1. Glioblastoma Bystander Cell Therapy: Improvements in Treatment and Insights into the Therapy Mechanisms
- Author
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Lourdes Sánchez-Cid, Nuria Rubio, Carolina Soler-Botija, José Becerra, Carolina Nogueira de Moraes, Olaia F. Vila, Sara Ramos-Romero, Marta Guerra-Rebollo, Jerónimo Blanco, Cristina Alcoholado, Cristina Garrido, Óscar Meca-Cortés, Ministerio de Economía y Competitividad (España), Catalonian Institute for Advanced Chemistry (IQAC-CSIC), Biomaterials and Nanomedicine (CIBER-BBN), Universidade Estadual Paulista (Unesp), Biomedical Research Institute of Málaga (IBIMA), Health Science Research Institute Germans Trias i Pujol, Carlos III Health Institute, Columbia University, University of Barcelona, and Málaga
- Subjects
0301 basic medicine ,Cancer Research ,Cells ,Therapeutic Procedure ,lcsh:RC254-282 ,Article ,Cell therapy ,03 medical and health sciences ,0302 clinical medicine ,in vivo glioblastoma model ,Neoplasms ,Bystander effect ,glioblastoma bystander therapy ,Cytotoxic T cell ,Bioluminescence imaging ,Medicine ,Pharmacology (medical) ,clarity ,mesenchymal stem cell ,HVS-thymidine kinase ,Mesenchymal Stromal Cells ,business.industry ,Mesenchymal stem cell ,Extracellular vesicle ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,bioluminescence ,Tumor Debulking ,030104 developmental biology ,Oncology ,030220 oncology & carcinogenesis ,Cancer research ,Molecular Medicine ,transparent brain ,extracellular vesicle ,cell therapy ,business - Abstract
A preclinical model of glioblastoma (GB) bystander cell therapy using human adipose mesenchymal stromal cells (hAMSCs) is used to address the issues of cell availability, quality, and feasibility of tumor cure. We show that a fast proliferating variety of hAMSCs expressing thymidine kinase (TK) has therapeutic capacity equivalent to that of TK-expressing hAMSCs and can be used in a multiple-inoculation procedure to reduce GB tumors to a chronically inhibited state. We also show that up to 25% of unmodified hAMSCs can be tolerated in the therapeutic procedure without reducing efficacy. Moreover, mimicking a clinical situation, tumor debulking previous to cell therapy inhibits GB tumor growth. To understand these striking results at a cellular level, we used a bioluminescence imaging strategy and showed that tumor-implanted therapeutic cells do not proliferate, are unaffected by GCV, and spontaneously decrease to a stable level. Moreover, using the CLARITY procedure for tridimensional visualization of fluorescent cells in transparent brains, we find therapeutic cells forming vascular-like structures that often associate with tumor cells. In vitro experiments show that therapeutic cells exposed to GCV produce cytotoxic extracellular vesicles and suggest that a similar mechanism may be responsible for the in vivo therapeutic effectiveness of TK-expressing hAMSCs. © 2018 The Author(s), This work was funded by the Spanish Ministry of Science and Innovation (MICINN) (grant SAF2015-64927-C2-1-R), CIBER-BBN, CIBER Cardiovascular (grant CB16/11/00403), Instituto de Salud Carlos III, Red Temática de Investigación Cooperativa TerCel, and the Spanish Ministry of Economy and Competitiveness (MINECO) (grant BIO2015-66266-R). The authors specially thank Dr. Josep Roca from Delfos hospital (Dr. Roca i Noguera aesthetic surgery team) for the kind donation of liposuction for hAMSCs preparation, and to the services of cell culture (Catalonian Institute for Advanced Chemistry-Spanish National Research Council [IQAC-CISC]), animal care (IQAC-CSIC), cell sorting (Scientific and Technological Centers [CCiT]-University of Barcelona), confocal microscopy (CCiT-University of Barcelona), and Central Services for Research Support (SCAI) at the University of Málaga for their technician and specialized support.
- Published
- 2018