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{"title"=>"VE-cadherin-independent cancer cell incorporation into the vascular endothelium precedes transmigration", "type"=>"journal", "authors"=>[{"first_name"=>"Susan M.", "last_name"=>"Hamilla", "scopus_author_id"=>"41761756300"}, {"first_name"=>"Kimberly M.", "last_name"=>"Stroka", "scopus_author_id"=>"26644496200"}, {"first_name"=>"Helim", "last_name"=>"Aranda-Espinoza", "scopus_author_id"=>"6603631693"}], "year"=>2014, "source"=>"PLoS ONE", "identifiers"=>{"sgr"=>"84907482219", "doi"=>"10.1371/journal.pone.0109748", "issn"=>"19326203", "pui"=>"600087004", "isbn"=>"1932-6203<p>", "pmid"=>"25275457", "scopus"=>"2-s2.0-84907482219"}, "id"=>"4e67a4de-14b9-3d43-a9c3-8d672547a2e3", "abstract"=>"Metastasis is accountable for 90% of cancer deaths. During metastasis, tumor cells break away from the primary tumor, enter the blood and the lymph vessels, and use them as highways to travel to distant sites in the body to form secondary tumors. Cancer cell migration through the endothelium and into the basement membrane represents a critical step in the metastatic cascade, yet it is not well understood. This process is well characterized for immune cells that routinely transmigrate through the endothelium to sites of infection, inflammation, or injury. Previous studies with leukocytes have demonstrated that this step depends heavily on the activation status of the endothelium and subendothelial substrate stiffness. Here, we used a previously established in vitro model of the endothelium and live cell imaging, in order to observe cancer cell transmigration and compare this process to leukocytes. Interestingly, cancer cell transmigration includes an additional step, which we term 'incorporation', into the endothelial cell (EC) monolayer. During this phase, cancer cells physically displace ECs, leading to the dislocation of EC VE-cadherin away from EC junctions bordering cancer cells, and spread into the monolayer. In some cases, ECs completely detach from the matrix. Furthermore, cancer cell incorporation occurs independently of the activation status and the subendothelial substrate stiffness for breast cancer and melanoma cells, a notable difference from the process by which leukocytes transmigrate. Meanwhile, pancreatic cancer cell incorporation was dependent on the activation status of the endothelium and changed on very stiff subendothelial substrates. Collectively, our results provide mechanistic insights into tumor cell extravasation and demonstrate that incorporation is one of the earliest steps.", "link"=>"http://www.mendeley.com/research/vecadherinindependent-cancer-cell-incorporation-vascular-endothelium-precedes-transmigration", "reader_count"=>45, "reader_count_by_academic_status"=>{"Unspecified"=>1, "Professor > Associate Professor"=>1, "Student > Doctoral Student"=>2, "Researcher"=>7, "Student > Ph. D. Student"=>14, "Student > Postgraduate"=>2, "Student > Master"=>11, "Other"=>1, "Student > Bachelor"=>6}, "reader_count_by_user_role"=>{"Unspecified"=>1, "Professor > Associate Professor"=>1, "Student > Doctoral Student"=>2, "Researcher"=>7, "Student > Ph. D. Student"=>14, "Student > Postgraduate"=>2, "Student > Master"=>11, "Other"=>1, "Student > Bachelor"=>6}, "reader_count_by_subject_area"=>{"Engineering"=>12, "Unspecified"=>1, "Biochemistry, Genetics and Molecular Biology"=>5, "Mathematics"=>1, "Agricultural and Biological Sciences"=>19, "Medicine and Dentistry"=>6, "Chemistry"=>1}, "reader_count_by_subdiscipline"=>{"Engineering"=>{"Engineering"=>12}, "Medicine and Dentistry"=>{"Medicine and Dentistry"=>6}, "Chemistry"=>{"Chemistry"=>1}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>19}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>5}, "Mathematics"=>{"Mathematics"=>1}, "Unspecified"=>{"Unspecified"=>1}}, "group_count"=>2}

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• http://doi.org/10.1038/srep45835
• http://doi.org/10.3389/fmedt.2020.600616
• http://doi.org/10.1016/j.bbcan.2017.03.004
• http://doi.org/10.1007/s10439-019-02266-5
• http://doi.org/10.3389/fphys.2020.00365
• http://doi.org/10.1038/s41467-017-00884-y
• http://doi.org/10.1111/jcmm.14156
• http://doi.org/10.1088/1758-5090/aa869d
• http://doi.org/10.1177/0271678X17732025
• http://doi.org/10.1155/2017/8534371
• http://doi.org/10.1080/19336918.2015.1122156
• http://doi.org/10.1016/j.ymeth.2015.09.025
• http://doi.org/10.1007/s12195-019-00591-2
