Preventing the Activation or Cycling of the Rap1 GTPase Alters Adhesion and Cytoskeletal Dynamics and Blocks Metastatic Melanoma Cell Extravasation into the Lungs
The Rap1 GTPase is a master regulator of cell adhesion, polarity, and migration. We show that both blocking Rap1 activation and expressing a constitutively active form of Rap1 reduced the ability of B16F1 melanoma cells to extravasate from the microvasculature and form metastatic lesions in the lung...
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| Veröffentlicht in: | Cancer research (Chicago, Ill.) Ill.), 2010-06, Vol.70 (11), p.4590-4601 |
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| container_title | Cancer research (Chicago, Ill.) |
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| creator | FREEMAN, Spencer A MCLEOD, Sarah J DUKOWSKI, Janet AUSTIN, Pamela LEE, Crystal C. Y MILLEN-MARTIN, Brandie KUBES, Paul MCCAFFERTY, Donna-Marie GOLD, Michael R ROSKELLEY, Calvin D |
| description | The Rap1 GTPase is a master regulator of cell adhesion, polarity, and migration. We show that both blocking Rap1 activation and expressing a constitutively active form of Rap1 reduced the ability of B16F1 melanoma cells to extravasate from the microvasculature and form metastatic lesions in the lungs. This correlated with a decreased ability of the tumor cells to undergo transendothelial migration (TEM) in vitro and form dynamic, F-actin-rich pseudopodia that penetrate capillary endothelial walls in vivo. Using multiple tumor cell lines, we show that the inability to form these membrane protrusions, which likely promote TEM and extravasation, can be explained by altered adhesion dynamics and impaired cell polarization that result when Rap1 activation or cycling is perturbed. Thus, targeting Rap1 could be a useful approach for reducing the metastatic dissemination of tumor cells that undergo active TEM. |
| doi_str_mv | 10.1158/0008-5472.CAN-09-3414 |
| format | Article |
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Using multiple tumor cell lines, we show that the inability to form these membrane protrusions, which likely promote TEM and extravasation, can be explained by altered adhesion dynamics and impaired cell polarization that result when Rap1 activation or cycling is perturbed. Thus, targeting Rap1 could be a useful approach for reducing the metastatic dissemination of tumor cells that undergo active TEM.</description><identifier>ISSN: 0008-5472</identifier><identifier>EISSN: 1538-7445</identifier><identifier>DOI: 10.1158/0008-5472.CAN-09-3414</identifier><identifier>PMID: 20484042</identifier><identifier>CODEN: CNREA8</identifier><language>eng</language><publisher>Philadelphia, PA: American Association for Cancer Research</publisher><subject>Animals ; Antineoplastic agents ; Biological and medical sciences ; Cell Adhesion - physiology ; Cell Communication - physiology ; Cytoskeleton - enzymology ; Cytoskeleton - pathology ; Dermatology ; Endothelial Cells - cytology ; Endothelial Cells - enzymology ; Enzyme Activation ; Focal Adhesions - enzymology ; Focal Adhesions - pathology ; Humans ; Lung Neoplasms - blood supply ; Lung Neoplasms - enzymology ; Lung Neoplasms - prevention & control ; Lung Neoplasms - secondary ; Medical sciences ; Melanoma, Experimental - blood supply ; Melanoma, Experimental - enzymology ; Melanoma, Experimental - prevention & control ; Melanoma, Experimental - secondary ; Mice ; Mice, Inbred C57BL ; Pharmacology. Drug treatments ; rap1 GTP-Binding Proteins - metabolism ; Tumors ; Tumors of the skin and soft tissue. 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Y</creatorcontrib><creatorcontrib>MILLEN-MARTIN, Brandie</creatorcontrib><creatorcontrib>KUBES, Paul</creatorcontrib><creatorcontrib>MCCAFFERTY, Donna-Marie</creatorcontrib><creatorcontrib>GOLD, Michael R</creatorcontrib><creatorcontrib>ROSKELLEY, Calvin D</creatorcontrib><title>Preventing the Activation or Cycling of the Rap1 GTPase Alters Adhesion and Cytoskeletal Dynamics and Blocks Metastatic Melanoma Cell Extravasation into the Lungs</title><title>Cancer research (Chicago, Ill.)