2024-03-29T02:33:31Zhttp://digital.csic.es/dspace-oai/requestoai:digital.csic.es:10261/1692472020-12-13T09:02:14Zcom_10261_112com_10261_1col_10261_365
C3G promotes a selective release of angiogenic factors from activated mouse platelets to regulate angiogenesis and tumor metastasis
Martín-Granado, Víctor
Ortiz-Rivero, Sara
Carmona, Rita
Gutiérrez-Herrero, Sara
Barrera, Mario
San-Segundo, Laura
Sequera, Celia
Perdiguero, Pedro
Lozano, Francisco S.
Martin-Herrero, Francisco
González-Porras, José R.
Muñoz-Chápuli, Ramón
Porras, Almudena
Guerrero Arroyo, María del Carmen
Universidad Complutense de Madrid
Universidad de Salamanca
Junta de Castilla y León
European Commission
Ministerio de Economía y Competitividad (España)
Metastasis
Platelet secretome
Angiogenesis
Vamp-7
C3G
Previous observations indicated that C3G (RAPGEF1) promotes a-granule release, evidenced by the increase in P-selectin exposure on the platelet surface following its activation. The goal of the present study is to further characterize the potential function of C3G as a modulator of the platelet releasate and its implication in the regulation of angiogenesis. Proteomic analysis revealed a decreased secretion of anti-angiogenic factors from activated transgenic C3G and C3GΔCat platelets. Accordingly, the secretome from both transgenic platelets had an overall pro-angiogenic effect as evidenced by an in vitro capillary-tube formation assay with HUVECs (human umbilical vein endothelial cells) and by two in vivo models of heterotopic tumor growth. In addition, transgenic C3G expression in platelets greatly increased mouse melanoma cells metastasis. Moreover, immunofluorescence microscopy showed that the pro-angiogenic factors VEGF and bFGF were partially retained into a-granules in thrombin- and ADP-activated mouse platelets from both, C3G and C3GΔCat transgenic mice. The observed interaction between C3G and Vesicle-associated membrane protein (Vamp)-7 could explain these results. Concomitantly, increased platelet spreading in both transgenic platelets upon thrombin activation supports this novel function of C3G in a-granule exocytosis. Collectively, our data point out to the co-existence of Rap1GEF-dependent and independent mechanisms mediating C3G effects on platelet secretion, which regulates pathological angiogenesis in tumors and other contexts. The results herein support an important role for platelet C3G in angiogenesis and metastasis.
This work was supported by grants from the Spanish Ministry of Economy and Competitiveness [SAF2013-48210-C2-1-R and SAF2016-76588-C2-2-R to CG,
SAF2013-48210-C2-2-R and SAF2016-76588-C2-1-R to AP], by two grants from the Council of Education of Junta de Castilla y León, Spain [SA157A12-1 and SA017U16 to
CG] and by a grant from the Council of Health of Junta de Castilla y León, Spain [GRS 991/A/14 to FMH]. All funding was cosponsored by the European FEDER Program. VM-G
was supported by Dr. Moraza Foundation PhD fellowship. SG-H and CS are recipients of fellowships from the Salamanca University and the Complutense University,
respectively
Peer Reviewed
2018-08-30T09:10:53Z
2018-08-30T09:10:53Z
2017
2018-08-30T09:10:53Z
artículo
http://purl.org/coar/resource_type/c_6501
doi: 10.18632/oncotarget.22339
e-issn: 1949-2553
Oncotarget 8(67): 110994-111011 (2017)
http://hdl.handle.net/10261/169247
10.18632/oncotarget.22339
http://dx.doi.org/10.13039/501100000780
http://dx.doi.org/10.13039/501100002911
http://dx.doi.org/10.13039/501100003329
http://dx.doi.org/10.13039/501100014180
29340032
#PLACEHOLDER_PARENT_METADATA_VALUE#
#PLACEHOLDER_PARENT_METADATA_VALUE#
#PLACEHOLDER_PARENT_METADATA_VALUE#
#PLACEHOLDER_PARENT_METADATA_VALUE#
info:eu-repo/grantAgreement/MINECO/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/SAF2016-76588-C2-1-R
info:eu-repo/grantAgreement/MINECO/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/SAF2013-48210-C2-2-R
info:eu-repo/grantAgreement/MINECO/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/SAF2016-76588-C2-2-R
info:eu-repo/grantAgreement/MINECO/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/SAF2013-48210-C2-1-R
Publisher's version
https://doi.org/10.18632/oncotarget.22339
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