Adrian J M Bailey1,2,3, Alvin Tieu1,2,4, Manika Gupta1,3, Mitchell Slobodian1, Risa Shorr1,5, Tim Ramsay1,3,6, Rosendo A Rodriguez3, Dean A Fergusson1,3,6, Manoj M Lalu1,2,4,7, David S Allan8,9,10,11. 1. Clinical Epidemiology, Ottawa Hospital Research Institute, Box 704, 501 Smyth Rd, ON, K1H 8L6, Ottawa, Canada. 2. Regenerative Medicine Programs, Ottawa Hospital Research Institute, Ottawa, ON, Canada. 3. Departments of Medicine, University of Ottawa, Ottawa, ON, Canada. 4. Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, Canada. 5. Medical Library and Learning Services, The Ottawa Hospital, Ottawa, ON, Canada. 6. School of Epidemiology and Public Health, University of Ottawa, Ottawa, ON, Canada. 7. Anesthesiology and Pain Medicine, University of Ottawa, Ottawa, ON, Canada. 8. Clinical Epidemiology, Ottawa Hospital Research Institute, Box 704, 501 Smyth Rd, ON, K1H 8L6, Ottawa, Canada. daallan@toh.ca. 9. Regenerative Medicine Programs, Ottawa Hospital Research Institute, Ottawa, ON, Canada. daallan@toh.ca. 10. Departments of Medicine, University of Ottawa, Ottawa, ON, Canada. daallan@toh.ca. 11. Biochemistry, Microbiology & Immunology, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada. daallan@toh.ca.
Abstract
BACKGROUND: Mesenchymal stromal cell derived extracellular vesicles (MSC-EVs) have been implicated in the regulation of tumor growth. Studies remain preclinical with effects ranging from inhibition of tumor growth to cancer progression. A systematic review and meta-analysis is needed to clarify the effect of MSC-EVs on tumor growth to facilitate potential translation to clinical trials. METHODS: A systematic search of the literature (MEDLINE, Embase, and BIOSIS databases to June 1, 2019) identified all pre-clinical controlled studies investigating the effect of MSC-EVs on tumor growth. Study selection and data extraction were performed in duplicate. Potential risk of bias was assessed using the SYRCLE tool. A random effects meta-analysis of reduction in tumor weight/volume (primary outcome) was performed. RESULTS: We identified 29 articles and 22 reported data on tumor responses that were included for meta-analysis. Studies were associated with unclear risk of bias in a large proportion of domains in accordance with the SYRCLE tool for determining risk of bias in preclinical studies. A high risk of bias was not identified in any study. MSC-EVs had a mixed response on tumor progression with some studies reporting inhibition of tumor growth and others reporting tumor progression. Overall, MSC-EVs exerted a non-significant reduction in tumor growth compared to controls (standardized mean difference (SMD) -0.80, 95 % CI -1.64 to 0.03, p = 0.06, I2 = 87 %). Some studies reported increased tumor growth which aligned with their stated hypothesis and some interrogated mechanisms in cancer biology. EVs isolated from MSCs that overexpressed anti-tumor RNAs were associated with significant tumor reduction in meta-analysis (SMD - 2.40, 95 % CI -3.36 to -1.44, p < 0.001). Heterogeneity between studies was observed and included aspects of study design such as enrichment of MSC-EVs with specific anti-tumor molecules, tissue source of MSCs, method of EV isolation, characterization of MSCs and EVs, dosage and administration schedules, and tissue type and source of tumor cells studied. CONCLUSIONS: MSC-EVs are associated with mixed effects on tumor growth in animal models of cancer. In studies where anti-tumor RNAs are packaged in EVs, a significant reduction in tumor growth was observed. Reducing heterogeneity in study design may accelerate our understanding of the potential effects of MSC-EVs on cancer. [274 words] Forest plot of MSC-EV effect on tumor growth accordinggenetic modification of EVs in animal studies identified from a systematicreview of the literature. All cohorts from studies with multiple interventiongroups are presented separately with control groups divided equally among thegroups. M, modified; H, hypoxia.