• http://doi.org/10.1186/s12987-020-0177-y
• http://doi.org/10.1007/s10439-015-1517-y
• http://doi.org/10.1091/mbc.E16-03-0194
• http://doi.org/10.1002/smll.201804111

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• {"type"=>"COMMENT", "annotationUri"=>"info:doi/10.1371/annotation/a1df7b65-540d-4b7b-8f05-ee94513b6a01", "title"=>"Citation - transcellular migration", "body"=>"I would like to comment on a single point in the introduction of the paper. The authors state the following: “Cancer cells have been observed to migrate through the EC cell body [10]” and “(a) cancer cells may migrate through the EC body [10]”.\nIn ref. 10 (Heyder et al., J Cancer Res Clin Oncol 128: 533-38, 2002) however, the authors do not deal at all with the transcellular migration of tumor cells through endothelial cells. In the literature there is very few evidence of the transmigration of cancer cells through the endothelial cell body; here are two papers in the topic: Khuon et al., J Cell Sci 123:431-40, 2010; Arvanitis et al., PLoS One 9:e89758, 2014.\nDue to the paucity of data regarding transcellular migration of metastatic cells through endothelial cells, I feel of special importance to cite relevant publications.", "isRemoved"=>false, "created"=>"2015-04-13T13:43:21Z", "lastModified"=>"2015-04-13T13:43:21Z", "creator"=>{"userId"=>"503302"}, "highlightedText"=>"", "competingInterestStatement"=>{"creatorWasPrompted"=>true, "hasCompetingInterests"=>false}, "parentArticle"=>{"doi"=>"info:doi/10.1371/journal.pone.0109748", "state"=>"published", "journals"=>{"PLoSONE"=>{"journalKey"=>"PLoSONE", "eIssn"=>"1932-6203", "title"=>"PLOS ONE"}}}, "replyTreeSize"=>0, "mostRecentActivity"=>"2015-04-13T13:43:21Z", "replies"=>[]}

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• {"title"=>"File:VE-Cadherin-Independent-Cancer-Cell-Incorporation-into-the-Vascular-Endothelium-Precedes-pone.0109748.s005.ogv", "url"=>"http://commons.wikimedia.org/wiki/File:VE-Cadherin-Independent-Cancer-Cell-Incorporation-into-the-Vascular-Endothelium-Precedes-pone.0109748.s005.ogv", "timestamp"=>"2018-01-29T12:26:25Z"}
• {"title"=>"File:VE-Cadherin-Independent-Cancer-Cell-Incorporation-into-the-Vascular-Endothelium-Precedes-pone.0109748.s006.ogv", "url"=>"http://commons.wikimedia.org/wiki/File:VE-Cadherin-Independent-Cancer-Cell-Incorporation-into-the-Vascular-Endothelium-Precedes-pone.0109748.s006.ogv", "timestamp"=>"2018-01-29T12:26:26Z"}

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Figshare

• {"files"=>["https://ndownloader.figshare.com/files/1702984"], "description"=>"<p>(A) Phase contrast image of MDA-MB-231 cells (bright white) atop a human umbilical vein endothelial (HUVEC) monolayer. Scale bar is 20 µm. (B) MDA-MB-231 cell (black arrows) begins to incorporate into the endothelium, as indicated by its change in phase contrast microscopy from bright white to darkened. Scale bar is 20 µm and applies to all images in panel B. Length of time after plating MDA-MB-231 cells on the endothelium is indicated in the upper right corner of each image in hour:minute:second format. The final percentage of incorporation for this experiment was 95%. (C) Phase contrast image sequence of a neutrophil transmigrating through a TNF-α-activated endothelium. Scale bar is 20 µm and applies to all images in panel C. Length of time after plating neutrophils on the endothelium is indicated in the upper right corner of each image in hour:minute:second format.</p>", "links"=>[], "tags"=>["cancer cell incorporation", "tumor cell extravasation", "cancer cells", "Vascular Endothelium Precedes Transmigration Metastasis", "ec", "endothelium", "activation status", "subendothelial substrate stiffness", "Cancer cell migration", "pancreatic cancer cell incorporation", "cancer cell transmigration"], "article_id"=>1192160, "categories"=>["Biological Sciences"], "users"=>["Susan M. Hamilla", "Kimberly M. Stroka", "Helim Aranda-Espinoza"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0109748.g001", "stats"=>{"downloads"=>1, "page_views"=>4, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Incorporation_of_MDA_MB_231_metastatic_breast_cancer_cells_is_a_first_step_in_the_extravasation_process_/1192160", "title"=>"Incorporation of MDA-MB-231 metastatic breast cancer cells is a first step in the extravasation process.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-10-02 03:55:14"}
