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

Registo completo
Campo DCValorIdioma
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.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.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.description.sponsorshipThis study was supported by Fundacao de Amparo a Pesquisa do Estado de Sao Paulo [grant no 2014/24400-0; 2013/05172-4 (Postdoctoral fellowship)]; and Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior/PRODOC [grant no 3193-32/2010]. S.S., F.F.F. S.S.M.E. designed research, analyzed data and, wrote the paper; S.S. and F.F.F. performed all experiments; M.T., P.C.P, R.R.M, D.K.A.F., G.N.B, A.F.E. performed some experiments; V.L.V and R.M.R analyzed data and, wrote the paperpor
dc.subjectBRAF-resistant melanomapor
dc.subjectTumor microenvironmentpor
dc.subject3D skin reconstructionpor
dc.subjectMMP-2, BRAF-resistant melanomapor
dc.subjectTumor microenvironment, secretome, 3D skin reconstructionpor
dc.titleVemurafenib resistance increases melanoma invasiveness and modulates the tumor microenvironment by MMP-2 upregulationpor
degois.publication.titlePharmacological Researchpor
dc.subject.wosScience & Technologypor
sdum.journalPharmacological Researchpor
Aparece nas coleções:ICVS - Artigos em Revistas Internacionais com Referee

Ficheiros deste registo:
Ficheiro Descrição TamanhoFormato 
sandri2016.pdf1,04 MBAdobe PDFVer/Abrir  Solicitar cópia ao autor!

Partilhe no FacebookPartilhe no TwitterPartilhe no DeliciousPartilhe no LinkedInPartilhe no DiggAdicionar ao Google BookmarksPartilhe no MySpacePartilhe no Orkut
Exporte no formato BibTex mendeley Exporte no formato Endnote Adicione ao seu Currículo DeGóis