BACKGROUND: Mesenchymal stromal cell derived extracellular vesicles (MSC-EVs) have been implicated in the regulation of tumor growth. Studies remain preclinical with effects ranging from inhibition of tumor growth to cancer progression. A systematic review and meta-analysis is needed to clarify the effect of MSC-EVs on tumor growth to facilitate potential translation to clinical trials. METHODS: A systematic search of the literature (MEDLINE, Embase, and BIOSIS databases to June 1, 2019) identified all pre-clinical controlled studies investigating the effect of MSC-EVs on tumor growth. Study selection and data extraction were performed in duplicate. Potential risk of bias was assessed using the SYRCLE tool. A random effects meta-analysis of reduction in tumor weight/volume (primary outcome) was performed. RESULTS: We identified 29 articles and 22 reported data on tumor responses that were included for meta-analysis. Studies were associated with unclear risk of bias in a large proportion of domains in accordance with the SYRCLE tool for determining risk of bias in preclinical studies. A high risk of bias was not identified in any study. MSC-EVs had a mixed response on tumor progression with some studies reporting inhibition of tumor growth and others reporting tumor progression. Overall, MSC-EVs exerted a non-significant reduction in tumor growth compared to controls (standardized mean difference (SMD) -0.80, 95 % CI -1.64 to 0.03, p = 0.06, I2 = 87 %). Some studies reported increased tumor growth which aligned with their stated hypothesis and some interrogated mechanisms in cancer biology. EVs isolated from MSCs that overexpressed anti-tumor RNAs were associated with significant tumor reduction in meta-analysis (SMD - 2.40, 95 % CI -3.36 to -1.44, p < 0.001). Heterogeneity between studies was observed and included aspects of study design such as enrichment of MSC-EVs with specific anti-tumor molecules, tissue source of MSCs, method of EV isolation, characterization of MSCs and EVs, dosage and administration schedules, and tissue type and source of tumor cells studied. CONCLUSIONS: MSC-EVs are associated with mixed effects on tumor growth in animal models of cancer. In studies where anti-tumor RNAs are packaged in EVs, a significant reduction in tumor growth was observed. Reducing heterogeneity in study design may accelerate our understanding of the potential effects of MSC-EVs on cancer. [274 words] Forest plot of MSC-EV effect on tumor growth accordinggenetic modification of EVs in animal studies identified from a systematicreview of the literature. All cohorts from studies with multiple interventiongroups are presented separately with control groups divided equally among thegroups. M, modified; H, hypoxia.
Authors: María Yáñez-Mó; Pia R-M Siljander; Zoraida Andreu; Apolonija Bedina Zavec; Francesc E Borràs; Edit I Buzas; Krisztina Buzas; Enriqueta Casal; Francesco Cappello; Joana Carvalho; Eva Colás; Anabela Cordeiro-da Silva; Stefano Fais; Juan M Falcon-Perez; Irene M Ghobrial; Bernd Giebel; Mario Gimona; Michael Graner; Ihsan Gursel; Mayda Gursel; Niels H H Heegaard; An Hendrix; Peter Kierulf; Katsutoshi Kokubun; Maja Kosanovic; Veronika Kralj-Iglic; Eva-Maria Krämer-Albers; Saara Laitinen; Cecilia Lässer; Thomas Lener; Erzsébet Ligeti; Aija Linē; Georg Lipps; Alicia Llorente; Jan Lötvall; Mateja Manček-Keber; Antonio Marcilla; Maria Mittelbrunn; Irina Nazarenko; Esther N M Nolte-'t Hoen; Tuula A Nyman; Lorraine O'Driscoll; Mireia Olivan; Carla Oliveira; Éva Pállinger; Hernando A Del Portillo; Jaume Reventós; Marina Rigau; Eva Rohde; Marei Sammar; Francisco Sánchez-Madrid; N Santarém; Katharina Schallmoser; Marie Stampe Ostenfeld; Willem Stoorvogel; Roman Stukelj; Susanne G Van der Grein; M Helena Vasconcelos; Marca H M Wauben; Olivier De Wever Journal: J Extracell Vesicles Date: 2015-05-14
Authors: L Kordelas; V Rebmann; A-K Ludwig; S Radtke; J Ruesing; T R Doeppner; M Epple; P A Horn; D W Beelen; B Giebel Journal: Leukemia Date: 2014-04 Impact factor: 11.528
Authors: Zorana J Andersen; Marie Pedersen; Gudrun Weinmayr; Massimo Stafoggia; Claudia Galassi; Jeanette T Jørgensen; Johan N Sommar; Bertil Forsberg; David Olsson; Bente Oftedal; Gunn Marit Aasvang; Per Schwarze; Andrei Pyko; Göran Pershagen; Michal Korek; Ulf De Faire; Claes-Göran Östenson; Laura Fratiglioni; Kirsten T Eriksen; Aslak H Poulsen; Anne Tjønneland; Elvira Vaclavik Bräuner; Petra H Peeters; Bas Bueno-de-Mesquita; Andrea Jaensch; Gabriele Nagel; Alois Lang; Meng Wang; Ming-Yi Tsai; Sara Grioni; Alessandro Marcon; Vittorio Krogh; Fulvio Ricceri; Carlotta Sacerdote; Enrica Migliore; Roel Vermeulen; Ranjeet Sokhi; Menno Keuken; Kees de Hoogh; Rob Beelen; Paolo Vineis; Giulia Cesaroni; Bert Brunekreef; Gerard Hoek; Ole Raaschou-Nielsen Journal: Neuro Oncol Date: 2018-02-19 Impact factor: 12.300
Authors: Alvin Tieu; Mitchell Slobodian; Dean A Fergusson; Joshua Montroy; Dylan Burger; Duncan J Stewart; Risa Shorr; David S Allan; Manoj M Lalu Journal: Syst Rev Date: 2019-12-12
Authors: Alvin Tieu; Kevin Hu; Catherine Gnyra; Joshua Montroy; Dean A Fergusson; David S Allan; Duncan J Stewart; Bernard Thébaud; Manoj M Lalu Journal: J Extracell Vesicles Date: 2021-10