. (G, H) Example of a flow cytometry experiment (G) and subsequent quantification (H) of the level of apoptosis induced by either DMBA (G, H) or serum starvation (H) in wild-type and <i>Vav2</i><sup>−/−</sup>;<i>Vav3</i><sup>−/−</sup> keratinocytes ectopically expressing GFP either alone (G, H) or in combination with HA-Vav2 (H) or Myc-Vav3 (G, H) (<i>n</i> = 3). In (G), only the gated GFP<sup>+</sup> cells are shown.</p>", "links"=>[], "tags"=>["Molecular cell biology", "Signal transduction", "oncology", "Basic cancer research", "proteins", "initiation"], "article_id"=>751649, "categories"=>["Medicine", "Biological Sciences"], "users"=>["Mauricio Menacho-Márquez", "Ramon Garcia-Escudero", "Virginia Ojeda", "Antonio Abad", "Pilar Delgado", "Clotilde Costa", "Sergio Ruiz", "Balbino Alarcón", "Jesús M. Paramio", "Xosé R. Bustelo"], "doi"=>"https://dx.doi.org/10.1371/journal.pbio.1001615.g002", "stats"=>{"downloads"=>1, "page_views"=>7, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Vav_proteins_participate_in_the_initiation_phase_of_skin_tumors_/751649", "title"=>"Vav proteins participate in the initiation phase of skin tumors.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-07-23 01:36:21"}
  • {"files"=>["https://ndownloader.figshare.com/files/1126585"], "description"=>"<p>(A) Scheme of the experiments made in this section. (B–D) Example of immunofluorescence experiments (B; scale bar, 100 µm) and quantification of the hyperplasia (C, green color cells) and number of BrdU<sup>+</sup> keratinocytes (D) in the epidermis of TPA-treated mice of indicated genotypes (<i>n</i> = 6). In (B), sections were stained with antibodies to keratin 14 (ID number: 16664), DAPI, and rhodamine-phalloidin to reveal K14 (green color), cell nuclei (blue color), and F-actin (red color), respectively. TPA-1 refers to tissue samples harvested either 24 (C) or 17 (D) h after the TPA stimulation. ET, epidermal thickness. (E) Quantification of the number of BrdU<sup>+</sup> keratinocytes at the indicated times after a single topic application of TPA in animals of indicated genotypes (<i>n</i> = 3). (F) Phosphorylation and expression status of indicated proteins in the epidermis of wild-type and <i>Vav2</i><sup>−/−</sup>;<i>Vav3</i><sup>−/−</sup> mice at the indicated times after a single topic application of TPA. Tubulin α (ID number: 22142) was used as loading control. WB, Western blot. (G–I) Example (G; scale bar, 100 µm) and quantification of the neutrophil infiltration (H, green color) and edema (I) induced by TPA in mice of indicated genotypes (<i>n</i> = 3). In (G), the sections were stained with antibodies to myeloperoxydase (MPO, ID number: 17523), DAPI, and rhodamine-phalloidin to decorate neutrophils (green color), nuclei (blue color), and F-actin (red color), respectively. TST, total skin thickness.</p>", "links"=>[], "tags"=>["Molecular cell biology", "Signal transduction", "oncology", "Basic cancer research", "proteins", "pleiotropic"], "article_id"=>751652, "categories"=>["Medicine", "Biological Sciences"], "users"=>["Mauricio Menacho-Márquez", "Ramon Garcia-Escudero", "Virginia Ojeda", "Antonio Abad", "Pilar Delgado", "Clotilde Costa", "Sergio Ruiz", "Balbino Alarcón", "Jesús M. Paramio", "Xosé R. Bustelo"], "doi"=>"https://dx.doi.org/10.1371/journal.pbio.1001615.g003", "stats"=>{"downloads"=>6, "page_views"=>12, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Vav_proteins_play_pleiotropic_roles_during_the_skin_tumor_promotion_phase_/751652", "title"=>"Vav proteins play pleiotropic roles during the skin tumor promotion phase.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-07-23 01:36:21"}
