A critical role of platelet TGF-β release in podoplanin-mediated tumour invasion and metastasis
Identifieur interne : 000438 ( Pmc/Checkpoint ); précédent : 000437; suivant : 000439A critical role of platelet TGF-β release in podoplanin-mediated tumour invasion and metastasis
Auteurs : Ai Takemoto [Japon] ; Mina Okitaka [Japon] ; Satoshi Takagi [Japon] ; Miho Takami [Japon] ; Shigeo Sato [Japon] ; Makoto Nishio [Japon] ; Sakae Okumura [Japon] ; Naoya Fujita [Japon]Source :
- Scientific Reports [ 2045-2322 ] ; 2017.
Abstract
The tumour microenvironment is critical for various characteristics of tumour malignancies. Platelets, as part of the tumour microenvironment, are associated with metastasis formation via increasing the rate of tumour embolus formation in microvasculature. However, the mechanisms underlying the ability of tumour cells to acquire invasiveness and extravasate into target organs at the site of embolization remain unclear. In this study, we reported that platelet aggregation-inducing factor podoplanin expressed on tumour cell surfaces were found to not only promote the formation of tumour-platelet aggregates via interaction with platelets, but also induced the epithelial-mesenchymal transition (EMT) of tumour cells by enhancing transforming growth factor-β (TGF-β) release from platelets.
Url:
DOI: 10.1038/srep42186
PubMed: 28176852
PubMed Central: 5297242
Affiliations:
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135-8550,<country>Japan</country></nlm:aff><country xml:lang="fr">Japon</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="a2"><institution>Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo</institution>, Kashiwa, Chiba 277-8561,<country>Japan</country></nlm:aff><country xml:lang="fr">Japon</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Takagi, Satoshi" sort="Takagi, Satoshi" uniqKey="Takagi S" first="Satoshi" last="Takagi">Satoshi Takagi</name><affiliation wicri:level="1"><nlm:aff id="a1"><institution>Division of Experimental Chemotherapy, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research</institution>, Tokyo 135-8550,<country>Japan</country></nlm:aff><country xml:lang="fr">Japon</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Takami, Miho" sort="Takami, Miho" uniqKey="Takami M" first="Miho" last="Takami">Miho Takami</name><affiliation wicri:level="1"><nlm:aff id="a1"><institution>Division of Experimental Chemotherapy, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research</institution>, Tokyo 135-8550,<country>Japan</country></nlm:aff><country xml:lang="fr">Japon</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Sato, Shigeo" sort="Sato, Shigeo" uniqKey="Sato S" first="Shigeo" last="Sato">Shigeo Sato</name><affiliation wicri:level="1"><nlm:aff id="a1"><institution>Division of Experimental Chemotherapy, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research</institution>, Tokyo 135-8550,<country>Japan</country></nlm:aff><country xml:lang="fr">Japon</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Nishio, Makoto" sort="Nishio, Makoto" uniqKey="Nishio M" first="Makoto" last="Nishio">Makoto Nishio</name><affiliation wicri:level="1"><nlm:aff id="a3"><institution>Department of Thoracic Center, Cancer Institute Hospital, Japanese Foundation for Cancer Research</institution>, Tokyo 135-8550,<country>Japan</country></nlm:aff><country xml:lang="fr">Japon</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Okumura, Sakae" sort="Okumura, Sakae" uniqKey="Okumura S" first="Sakae" last="Okumura">Sakae Okumura</name><affiliation wicri:level="1"><nlm:aff id="a3"><institution>Department of Thoracic Center, Cancer Institute Hospital, Japanese Foundation for Cancer Research</institution>, Tokyo 135-8550,<country>Japan</country></nlm:aff><country xml:lang="fr">Japon</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Fujita, Naoya" sort="Fujita, Naoya" uniqKey="Fujita N" first="Naoya" last="Fujita">Naoya Fujita</name><affiliation wicri:level="1"><nlm:aff id="a1"><institution>Division of Experimental Chemotherapy, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research</institution>, Tokyo 135-8550,<country>Japan</country></nlm:aff><country