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1.
Oncotarget ; 7(34): 54795-54810, 2016 Aug 23.
Artigo em Inglês | MEDLINE | ID: mdl-27458162

RESUMO

Adoptively transferred mesenchymal stem cells (MSCs) home to solid tumors. Biologic features within the tumor environment can be used to selectively activate transgenes in engineered MSCs after tumor invasion. One of the characteristic features of solid tumors is hypoxia. We evaluated a hypoxia-based imaging and therapy strategy to target expression of the sodium iodide symporter (NIS) gene to experimental hepatocellular carcinoma (HCC) delivered by MSCs.MSCs engineered to express transgenes driven by a hypoxia-responsive promoter showed robust transgene induction under hypoxia as demonstrated by mCherry expression in tumor cell spheroid models, or radioiodide uptake using NIS. Subcutaneous and orthotopic HCC xenograft mouse models revealed significant levels of perchlorate-sensitive NIS-mediated tumoral radioiodide accumulation by tumor-recruited MSCs using 123I-scintigraphy or 124I-positron emission tomography. Functional NIS expression was further confirmed by ex vivo 123I-biodistribution analysis. Administration of a therapeutic dose of 131I in mice treated with NIS-transfected MSCs resulted in delayed tumor growth and reduced tumor perfusion, as shown by contrast-enhanced sonography, and significantly prolonged survival of mice bearing orthotopic HCC tumors. Interestingly, radioiodide uptake into subcutaneous tumors was not sufficient to induce therapeutic effects. Our results demonstrate the potential of using tumor hypoxia-based approaches to drive radioiodide therapy in non-thyroidal tumors.


Assuntos
Radioisótopos do Iodo/uso terapêutico , Neoplasias Hepáticas Experimentais/radioterapia , Neoplasias Hepáticas/radioterapia , Células-Tronco Mesenquimais/metabolismo , Simportadores/metabolismo , Animais , Linhagem Celular Tumoral , Terapia Combinada , Feminino , Humanos , Hipóxia , Radioisótopos do Iodo/farmacocinética , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas Experimentais/genética , Neoplasias Hepáticas Experimentais/metabolismo , Transplante de Células-Tronco Mesenquimais/métodos , Camundongos Nus , Simportadores/genética , Transfecção , Ensaios Antitumorais Modelo de Xenoenxerto
2.
Expert Opin Biol Ther ; 16(9): 1079-92, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27270211

RESUMO

INTRODUCTION: Mesenchymal stromal cells (MSCs) are non-hematopoietic progenitor cells that have been exploited as vehicles for cell-based cancer therapy. The general approach is based on the innate potential of adoptively applied MSC to undergo facilitated recruitment to malignant tissue. MSC from different tissue sources have been engineered using a variety of therapy genes that have shown efficacy in solid tumor models. AREAS COVERED: In this review we will focus on the current developments of MSC-based gene therapy, in particular the diverse approaches that have been used for MSCs-targeted tumor therapy. We also discuss some outstanding issues and general prospects for their clinical application. EXPERT OPINION: The use of modified mesenchymal stem cells as therapy vehicles for the treatment of solid tumors has progressed to the first generation of clinical trials, but the general field is still in its infancy. There are many questions that need to be addressed if this very complex therapy approach is widely applied in clinical settings. More must be understood about the mechanisms underlying tumor tropism and we need to identify the optimal source of the cells used. Outstanding issues also include the therapy transgenes used, and which tumor types represent viable targets for this therapy.


Assuntos
Terapia Genética/métodos , Transplante de Células-Tronco Mesenquimais/métodos , Células-Tronco Mesenquimais/fisiologia , Neoplasias/terapia , Animais , Terapia Baseada em Transplante de Células e Tecidos/métodos , Engenharia Genética/métodos , Humanos , Neoplasias/genética , Neoplasias/imunologia , Transgenes/genética
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