  • {"files"=>["https://ndownloader.figshare.com/files/1126587"], "description"=>"<p>(A) Scheme of the bone marrow reconstitution experiments used to generate data in panels (B) and (C). BM, bone marrow. (B, C) Example (B; scale bar, 100 µm) and quantification (C) of the epithelial hyperplasia induced upon four daily applications of TPA in the skin of wild-type and <i>Vav2</i><sup>−/−</sup>;<i>Vav3</i><sup>−/−</sup> C57BL/10 mice previously reconstituted with a wild-type hematopoietic system (C57BL/6-Ly5.1 genetic background) (<i>n</i> = 3 animals/genotype). In (B), sections were stained with antibodies to K14, DAPI, and rhodamine-phalloidin to reveal K14 (green color), cell nuclei (blue color), and F-actin (red color), respectively. (D) Scheme of the bone marrow reconstitution experiments used to generate data in panels (E) and (F). (E, F) Example (E; scale bar, 100 µm) and quantification (F) of the epidermal thickness induced by four daily applications of TPA in the skin of wild-type C57BL/6-Ly5.1 mice whose hematopoietic systems had been reconstituted with either wild-type or <i>Vav2</i><sup>−/−</sup>;<i>Vav3</i><sup>−/−</sup> bone marrow cells (C57BL/10 genetic background) (<i>n</i> = 3 animals/genotype). Panels shown in (E) were stained as in panel (B).</p>", "links"=>[], "tags"=>["Molecular cell biology", "Signal transduction", "oncology", "Basic cancer research", "defective", "proliferation", "epidermis", "mice", "hematopoietic"], "article_id"=>751654, "categories"=>["Medicine", "Biological Sciences"], "users"=>["Mauricio Menacho-Márquez", "Ramon Garcia-Escudero", "Virginia Ojeda", "Antonio Abad", "Pilar Delgado", "Clotilde Costa", "Sergio Ruiz", "Balbino Alarcón", "Jesús M. Paramio", "Xosé R. Bustelo"], "doi"=>"https://dx.doi.org/10.1371/journal.pbio.1001615.g004", "stats"=>{"downloads"=>1, "page_views"=>5, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_The_defective_proliferation_of_the_epidermis_of_Vav2_8722_8722_Vav3_8722_8722_mice_is_not_due_to_a_defective_hematopoietic_system_/751654", "title"=>"The defective proliferation of the epidermis of <i>Vav2</i><sup>−/−</sup>;<i>Vav3</i><sup>−/−</sup> mice is not due to a defective hematopoietic system.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-07-23 01:36:21"}
  • {"files"=>["https://ndownloader.figshare.com/files/1126589"], "description"=>"<p>(A) Quantification by flow cytometry of the number of EdU<sup>+</sup>, S-phase cells induced by the stimulation of quiescent keratinocytes of the indicated genotypes with either TPA or a synthetic keratinocyte growth media (CnT07). (B) Phosphorylation and expression status of Erk and Stat3 proteins in TPA-stimulated keratinocytes of indicated genotypes. (C) Rac1 (upper panel) and RhoA (lower panel) activation levels induced by the stimulation of quiescent keratinocytes of indicated genotypes with TPA (<i>n</i> = 3). (D) Phosphorylation and expression status of Erk proteins in either serum- (two upper panels) or CnT07-stimulated (two bottom panels) keratinocytes of indicated genotypes. (E) Rac1 activation levels induced by the stimulation of quiescent keratinocytes with either serum (left panel) or CnT07 media (right panel) (<i>n</i> = 3). (F) Immunoprecipitation experiments showing the tyrosine phosphorylation levels of endogenous Vav2 (top panel) and ectopically expressed HA-Vav2 (third panel from top) in wild-type keratinocytes treated with TPA (+) in the absence (−) or the presence (+) of the indicated drugs (<i>n</i> = 2). Due to problems with the detection of the endogenous proteins after blot stripping, the loading control shown in the second panel from top was made using a parallel immunoprecipitation with the same anti-Vav2 antibody. GF, GF109203X; IP, immunoprecipitation. (G) Western blot of total cellular extracts showing the levels of phosphorylation (top) and expression (bottom) of Erk proteins in wild-type keratinocytes stimulated as indicated in (F) (<i>n</i> = 3). (H) Rac1 activation levels induced by TPA in wild-type keratinocytes under the indicated experimental conditions (<i>n</i> = 3). Go, Gö 6976; sh<i>Fyn</i>, cells infected with a Fyn-specific shRNA.</p>", "links"=>[], "tags"=>["Molecular cell biology", "Signal transduction", "oncology", "Basic cancer research", "routes"], "article_id"=>751656, "categories"=>["Medicine", "Biological Sciences"], "users"=>["Mauricio Menacho-Márquez", "Ramon Garcia-Escudero", "Virginia Ojeda", "Antonio Abad", "Pilar Delgado", "Clotilde Costa", "Sergio Ruiz", "Balbino Alarcón", "Jesús M. Paramio", "Xosé R. Bustelo"], "doi"=>"https://dx.doi.org/10.1371/journal.pbio.1001615.g005", "stats"=>{"downloads"=>1, "page_views"=>9, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Vav_dependent_routes_in_keratinocytes_/751656", "title"=>"Vav-dependent routes in keratinocytes.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-07-23 01:36:21"}
