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Syngeneic mesenchymal stem cells loaded with telomerase-dependent oncolytic adenoviruses enhance anti-metastatic efficacy.

Yang, Mei-Lin; Hu, Che-Yuan; Lee, Ya-Che; Chang, Chao-Ching; Chen, Yi-Cheng; Lee, Pei-Ru; Su, Bing-Hua; Chen, Pi-Che; Shiau, Ai-Li; Shieh, Gia-Shing; Wu, Chao-Liang; Wu, Pensee


Mei-Lin Yang

Che-Yuan Hu

Ya-Che Lee

Chao-Ching Chang

Yi-Cheng Chen

Pei-Ru Lee

Bing-Hua Su

Pi-Che Chen

Ai-Li Shiau

Gia-Shing Shieh

Chao-Liang Wu


Oncolytic adenoviruses have emerged as a promising therapeutic approach for cancer therapy. However, systemic delivery of the viruses to metastatic tumors remains a major challenge. Mesenchymal stem cells (MSCs) possess tumor tropism property and can be used as cellular vehicles for delivering oncolytic adenoviruses to tumor sites. Since telomerase activity is found in ~90% of human carcinomas, but undetected in normal adult cells, the human telomerase reverse transcriptase gene (TERT) promoter can be exploited for regulating the replication of oncolytic adenoviruses. Here, we evaluated the antitumor effects of syngeneic murine MSCs loaded with the luciferase-expressing, telomerase-dependent oncolytic adenovirus Ad.GS2 (MSC-Ad.GS2) and Ad.GS2 alone on metastatic MBT-2 bladder tumors. MSCs supported a low degree of Ad.GS2 replication, which could be augmented by coculture with MBT-2 cells or tumor-conditioned medium (TCM), suggesting that viral replication is increased when MSC-Ad.GS2 migrates to tumor sites. MBT-2 cells and TCM enhanced viral replication in Ad.GS2-infected MSCs. SDF-1 is a stem cell homing factor. Our results suggest that the SDF-1/STAT3/TERT signaling axis in MSCs in response to the tumor microenvironment may contribute to the enhanced replication of Ad.GS2 carried by MSCs. Notably, we demonstrate the potent therapeutic efficacy of systemically delivered MSC-Ad.GS2 in pleural disseminated tumor and experimental metastasis models using intrapleural and tail vein injection of MBT-2 cells, respectively. Treatment with MSC-Ad.GS2 significantly reduced tumor growth and prolonged the survival of mice bearing metastatic bladder tumors. Since telomerase is expressed in a broad spectrum of cancers, this therapeutic strategy may be broadly applicable. [Abstract copyright: © The Author(s) 2024. Published by Oxford University Press.]


Yang, M.-L., Hu, C.-Y., Lee, Y.-C., Chang, C.-C., Chen, Y.-C., Lee, P.-R., …Wu, P. (in press). Syngeneic mesenchymal stem cells loaded with telomerase-dependent oncolytic adenoviruses enhance anti-metastatic efficacy. Stem Cells Translational Medicine, Article szae039.

Journal Article Type Article
Acceptance Date Apr 11, 2024
Online Publication Date Jun 12, 2024
Deposit Date Jul 4, 2024
Journal Stem cells translational medicine
Print ISSN 2157-6564
Electronic ISSN 2157-6580
Publisher AlphaMed Press
Peer Reviewed Peer Reviewed
Article Number szae039
Keywords oncolytic adenovirus, mesenchymal stem cell, telomerase, TERT, tumor microenvironment, metastasis, bladder cancer, SDF-1
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