xml:lang="fr">Japon</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="a2"><institution>Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo</institution>, Kashiwa, Chiba 277-8561,<country>Japan</country></nlm:aff><country xml:lang="fr">Japon</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno 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wicri:level="1"><nlm:aff id="a1"><institution>Division of Experimental Chemotherapy, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research</institution>, Tokyo 135-8550,<country>Japan</country></nlm:aff><country xml:lang="fr">Japon</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Okitaka, Mina" sort="Okitaka, Mina" uniqKey="Okitaka M" first="Mina" last="Okitaka">Mina Okitaka</name><affiliation wicri:level="1"><nlm:aff id="a1"><institution>Division of Experimental Chemotherapy, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research</institution>, Tokyo 135-8550,<country>Japan</country></nlm:aff><country xml:lang="fr">Japon</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="a2"><institution>Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo</institution>, Kashiwa, Chiba 277-8561,<country>Japan</country></nlm:aff><country xml:lang="fr">Japon</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Takagi, Satoshi" sort="Takagi, Satoshi" uniqKey="Takagi S" first="Satoshi" last="Takagi">Satoshi Takagi</name><affiliation wicri:level="1"><nlm:aff id="a1"><institution>Division of Experimental Chemotherapy, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research</institution>, Tokyo 135-8550,<country>Japan</country></nlm:aff><country xml:lang="fr">Japon</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Takami, Miho" sort="Takami, Miho" uniqKey="Takami M" first="Miho" last="Takami">Miho Takami</name><affiliation wicri:level="1"><nlm:aff id="a1"><institution>Division of Experimental Chemotherapy, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research</institution>, Tokyo 135-8550,<country>Japan</country></nlm:aff><country xml:lang="fr">Japon</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Sato, Shigeo" sort="Sato, Shigeo" uniqKey="Sato S" first="Shigeo" last="Sato">Shigeo Sato</name><affiliation wicri:level="1"><nlm:aff id="a1"><institution>Division of Experimental Chemotherapy, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research</institution>, Tokyo 135-8550,<country>Japan</country></nlm:aff><country xml:lang="fr">Japon</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Nishio, Makoto" sort="Nishio, Makoto" uniqKey="Nishio M" first="Makoto" last="Nishio">Makoto Nishio</name><affiliation wicri:level="1"><nlm:aff id="a3"><institution>Department of Thoracic Center, Cancer Institute Hospital, Japanese Foundation for Cancer Research</institution>, Tokyo 135-8550,<country>Japan</country></nlm:aff><country xml:lang="fr">Japon</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Okumura, Sakae" sort="Okumura, Sakae" uniqKey="Okumura S" first="Sakae" last="Okumura">Sakae Okumura</name><affiliation wicri:level="1"><nlm:aff id="a3"><institution>Department of Thoracic Center, Cancer Institute Hospital, Japanese Foundation for Cancer Research</institution>, Tokyo 135-8550,<country>Japan</country></nlm:aff><country xml:lang="fr">Japon</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Fujita, Naoya" sort="Fujita, Naoya" uniqKey="Fujita N" first="Naoya" last="Fujita">Naoya Fujita</name><affiliation wicri:level="1"><nlm:aff id="a1"><institution>Division of Experimental Chemotherapy, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research</institution>, Tokyo 135-8550,<country>Japan</country></nlm:aff><country xml:lang="fr">Japon</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="a2"><institution>Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo</institution>, Kashiwa, Chiba 277-8561,<country>Japan</country></nlm:aff><country xml:lang="fr">Japon</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author></analytic><series><title level="j">Scientific Reports</title><idno type="eISSN">2045-2322</idno><imprint><date when="2017">2017</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>The tumour microenvironment is critical for various