  • {"files"=>["https://ndownloader.figshare.com/files/1126591"], "description"=>"<p>(A) Quantification by flow cytometry of the apoptosis induced in pure (No) and genotypically mixed (Yes) cultures of wild-type and <i>Vav2</i><sup>−/−</sup>;<i>Vav3</i><sup>−/−</sup> keratinocytes upon 12 h in complete media with DMBA or under serum-free media conditions. (B) Quantification by flow cytometry of the apoptosis observed in wild-type and <i>Vav2</i><sup>−/−</sup>;<i>Vav3</i><sup>−/−</sup> keratinocytes kept for 12 h with serum, without serum, or without serum plus the indicated extracellular factors (<i>n</i> = 3). (C) Determination by flow cytometry of the percentage of wild-type and <i>Vav2</i><sup>−/−</sup>;<i>Vav3</i><sup>−/−</sup> keratinocytes that have entered S phase after 4.5 h under the indicated culture conditions (<i>n</i> = 3). (D–F) Phosphorylation and expression status of Erk and Stat3 in serum-starved wild-type and <i>Vav2</i><sup>−/−</sup>;<i>Vav3</i><sup>−/−</sup> keratinocytes stimulated with either EGF (D) or IL6 (E–G) for the indicated periods of time. In panels (F) and (G), keratinocytes were transduced with empty and Vav-encoding lentiviruses prior to the starvation and stimulation steps as indicated in the respective panel (<i>n</i> = 3). (H) Tyrosine phosphorylation levels of endogenous Vav2 (top panel) in wild-type keratinocytes treated with the indicated agents for 5 min (<i>n</i> = 2). Due to problems with the detection of the endogenous proteins after blot stripping, the loading control shown in the second panel from top was made using a parallel immunoprecipitation with the same anti-Vav2 antibody.</p>", "links"=>[], "tags"=>["Molecular cell biology", "Signal transduction", "oncology", "Basic cancer research", "proteins", "keratinocyte"], "article_id"=>751658, "categories"=>["Medicine", "Biological Sciences"], "users"=>["Mauricio Menacho-Márquez", "Ramon Garcia-Escudero", "Virginia Ojeda", "Antonio Abad", "Pilar Delgado", "Clotilde Costa", "Sergio Ruiz", "Balbino Alarcón", "Jesús M. Paramio", "Xosé R. Bustelo"], "doi"=>"https://dx.doi.org/10.1371/journal.pbio.1001615.g006", "stats"=>{"downloads"=>0, "page_views"=>2, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Vav_proteins_are_involved_in_the_engagement_and_signaling_efficiency_of_keratinocyte_autocrine_paracrine_loops_/751658", "title"=>"Vav proteins are involved in the engagement and signaling efficiency of keratinocyte autocrine/paracrine loops.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-07-23 01:36:21"}
  • {"files"=>["https://ndownloader.figshare.com/files/1126592"], "description"=>"<p>(A–D) Quantification of the epidermal hyperplasia (A, C) and BrdU incorporation (B, D) observed in wild-type and <i>Vav2</i><sup>−/−</sup>;<i>Vav3</i><sup>−/−</sup> mice upon 24 (A, C) or 17 (B, D) h after indicated treatments (<i>n</i> = 4). TPA and extracellular factors were applied topically and intradermally, respectively. (E–F) Quantification of the neutrophil infiltration in wild-type (E, F), <i>Vav2</i><sup>−/−</sup>;<i>Vav3</i><sup>−/−</sup> (E, F), and <i>Vav1</i><sup>−/−</sup>;<i>Vav2</i><sup>−/−</sup>;<i>Vav3</i><sup>−/−</sup> (<i>TKO</i>) (F) mice upon 24 h treatments with the indicated stimuli (<i>n</i> = 4). In panel (F), the right graph represents data obtained upon IL6 injections. TPA and extracellular factors were applied topically and intradermally, respectively.</p>", "links"=>[], "tags"=>["Molecular cell biology", "Signal transduction", "oncology", "Basic cancer research", "defects", "mice", "tumorigenesis"], "article_id"=>751659, "categories"=>["Medicine", "Biological Sciences"], "users"=>["Mauricio Menacho-Márquez", "Ramon Garcia-Escudero", "Virginia Ojeda", "Antonio Abad", "Pilar Delgado", "Clotilde Costa", "Sergio Ruiz", "Balbino Alarcón", "Jesús M. Paramio", "Xosé R. Bustelo"], "doi"=>"https://dx.doi.org/10.1371/journal.pbio.1001615.g007", "stats"=>{"downloads"=>1, "page_views"=>4, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_The_defects_of_Vav2_Vav3_deficient_mice_in_the_promotion_phase_of_skin_tumorigenesis_have_an_autocrine_paracrine_basis_/751659", "title"=>"The defects of Vav2/Vav3-deficient mice in the promotion phase of skin tumorigenesis have an autocrine/paracrine basis.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-07-23 01:36:21"}
