Utilize este identificador para referenciar este registo: http://hdl.handle.net/1822/45097

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dc.contributor.authorSandri, Silvanapor
dc.contributor.authorFlores, Fernanda Faiãopor
dc.contributor.authorTiago, Manoelapor
dc.contributor.authorPennacchi, Paula C.por
dc.contributor.authorMassaro, Renato Ramospor
dc.contributor.authorFernandes, Débora Kristina Alvespor
dc.contributor.authorBerardinelli, Gustavo N.por
dc.contributor.authorEvangelista, Adriane F.por
dc.contributor.authorVazquez, Vinícius de Limapor
dc.contributor.authorReis, R. M.por
dc.contributor.other[et. al.]-
dc.date.accessioned2017-03-20T17:36:05Z-
dc.date.issued2016-
dc.identifier.citationSandri, S., Faião-Flores, F., Tiago, M., Pennacchi, P. C., Massaro, R. R., Alves-Fernandes, D. K., . . . Maria-Engler, S. S. (2016). Vemurafenib resistance increases melanoma invasiveness and modulates the tumor microenvironment by MMP-2 upregulation. [Article]. Pharmacological Research, 111, 523-533. doi: 10.1016/j.phrs.2016.07.017-
dc.identifier.issn1043-6618por
dc.identifier.urihttp://hdl.handle.net/1822/45097-
dc.description.abstractThe BRAF(V600E) mutation confers constitutive kinase activity and accounts for >90% of BRAF mutations in melanoma. This genetic alteration is a current therapeutic target; however, the antitumorigenic effects of the BRAF(V600E) inhibitor vemurafenib are short-lived and the majority of patients present tumor relapse in a short period after treatment. Characterization of vemurafenib resistance has been essential to the efficacy of next generation therapeutic strategies. Herein, we found that acute BRAF inhibition induced a decrease in active MMP-2, MT1-MMP and MMP-9, but did not modulate the metalloproteinase inhibitors TIMP-2 or RECK in naive melanoma cells. In vemurafenib-resistant melanoma cells, we observed a lower growth rate and an increase in EGFR phosphorylation followed by the recovery of active MMP-2 expression, a mediator of cancer metastasis. Furthermore, we found a different profile of MMP inhibitor expression, characterized by TIMP-2 downregulation and RECK upregulation. In a 3D spheroid model, the invasion index of vemurafenib-resistant melanoma cells was more evident than in its non-resistant counterpart. We confirmed this pattern in a matrigel invasion assay and demonstrated that use of a matrix metalloproteinase inhibitor reduced the invasion of vemurafenib resistant melanoma cells but not drug naive cells. Moreover, we did not observe a delimited group of cells invading the dermis in vemurafenib-resistant melanoma cells present in a reconstructed skin model. The same MMP-2 and RECK upregulation profile was found in this 3D skin model containing vemurafenib-resistant melanoma cells. Acute vemurafenib treatment induces the disorganization of collagen fibers and consequently, extracellular matrix remodeling, with this pattern observed even after the acquisition of resistance. Altogether, our data suggest that resistance to vemurafenib induces significant changes in the tumor microenvironment mainly by MMP-2 upregulation, with a corresponding increase in cell invasiveness.por
dc.language.isoengpor
dc.publisherElsevierpor
dc.rightsclosedAccesspor
dc.subjectMetalloproteinasepor
dc.subjectMMP-2por
dc.subjectBRAF-resistant melanomapor
dc.subjectVemurafenibpor
dc.subjectTumor microenvironmentpor
dc.subjectSecretomepor
dc.subject3D skin reconstructionpor
dc.titleVemurafenib resistance increases melanoma invasiveness and modulates the tumor microenvironment by MMP-2 upregulationpor
dc.typearticle-
dc.peerreviewedyespor
dc.relation.publisherversionhttp://www.sciencedirect.com/science/article/pii/S1043661816303760por
dc.publicationstatuspublished-
degois.publication.firstPage523por
degois.publication.lastPage533por
degois.publication.titlePharmacological Researchpor
degois.publication.volume111por
dc.date.updated2017-03-01T15:25:27Z-
dc.identifier.doi10.1016/j.phrs.2016.07.017por
dc.description.publicationversioninfo:eu-repo/semantics/publishedVersionpor
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