• {"files"=>["https://ndownloader.figshare.com/files/1702993"], "description"=>"<p>(A) Cumulative fraction of ECs or MDA-MB-231 cells (231), SW1990 (1990), and A375 cells incorporated into the endothelium as a function of time after plating. Data points represent mean ± SEM for at least 3 independent experiments (N>20 cells for each experiment). (B) Final fraction of MDA-MB-231 cells incorporated into the untreated or TNF-α-treated endothelium after 15 hours. Bars represent mean, while error bars represent SEM of at least 3 independent experiments. P>0.05 between these values indicates there is no statistical difference (n.s.). (C) Final fraction of MDA-MB-231 breast cancer cells, ECs, A375 melanoma cells, and SW1990 pancreatic cells incorporated into the endothelium after 15 hours. Bars represent mean, while error bars represent SEM of at least 3 independent experiments. (*) indicates significance (P<0.05) when compared to ECs. (D) Plot of spreading area versus time reveals differences in spreading dynamics for MDA-MB-231 cells spreading onto a fibronectin-coated coverslip (“single cells”) or into an untreated endothelium (“into monolayer”).</p>", "links"=>[], "tags"=>["cancer cell incorporation", "tumor cell extravasation", "cancer cells", "Vascular Endothelium Precedes Transmigration Metastasis", "ec", "endothelium", "activation status", "subendothelial substrate stiffness", "Cancer cell migration", "pancreatic cancer cell incorporation", "cancer cell transmigration"], "article_id"=>1192169, "categories"=>["Biological Sciences"], "users"=>["Susan M. Hamilla", "Kimberly M. Stroka", "Helim Aranda-Espinoza"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0109748.g003", "stats"=>{"downloads"=>1, "page_views"=>13, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Incorporation_of_MDA_MB_231_does_not_depend_on_whether_the_endothelium_is_activated_by_TNF_945_/1192169", "title"=>"Incorporation of MDA-MB-231 does not depend on whether the endothelium is activated by TNF-α.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-10-02 03:55:14"}
• {"files"=>["https://ndownloader.figshare.com/files/1702990"], "description"=>"<p>Phase contrast (left) and DiIC₁₆ fluorescence (right) images of MDA-MB-231 cells plated onto an untreated HUVEC monolayer, at time points immediately after plating (top) and after 16 hours of interaction with the endothelium (bottom). Red arrows point to phase-white cells that do not emit fluorescence; these are endothelial cells that have been forced out of the monolayer and thus have detached and become rounded. Scale bar is 25 µm and applies to all images.</p>", "links"=>[], "tags"=>["cancer cell incorporation", "tumor cell extravasation", "cancer cells", "Vascular Endothelium Precedes Transmigration Metastasis", "ec", "endothelium", "activation status", "subendothelial substrate stiffness", "Cancer cell migration", "pancreatic cancer cell incorporation", "cancer cell transmigration"], "article_id"=>1192166, "categories"=>["Biological Sciences"], "users"=>["Susan M. Hamilla", "Kimberly M. Stroka", "Helim Aranda-Espinoza"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0109748.g002", "stats"=>{"downloads"=>2, "page_views"=>14, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_MDA_MB_231_incorporation_causes_detachment_and_rounding_of_some_endothelial_cells_/1192166", "title"=>"MDA-MB-231 incorporation causes detachment and rounding of some endothelial cells.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-10-02 03:55:14"}
• {"files"=>["https://ndownloader.figshare.com/files/1703001"], "description"=>"<p>(A) Cumulative fraction of MDA-MB-231 cells incorporated into endothelial cells on a fibronectin-coated 0.87 kPa or 280 kPa polyacrylamide gel, or glass (50 GPa). Data points represent mean ± SEM for at least 3 independent experiments (N>20 cells for each experiment). (B) Final fraction of MDA-MB-231 cells incorporated into the (untreated) endothelium as a function of subendothelial substrate stiffness. Bars represent mean, while error bars represent SEM of at least 3 independent experiments. P>0.05 between these values indicates there is no statistical difference (n.s.). (C) Time for MDA-MB-231 cells to complete incorporation is independent of the mechanical properties of the substrate below the endothelial cells. Endothelial cells on fibronectin-coated glass coverslips (50 GPa) or polyacrylamide gels (0.87 kPa or 280 kPa) were left untreated (no TNF) or treated with TNF-α (TNF). No statistical difference in incorporation time was measured as a function of subendothelial substrate stiffness or endothelial cell treatment (P>0.05).