characteristics of tumour malignancies. Platelets, as part of the tumour microenvironment, are associated with metastasis formation via increasing the rate of tumour embolus formation in microvasculature. However, the mechanisms underlying the ability of tumour cells to acquire invasiveness and extravasate into target organs at the site of embolization remain unclear. In this study, we reported that platelet aggregation-inducing factor podoplanin expressed on tumour cell surfaces were found to not only promote the formation of tumour-platelet aggregates via interaction with platelets, but also induced the epithelial-mesenchymal transition (EMT) of tumour cells by enhancing transforming growth factor-β (TGF-β) release from platelets. <italic>In vitro</italic> and <italic>in vivo</italic> analyses revealed that podoplanin-mediated EMT resulted in increased invasiveness and extravasation of tumour cells. Treatment of mice with a TGF-β-neutralizing antibody statistically suppressed podoplanin-mediated distant metastasis <italic>in vivo</italic>, suggesting that podoplanin promoted haematogenous metastasis in part by releasing TGF-β from platelets that was essential for EMT of tumour cells. Therefore, our findings suggested that blocking the TGF-β signalling pathway might be a promising strategy for suppressing podoplanin-mediated haematogenous metastasis <italic>in vivo</italic>.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Gay, L J" uniqKey="Gay L">L. J. Gay</name></author><author><name sortKey="Felding Habermann, B" uniqKey="Felding Habermann B">B. Felding-Habermann</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Bambace, N M" uniqKey="Bambace N">N. M. Bambace</name></author><author><name sortKey="Holmes, C E" uniqKey="Holmes C">C. E. 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<front><journal-meta><journal-id journal-id-type="nlm-ta">Sci Rep</journal-id><journal-id journal-id-type="iso-abbrev">Sci Rep</journal-id><journal-title-group><journal-title>Scientific Reports</journal-title></journal-title-group><issn pub-type="epub">2045-2322</issn><publisher><publisher-name>Nature Publishing Group</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">28176852</article-id><article-id pub-id-type="pmc">5297242</article-id><article-id pub-id-type="pii">srep42186</article-id><article-id pub-id-type="doi">10.1038/srep42186</article-id><article-categories><subj-group subj-group-type="heading"><subject>Article</subject></subj-group></article-categories><title-group><article-title>A critical role of platelet TGF-β release in podoplanin-mediated tumour invasion and metastasis</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Takemoto</surname><given-names>Ai</given-names></name><xref ref-type="aff" rid="a1">1</xref></contrib><contrib contrib-type="author"><name><surname>Okitaka</surname><given-names>Mina</given-names></name><xref ref-type="aff" rid="a1">1</xref><xref ref-type="aff" rid="a2">2</xref></contrib><contrib contrib-type="author"><name><surname>Takagi</surname><given-names>Satoshi</given-names></name><xref ref-type="aff" rid="a1">1</xref></contrib><contrib contrib-type="author"><name><surname>Takami</surname><given-names>Miho</given-names></name><xref ref-type="aff" rid="a1">1</xref></contrib><contrib contrib-type="author"><name><surname>Sato</surname><given-names>Shigeo</given-names></name><xref ref-type="aff" rid="a1">1</xref></contrib><contrib contrib-type="author"><name><surname>Nishio</surname><given-names>Makoto</given-names></name><xref ref-type="aff" rid="a3">3</xref></contrib><contrib contrib-type="author"><name><surname>Okumura</surname><given-names>Sakae</given-names></name><xref ref-type="aff" rid="a3">3</xref></contrib><contrib contrib-type="author"><name><surname>Fujita</surname><given-names>Naoya</given-names></name><xref ref-type="corresp" rid="c1">a</xref><xref ref-type="aff" rid="a1">1</xref><xref ref-type="aff" rid="a2">2</xref></contrib><aff id="a1"><label>1</label><institution>Division of Experimental Chemotherapy, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research</institution>, Tokyo 135-8550,<country>Japan</country></aff><aff