</title><addtitle>Cancer Res</addtitle><description>The Rap1 GTPase is a master regulator of cell adhesion, polarity, and migration. We show that both blocking Rap1 activation and expressing a constitutively active form of Rap1 reduced the ability of B16F1 melanoma cells to extravasate from the microvasculature and form metastatic lesions in the lungs. This correlated with a decreased ability of the tumor cells to undergo transendothelial migration (TEM) in vitro and form dynamic, F-actin-rich pseudopodia that penetrate capillary endothelial walls in vivo. Using multiple tumor cell lines, we show that the inability to form these membrane protrusions, which likely promote TEM and extravasation, can be explained by altered adhesion dynamics and impaired cell polarization that result when Rap1 activation or cycling is perturbed. Thus, targeting Rap1 could be a useful approach for reducing the metastatic dissemination of tumor cells that undergo active TEM.</description><subject>Animals</subject><subject>Antineoplastic agents</subject><subject>Biological and medical sciences</subject><subject>Cell Adhesion - physiology</subject><subject>Cell Communication - physiology</subject><subject>Cytoskeleton - enzymology</subject><subject>Cytoskeleton - pathology</subject><subject>Dermatology</subject><subject>Endothelial Cells - cytology</subject><subject>Endothelial Cells - enzymology</subject><subject>Enzyme Activation</subject><subject>Focal Adhesions - enzymology</subject><subject>Focal Adhesions - pathology</subject><subject>Humans</subject><subject>Lung Neoplasms - blood supply</subject><subject>Lung Neoplasms - enzymology</subject><subject>Lung Neoplasms - prevention & control</subject><subject>Lung Neoplasms - secondary</subject><subject>Medical sciences</subject><subject>Melanoma, Experimental - blood supply</subject><subject>Melanoma, Experimental - enzymology</subject><subject>Melanoma, Experimental - prevention & control</subject><subject>Melanoma, Experimental - secondary</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Pharmacology. Drug treatments</subject><subject>rap1 GTP-Binding Proteins - metabolism</subject><subject>Tumors</subject><subject>Tumors of the skin and soft tissue. 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Y</au><au>MILLEN-MARTIN, Brandie</au><au>KUBES, Paul</au><au>MCCAFFERTY, Donna-Marie</au><au>GOLD, Michael R</au><au>ROSKELLEY, Calvin D</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Preventing the Activation or Cycling of the Rap1 GTPase Alters Adhesion and Cytoskeletal Dynamics and Blocks Metastatic Melanoma Cell Extravasation into the Lungs</atitle><jtitle>Cancer research (Chicago, Ill.)</jtitle><addtitle>Cancer Res</addtitle><date>2010-06-01</date><risdate>2010</risdate><volume>70</volume><issue>11</issue><spage>4590</spage><epage>4601</epage><pages>4590-4601</pages><issn>0008-5472</issn><eissn>1538-7445</eissn><coden>CNREA8</coden><abstract>The Rap1 GTPase is a master regulator of cell adhesion, polarity, and migration. We show that both blocking Rap1 activation and expressing a constitutively active form of Rap1 reduced the ability of B16F1 melanoma cells to extravasate from the microvasculature and form metastatic lesions in the lungs. 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| ispartof | Cancer research (Chicago, Ill.), 2010-06, Vol.70 (11), p.4590-4601 |
| issn | 0008-5472 1538-7445 |
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| source | MEDLINE; American Association for Cancer Research; EZB-FREE-00999 freely available EZB journals |
| subjects | Animals Antineoplastic agents Biological and medical sciences Cell Adhesion - physiology Cell Communication - physiology Cytoskeleton - enzymology Cytoskeleton - pathology Dermatology Endothelial Cells - cytology Endothelial Cells - enzymology Enzyme Activation Focal Adhesions - enzymology Focal Adhesions - pathology Humans Lung Neoplasms - blood supply Lung Neoplasms - enzymology Lung Neoplasms - prevention & control Lung Neoplasms - secondary Medical sciences Melanoma, Experimental - blood supply Melanoma, Experimental - enzymology Melanoma, Experimental - prevention & control Melanoma, Experimental - secondary Mice Mice, Inbred C57BL Pharmacology. Drug treatments rap1 GTP-Binding Proteins - metabolism Tumors Tumors of the skin and soft tissue. Premalignant lesions |
| title | Preventing the Activation or Cycling of the Rap1 GTPase Alters Adhesion and Cytoskeletal Dynamics and Blocks Metastatic Melanoma Cell Extravasation into the Lungs |
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