</p>", "links"=>[], "tags"=>["cancer cell incorporation", "tumor cell extravasation", "cancer cells", "Vascular Endothelium Precedes Transmigration Metastasis", "ec", "endothelium", "activation status", "subendothelial substrate stiffness", "Cancer cell migration", "pancreatic cancer cell incorporation", "cancer cell transmigration"], "article_id"=>1192177, "categories"=>["Biological Sciences"], "users"=>["Susan M. Hamilla", "Kimberly M. Stroka", "Helim Aranda-Espinoza"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0109748.g005", "stats"=>{"downloads"=>2, "page_views"=>26, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Incorporation_of_MDA_MB_231_does_not_depend_on_subendothelial_substrate_stiffness_/1192177", "title"=>"Incorporation of MDA-MB-231 does not depend on subendothelial substrate stiffness.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-10-02 03:55:14"}
• {"files"=>["https://ndownloader.figshare.com/files/1703141", "https://ndownloader.figshare.com/files/1703142", "https://ndownloader.figshare.com/files/1703143", "https://ndownloader.figshare.com/files/1703144", "https://ndownloader.figshare.com/files/1703145", "https://ndownloader.figshare.com/files/1703146"], "description"=>"<div><p>Metastasis is accountable for 90% of cancer deaths. During metastasis, tumor cells break away from the primary tumor, enter the blood and the lymph vessels, and use them as highways to travel to distant sites in the body to form secondary tumors. Cancer cell migration through the endothelium and into the basement membrane represents a critical step in the metastatic cascade, yet it is not well understood. This process is well characterized for immune cells that routinely transmigrate through the endothelium to sites of infection, inflammation, or injury. Previous studies with leukocytes have demonstrated that this step depends heavily on the activation status of the endothelium and subendothelial substrate stiffness. Here, we used a previously established <i>in vitro</i> model of the endothelium and live cell imaging, in order to observe cancer cell transmigration and compare this process to leukocytes. Interestingly, cancer cell transmigration includes an additional step, which we term ‘incorporation’, into the endothelial cell (EC) monolayer. During this phase, cancer cells physically displace ECs, leading to the dislocation of EC VE-cadherin away from EC junctions bordering cancer cells, and spread into the monolayer. In some cases, ECs completely detach from the matrix. Furthermore, cancer cell incorporation occurs independently of the activation status and the subendothelial substrate stiffness for breast cancer and melanoma cells, a notable difference from the process by which leukocytes transmigrate. Meanwhile, pancreatic cancer cell incorporation was dependent on the activation status of the endothelium and changed on very stiff subendothelial substrates. Collectively, our results provide mechanistic insights into tumor cell extravasation and demonstrate that incorporation is one of the earliest steps.</p></div>", "links"=>[], "tags"=>["cancer cell incorporation", "tumor cell extravasation", "cancer cells", "Vascular Endothelium Precedes Transmigration Metastasis", "ec", "endothelium", "activation status", "subendothelial substrate stiffness", "Cancer cell migration", "pancreatic cancer cell incorporation", "cancer cell transmigration"], "article_id"=>1192272, "categories"=>["Biological Sciences"], "users"=>["Susan M. Hamilla", "Kimberly M. Stroka", "Helim Aranda-Espinoza"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0109748.s001", "https://dx.doi.org/10.1371/journal.pone.0109748.s002", "https://dx.doi.org/10.1371/journal.pone.0109748.s003", "https://dx.doi.org/10.1371/journal.pone.0109748.s004", "https://dx.doi.org/10.1371/journal.pone.0109748.s005", "https://dx.doi.org/10.1371/journal.pone.0109748.s006"], "stats"=>{"downloads"=>16, "page_views"=>24, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_VE_Cadherin_Independent_Cancer_Cell_Incorporation_into_the_Vascular_Endothelium_Precedes_Transmigration_/1192272", "title"=>"VE-Cadherin-Independent Cancer Cell Incorporation into the Vascular Endothelium Precedes Transmigration", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2014-10-02 03:55:14"}