  • {"files"=>["https://ndownloader.figshare.com/files/1126594"], "description"=>"<p>(A–D) qRT-PCR experiments showing the relative abundance of indicated mRNAs in DMBA/TPA-induced papillomas (A, C) and DMBA/DMBA-induced carcinomas (B, D) in wild-type and <i>Vav2</i><sup>−/−</sup>;<i>Vav3</i><sup>−/−</sup> FVB mice. Values for each mRNA are given in relation to the levels seen in samples from control mice (which were given an arbitrary value of 1) (<i>n</i> = 4 mice per genotype). (E) Summary of the results obtained in this work. (Left panel) The Vav2/Vav3-dependent biological programs in the skin that favor tumor initiation and promotion. (Right panel) The above programs upon the deletion of <i>Vav2</i> and <i>Vav3</i> genes. Numbered gray circles indicate the three main signaling functions of Vav proteins. The intracellular and extracellular signaling programs are indicated on the left boxes. Intracellular and autocrine/paracrine signaling is indicated by black and gray arrows, respectively. The oncogenic route is shown in red. Stimulation steps are shown as green stars. Defective receptor signaling is induced as a stop sign. Normal and defective processes are shown in bold and normal font types, respectively.</p>", "links"=>[], "tags"=>["Molecular cell biology", "Signal transduction", "oncology", "Basic cancer research", "upr-egulation", "egf", "ligands", "vav", "family-dependent", "genes", "tumors", "developed"], "article_id"=>751661, "categories"=>["Medicine", "Biological Sciences"], "users"=>["Mauricio Menacho-Márquez", "Ramon Garcia-Escudero", "Virginia Ojeda", "Antonio Abad", "Pilar Delgado", "Clotilde Costa", "Sergio Ruiz", "Balbino Alarcón", "Jesús M. Paramio", "Xosé R. Bustelo"], "doi"=>"https://dx.doi.org/10.1371/journal.pbio.1001615.g008", "stats"=>{"downloads"=>0, "page_views"=>11, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Progressive_upr_egulation_of_EGF_family_ligands_and_Vav_family_dependent_genes_in_skin_tumors_developed_in_Vav2_8722_8722_Vav3_8722_8722_mice_/751661", "title"=>"Progressive upr-egulation of EGF family ligands and Vav family-dependent genes in skin tumors developed in <i>Vav2</i><sup>−/−</sup>;<i>Vav3</i><sup>−/−</sup> mice.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-07-23 01:36:21"}
  • {"files"=>["https://ndownloader.figshare.com/files/1126598", "https://ndownloader.figshare.com/files/1126599", "https://ndownloader.figshare.com/files/1126600", "https://ndownloader.figshare.com/files/1126601", "https://ndownloader.figshare.com/files/1126602", "https://ndownloader.figshare.com/files/1126603", "https://ndownloader.figshare.com/files/1126604", "https://ndownloader.figshare.com/files/1126605", "https://ndownloader.figshare.com/files/1126606", "https://ndownloader.figshare.com/files/1126607", "https://ndownloader.figshare.com/files/1126608", "https://ndownloader.figshare.com/files/1126609", "https://ndownloader.figshare.com/files/1126610"], "description"=>"<div><p>The catalytic activity of GDP/GTP exchange factors (GEFs) is considered critical to maintain the typically high activity of Rho GTPases found in cancer cells. However, the large number of them has made it difficult to pinpoint those playing proactive, nonredundant roles in tumors. In this work, we have investigated whether GEFs of the Vav subfamily exert such specific roles in skin cancer. Using genetically engineered mice, we show here that Vav2 and Vav3 favor cooperatively the initiation and promotion phases of skin tumors. Transcriptomal profiling and signaling experiments indicate such function is linked to the engagement of, and subsequent participation in, keratinocyte-based autocrine/paracrine programs that promote epidermal proliferation and recruitment of pro-inflammatory cells. This is a pathology-restricted mechanism because the loss of Vav proteins does not cause alterations in epidermal homeostasis. These results reveal a previously unknown Rho GEF-dependent pro-tumorigenic mechanism that influences the biology of cancer cells and their microenvironment. They also suggest that anti-Vav therapies may be of potential interest in skin tumor prevention and/or treatment.