id="a2"><label>2</label><institution>Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo</institution>, Kashiwa, Chiba 277-8561,<country>Japan</country></aff><aff id="a3"><label>3</label><institution>Department of Thoracic Center, Cancer Institute Hospital, Japanese Foundation for Cancer Research</institution>, Tokyo 135-8550,<country>Japan</country></aff></contrib-group><author-notes><corresp id="c1"><label>a</label><email>naoya.fujita@jfcr.or.jp</email></corresp></author-notes><pub-date pub-type="epub"><day>08</day><month>02</month><year>2017</year></pub-date><pub-date pub-type="collection"><year>2017</year></pub-date><volume>7</volume><elocation-id>42186</elocation-id><history><date date-type="received"><day>19</day><month>08</month><year>2016</year></date><date date-type="accepted"><day>06</day><month>01</month><year>2017</year></date></history><permissions><copyright-statement>Copyright © 2017, The Author(s)</copyright-statement><copyright-year>2017</copyright-year><copyright-holder>The Author(s)</copyright-holder><license license-type="open-access" xlink:href="http://creativecommons.org/licenses/by/4.0/"><pmc-comment>author-paid</pmc-comment>
<license-p>This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit <ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by/4.0/">http://creativecommons.org/licenses/by/4.0/</ext-link></license-p></license></permissions><abstract><p>The tumour microenvironment is critical for various characteristics of tumour malignancies. Platelets, as part of the tumour microenvironment, are associated with metastasis formation via increasing the rate of tumour embolus formation in microvasculature. However, the mechanisms underlying the ability of tumour cells to acquire invasiveness and extravasate into target organs at the site of embolization remain unclear. In this study, we reported that platelet aggregation-inducing factor podoplanin expressed on tumour cell surfaces were found to not only promote the formation of tumour-platelet aggregates via interaction with platelets, but also induced the epithelial-mesenchymal transition (EMT) of tumour cells by enhancing transforming growth factor-β (TGF-β) release from platelets. <italic>In vitro</italic> and <italic>in vivo</italic> analyses revealed that podoplanin-mediated EMT resulted in increased invasiveness and extravasation of tumour cells. Treatment of mice with a TGF-β-neutralizing antibody statistically suppressed podoplanin-mediated distant metastasis <italic>in vivo</italic>, suggesting that podoplanin promoted haematogenous metastasis in part by releasing TGF-β from platelets that was essential for EMT of tumour cells. Therefore, our findings suggested that blocking the TGF-β signalling pathway might be a promising strategy for suppressing podoplanin-mediated haematogenous metastasis <italic>in vivo</italic>.</p></abstract></article-meta></front><floats-group><fig id="f1"><label>Figure 1</label><caption><title>Podoplanin-mediated platelet aggregation promotes epithelial-mesenchymal transition in tumour cells.</title><p>(<bold>a</bold>) Immunoblot analysis showing podoplanin expression in UM-UC-5 and H226 but not in A549 cells. TopoIIβ was used as a loading control. (<bold>b</bold>) UM-UC-5, H226 and A549 cells (5 × 10<sup>4</sup> cells) were incubated with washed mouse platelets (5 × 10<sup>7</sup> platelets/200 μl assay) suspended in Tyrode’s buffer containing 2% platelet-poor plasma and 250 μM CaCl<sub>2</sub>. Light transmittance of samples was measured to determine the aggregation rate using an aggregometer. (<bold>c</bold>) Schematic representation of collection of tumour-platelet reactant supernatants. (<bold>d</bold>,<bold>e</bold>) Morphological and physiological changes in cells after treatment with or without supernatants of tumor-platelet reactants for 48 h. (<bold>d</bold>) Images were captured using phase-contrast microscopy (left panels) or immunofluorescence microscopy (right panels) after staining for E-cadherin (green), F-actin (red; phalloidin) and nuclear DNA (blue; Hoechst 33342). Scale bars represent 50 μm. (<bold>e</bold>) Cellular lysates were immunoblotted with antibodies to N-cadherin, claudin-1, podoplanin (PDPN, clone D2–40) and TopoIIβ.