• {"files"=>["https://ndownloader.figshare.com/files/1702998"], "description"=>"<p>(A) A representative MDA-MB-231 (green; Actin-GFP) cell infected with GFP-actin is shown spreading into a HUVEC monolayer (red; Phalloidin). Orthogonal projections are shown. (B) Schematic showing that a cancer cell (green) displaces ECs (red) by spreading between adjacent ECs during incorporation.</p>", "links"=>[], "tags"=>["cancer cell incorporation", "tumor cell extravasation", "cancer cells", "Vascular Endothelium Precedes Transmigration Metastasis", "ec", "endothelium", "activation status", "subendothelial substrate stiffness", "Cancer cell migration", "pancreatic cancer cell incorporation", "cancer cell transmigration"], "article_id"=>1192174, "categories"=>["Biological Sciences"], "users"=>["Susan M. Hamilla", "Kimberly M. Stroka", "Helim Aranda-Espinoza"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0109748.g004", "stats"=>{"downloads"=>2, "page_views"=>7, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Confocal_images_reveal_that_MDA_MB_231_cells_do_not_migrate_underneath_ECs_during_the_incorporation_process_/1192174", "title"=>"Confocal images reveal that MDA-MB-231 cells do not migrate underneath ECs during the incorporation process.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-10-02 03:55:14"}
• {"files"=>["https://ndownloader.figshare.com/files/1703026"], "description"=>"<p>DiIC₁₆-labeled MDA-MB-231 cells were plated onto endothelial cells expressing VE-cadherin-GFP (VE-cad-GFP). (A) Shown are differential interference contrast (DIC), DiIC₁₆ (red) fluorescence, and VE-cadherin-GFP (green) fluorescence, and overlay images. At this time point, one MDA-MB-231 has already incorporated into the endothelium (yellow arrows), and the VE-cadherin-GFP is still intact in the location directly below another MDA-MB-231 cell that has not yet begun to incorporate (red arrows). (B) Fluorescence timelapse sequence of a DiIC₁₆-labeled MDA-MB-231 cell (red) incorporating into an endothelium expressing VE-cadherin-GFP (green). Length of time after plating MDA-MB-231 cells on the endothelium is indicated in the upper right corner of each image in hour:minute format. Scale bar in panel A (DIC image) is 10 µm and applies to all images in this figure.</p>", "links"=>[], "tags"=>["cancer cell incorporation", "tumor cell extravasation", "cancer cells", "Vascular Endothelium Precedes Transmigration Metastasis", "ec", "endothelium", "activation status", "subendothelial substrate stiffness", "Cancer cell migration", "pancreatic cancer cell incorporation", "cancer cell transmigration"], "article_id"=>1192202, "categories"=>["Biological Sciences"], "users"=>["Susan M. Hamilla", "Kimberly M. Stroka", "Helim Aranda-Espinoza"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0109748.g007", "stats"=>{"downloads"=>1, "page_views"=>11, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Cancer_cell_incorporation_initiates_by_dislocating_VE_cadherin_at_endothelial_cell_junctions_/1192202", "title"=>"Cancer cell incorporation initiates by dislocating VE-cadherin at endothelial cell junctions.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-10-02 03:55:14"}
• {"files"=>["https://ndownloader.figshare.com/files/1703008"], "description"=>"<p>DiIC16-labeled HUVECs (A) or MDA-MB-231 (B) were plated onto endothelial cells expressing VE-cadherin-GFP (VE-cad-GFP). Images were captured following incorporation of each cell type. Scale bar is 10 µm and applies to all images in this figure.</p>", "links"=>[], "tags"=>["cancer cell incorporation", "tumor cell extravasation", "cancer cells", "Vascular Endothelium Precedes Transmigration Metastasis", "ec", "endothelium", "activation status", "subendothelial substrate stiffness", "Cancer cell migration", "pancreatic cancer cell incorporation", "cancer cell transmigration"], "article_id"=>1192184, "categories"=>["Biological Sciences"], "users"=>["Susan M. Hamilla", "Kimberly M. Stroka", "Helim Aranda-Espinoza"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0109748.g006", "stats"=>{"downloads"=>1, "page_views"=>15, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Endothelial_cells_do_not_express_VE_cadherin_along_borders_with_incorporated_cancer_cells_/1192184", "title"=>"Endothelial cells do not express VE-cadherin along borders with incorporated cancer cells.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-10-02 03:55:14"}

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Relative Metric

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F1000Prime