</p></div>", "links"=>[], "tags"=>["Molecular cell biology", "Signal transduction", "oncology", "Basic cancer research", "rho", "vav2", "vav3", "initiation", "engaging", "extracellular"], "article_id"=>751665, "categories"=>["Medicine", "Biological Sciences"], "users"=>["Mauricio Menacho-Márquez", "Ramon Garcia-Escudero", "Virginia Ojeda", "Antonio Abad", "Pilar Delgado", "Clotilde Costa", "Sergio Ruiz", "Balbino Alarcón", "Jesús M. Paramio", "Xosé R. Bustelo"], "doi"=>["https://dx.doi.org/10.1371/journal.pbio.1001615.s001", "https://dx.doi.org/10.1371/journal.pbio.1001615.s002", "https://dx.doi.org/10.1371/journal.pbio.1001615.s003", "https://dx.doi.org/10.1371/journal.pbio.1001615.s004", "https://dx.doi.org/10.1371/journal.pbio.1001615.s005", "https://dx.doi.org/10.1371/journal.pbio.1001615.s006", "https://dx.doi.org/10.1371/journal.pbio.1001615.s007", "https://dx.doi.org/10.1371/journal.pbio.1001615.s008", "https://dx.doi.org/10.1371/journal.pbio.1001615.s009", "https://dx.doi.org/10.1371/journal.pbio.1001615.s010", "https://dx.doi.org/10.1371/journal.pbio.1001615.s011", "https://dx.doi.org/10.1371/journal.pbio.1001615.s012", "https://dx.doi.org/10.1371/journal.pbio.1001615.s013"], "stats"=>{"downloads"=>25, "page_views"=>15, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_The_Rho_Exchange_Factors_Vav2_and_Vav3_Favor_Skin_Tumor_Initiation_and_Promotion_by_Engaging_Extracellular_Signaling_Loops_/751665", "title"=>"The Rho Exchange Factors Vav2 and Vav3 Favor Skin Tumor Initiation and Promotion by Engaging Extracellular Signaling Loops", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2013-07-23 01:36:21"}
  • {"files"=>["https://ndownloader.figshare.com/files/1126580"], "description"=>"<p>(A, B) Incidence (A) and number (B) of tumors in DMBA/TPA-treated FVB mice of indicated genotypes. The differences in tumor incidence up to week 10 (A) and in tumor number (B) were statistically significant (<i>p</i>≤0.001, <i>n</i> = 15 animals per genotype in each experiment). (C) Example of animals subjected to the above treatments for 16 wk. (D, E) Incidence (D) and number (E) of tumors in DMBA/TPA-treated C57BL/10 mice of indicated genotypes. The differences in tumor incidence up to week 15 (D) and in tumor number (E) were statistically significant (<i>p</i>≤0.001, <i>n</i> = 15 animals per genotype in each experiment). (F) Example of C57BL/10 mice of the indicated genotypes that were subjected to the above treatment for 16 wk. (G, H) Incidence (G) and number (H) of tumors in DMBA/DMBA-treated FVB mice of indicated genotypes. The differences in tumor incidence up to week 13 (G) and in tumor number (H) were statistically significant (<i>p</i>≤0.001, <i>n</i> = 15 animals per genotype in each experiment). (I) Example of animals subjected to the above treatments for 16 wk.</p>", "links"=>[], "tags"=>["Molecular cell biology", "Signal transduction", "oncology", "Basic cancer research", "vav2", "vav3", "cst"], "article_id"=>751647, "categories"=>["Medicine", "Biological Sciences"], "users"=>["Mauricio Menacho-Márquez", "Ramon Garcia-Escudero", "Virginia Ojeda", "Antonio Abad", "Pilar Delgado", "Clotilde Costa", "Sergio Ruiz", "Balbino Alarcón", "Jesús M. Paramio", "Xosé R. Bustelo"], "doi"=>"https://dx.doi.org/10.1371/journal.pbio.1001615.g001", "stats"=>{"downloads"=>4, "page_views"=>8, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Expression_of_Vav2_and_Vav3_is_important_for_CST_development_/751647", "title"=>"Expression of Vav2 and Vav3 is important for CST development.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-07-23 01:36:21"}

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Relative Metric

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