</p></caption><graphic xlink:href="srep42186-f1"></graphic></fig><fig id="f2"><label>Figure 2</label><caption><title>TGF-β released from platelets is critical for podoplanin-induced epithelial-mesenchymal transition.</title><p>(<bold>a</bold>) Measurement of TGF-β1 or PDGF-BB concentrations in tumour-platelet reactants using Bio-Plex suspension array system. Error bars indicate standard deviation (SD). <italic>**P</italic> < 0.01 by Student’s <italic>t</italic> test. (<bold>b</bold>,<bold>c</bold>) Morphological and physiological changes in cells after treatment with or without 3 ng/ml recombinant TGF-β1 for 48 h. (<bold>b</bold>) Cells were stained for E-cadherin (green), F-actin (red; phalloidin) and nuclear DNA (blue; Hoechst 33342). Scale bars represent 50 μm. (<bold>c</bold>) Cell lysates were immunoblotted with antibodies to N-cadherin, claudin-1, podoplanin (PDPN, clone D2-40) and TopoIIβ. (<bold>d</bold>) Cells were either left untreated or treated with supernatants of platelets alone (platelets), supernatants of platelet–cell reactants (platelets + cells), or 3 ng/ml of recombinant TGF-β1 for 0.5 h. The cell lysates were immunoblotted with antibodies against phospho-Smad2/3 (pSmad2/3), Smad3, and TopoIIβ.</p></caption><graphic xlink:href="srep42186-f2"></graphic></fig><fig id="f3"><label>Figure 3</label><caption><title>TGF-β/TGFβR signaling is involved in podoplanin-induced epithelial-mesenchymal transition in UM-UC-5 cells.</title><p>(<bold>a</bold>–<bold>c</bold>) UM-UC-5 cells were treated with or without TGF-β1 neutralizing mAb (1D11 mAb) or TGFβR inhibitors (LY2157299 or SB431542) for 2 h, followed by incubation with supernatants of UM-UC-5-platelet reactants for 48 h. Morphological and physiological changes in treated cells were examined by immunoblotting (<bold>a</bold>), immunofluorescence staining (<bold>b</bold>) and invasion assay using a matrigel-coated transwell chambers (<bold>c</bold>). (<bold>a</bold>) Cell lysates were immunoblotted with antibodies to N-cadherin, claudin-1, podoplanin (PDPN, clone D2-40) and TopoIIβ. (<bold>b</bold>) Cells were stained for anti-E-cadherin (green), F-actin (red; phalloidin) and nuclear DNA (blue; Hoechst 33342). Scale bars represent 50 μm. (<bold>c</bold>) Cells were either left untreated or treated with supernatants of UM-UC-5-platelet reactants for 48 h. Next, 5 × 10<sup>4</sup> UM-UC-5 cells were added to the upper chambers of matrigel-overlaid membranes. After incubation for an additional 48 h at 37 °C, cells migrating through the membranes were fixed and stained with crystal violet (lower panels; scale bars represent 200 μm). Optical density (OD) of crystal violet extracted from cells was measured at 540 nm and presented as a percentage of the OD values of control cells. All data are shown as means ± standard deviation (SD, n = 8). <italic>**P</italic> < 0.01 by the Mann-Whitney <italic>U</italic> test (upper panel).</p></caption><graphic xlink:href="srep42186-f3"></graphic></fig><fig id="f4"><label>Figure 4</label><caption><title>Podoplanin is necessary for TGF-β release from platelets and epithelial-mesenchymal transition.</title><p>UM-UC-5 cells were infected with lentivirus containing shRNA targeting human podoplanin (shPDPN_23 and shPDPN_26) or control (shControl). Cells with stable knockdown of podoplanin were used in the experiments. (<bold>a</bold>) Immunoblot analysis of podoplanin expression in shPDPN_23, shPDPN_26 and shControl cells. TopoIIβ was used as a loading control. (<bold>b</bold>) ShPDPN_23, shPDPN_26 and shControl cells (5 × 10<sup>4</sup> cells) were incubated with washed platelets (4 × 10<sup>7</sup> platelets/200 μl) suspended in Tyrode’s buffer containing 2% platelet-poor plasma and 250 μM CaCl<sub>2.</sub> Light transmittance of samples was measured to determine the aggregation rate using an aggregometer. (<bold>c</bold>) TGF-β1 concentrations in tumour-platelet reactants were determined by enzyme-linked immunosorbent assay. All data are shown as means ± standard deviation (SD, n = 3). <italic>**P</italic> < 0.01 by the Mann-Whitney <italic>U</italic> test. (<bold>d</bold>,<bold>e</bold>) Morphological and physiological changes in shPDPN_23, shPDPN_26 and shControl cells after treatment with or without supernatants of tumour-platelet reactants for 48 h. (<bold>d</bold>) Cells were stained for E-cadherin (green), F-actin (red; phalloidin) and nuclear DNA (blue; Hoechst 33342). Scale bars represent 50 μm. (<bold>e</bold>) Cell lysates were immunoblotted with antibodies to N-cadherin, claudin-1, podoplanin (PDPN, clone D2-40) and TopoIIβ (<bold>e</bold>). (<bold>f</bold>) Cells were either left untreated or treated with supernatants of stable transfectant-platelet reactants for 48 h. Next, treated transfectants (5 × 10<sup>4</sup>/well) were added to the upper chambers of matrigel-overlaid membranes. After incubation for an additional 48 h at 37 °C, cells migrating through matrigel-overlaid membranes were fixed and stained with crystal violet (lower panels; scale bars represent 200 μm). Optical density (OD) of crystal violet extracted from cells was measured at 540 nm and presented as percentages of the OD values of supernatant-untreated shcontrol cells. All data are shown as means ± SD (n = 8). N.S., not significant. <italic>**P</italic> < 0.01 by the Mann-Whitney <italic>U</italic> test (upper panel).</p></caption><graphic xlink:href="srep42186-f4"></graphic></fig><fig id="f5"><label>Figure 5</label><caption><title>Neutralization of TGF-β attenuates tumour extravasation and pulmonary metastasis.</title><p>(<bold>a</bold>) Mouse control IgG (Mouse IgG) or TGFβ neutralizing mAb (clone 1D11) (100 μg/mouse) was administrated by the intravenous (i.v.) route to 5-week-old male CB17/Icr-Prkdc<sup>scid</sup>/CrlCrlj mice 1 h before i.v. inoculation of UM-UC-5 cell suspensions (1.0 × 10<sup>6</sup>/mouse). In some experiments, 1D11 mAb was administrated 2 and 4 days after tumor cell inoculation (1D11 mAb (x3)). Mice were euthanized 30 days after cell inoculation and metastatic foci on the lung surface were counted. Bars represent mean values. <italic>**P</italic> < 0.01 by the Mann-Whitney <italic>U</italic> test. (<bold>b</bold>) Mouse control IgG (Mouse IgG) or TGFβ neutralizing mAb (clone 1D11) (100 μg/mouse) was administrated to 5-week-old male CB17/Icr-Prkdc<sup>scid</sup>/CrlCrlj mice 1 h before tumour inoculation. Calcein-AM-labeled UM-UC-5 cell suspensions were then inoculated (1.0 × 10<sup>6</sup>/mouse) into mice. After 30 min or 48 h after i.v. tumour inoculation, mice were euthanized and frozen lung sections were fixed and stained by Hoechst 33342. Representative merged images of calcein-AM-labeled UM-UC-5 cells (green) stained for nuclear DNA (blue) are shown. (<bold>c</bold>) The fluorescence intensity of calcein-AM was measured using BioRevo BZ-9000. N.S., not significant. <italic>*P</italic> < 0.05 by the Mann-Whitney <italic>U</italic> test.</p></caption><graphic xlink:href="srep42186-f5"></graphic></fig></floats-group></pmc><affiliations><list><country><li>Japon</li></country></list><tree><country name="Japon"><noRegion><name sortKey="Takemoto, Ai" sort="Takemoto, Ai" uniqKey="Takemoto A" first="Ai" last="Takemoto">Ai Takemoto</name></noRegion><name sortKey="Fujita, Naoya" sort="Fujita, Naoya" uniqKey="Fujita N" first="Naoya" last="Fujita">Naoya Fujita</name><name sortKey="Fujita, Naoya" sort="Fujita, Naoya" uniqKey="Fujita N" first="Naoya" last="Fujita">Naoya Fujita</name><name sortKey="Nishio, Makoto" sort="Nishio, Makoto" uniqKey="Nishio M" first="Makoto" last="Nishio">Makoto Nishio</name><name sortKey="Okitaka, Mina" sort="Okitaka, Mina" uniqKey="Okitaka M" first="Mina" last="Okitaka">Mina Okitaka</name><name sortKey="Okitaka, Mina" sort="Okitaka, Mina" uniqKey="Okitaka M" first="Mina" last="Okitaka">Mina Okitaka</name><name sortKey="Okumura, Sakae" sort="Okumura, Sakae" uniqKey="Okumura S" first="Sakae" last="Okumura">Sakae Okumura</name><name sortKey="Sato, Shigeo" sort="Sato, Shigeo" uniqKey="Sato S" first="Shigeo" last="Sato">Shigeo Sato</name><name sortKey="Takagi, Satoshi" sort="Takagi, Satoshi" uniqKey="Takagi S" first="Satoshi" last="Takagi">Satoshi Takagi</name><name sortKey="Takami, Miho" sort="Takami, Miho" uniqKey="Takami M" first="Miho" last="Takami">Miho Takami</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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