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

Mei-Lin Yang1,2, Che-Yuan Hu3, Ya-Che Lee4

  • 1Department of Medical Research, Ditmanson Medical Foundation Chia-Yi Christian Hospital, Chiayi, Taiwan.

Stem Cells Translational Medicine
|June 12, 2024
PubMed

Insights

Mesenchymal stem cells (MSCs) loaded with oncolytic adenovirus demonstrated potent therapeutic effects against metastatic bladder tumors. This strategy enhances viral delivery and replication within the tumor microenvironment, offering broad applicability for cancer therapy.

Area of Science:

  • Oncolytic virotherapy
  • Cancer biology
  • Stem cell therapy

Background:

  • Systemic delivery of oncolytic adenoviruses to metastatic tumors is challenging.
  • Mesenchymal stem cells (MSCs) exhibit tumor tropism and can serve as delivery vehicles.
  • Telomerase reverse transcriptase (TERT) promoter regulates oncolytic adenovirus replication, targeting cancer cells.

Purpose of the Study:

  • To evaluate the antitumor effects of MSCs loaded with telomerase-dependent oncolytic adenovirus (MSC-Ad.GS2) on metastatic MBT-2 bladder tumors.
  • To investigate the replication of Ad.GS2 within MSCs and its enhancement by the tumor microenvironment.
  • To assess the therapeutic efficacy of systemically delivered MSC-Ad.GS2 in preclinical metastasis models.

Main Methods:

  • Loading syngeneic murine MSCs with Ad.GS2 adenovirus.
  • Evaluating viral replication in MSCs upon co-culture with MBT-2 cells or tumor-conditioned medium (TCM).
  • Assessing therapeutic efficacy in pleural disseminated tumor and experimental metastasis models via intrapleural and tail vein injections.

Main Results:

  • MSCs supported Ad.GS2 replication, which was augmented by MBT-2 cells and TCM, indicating enhanced viral replication at tumor sites.
  • The SDF-1/STAT3/TERT signaling axis in MSCs, influenced by the tumor microenvironment, likely contributes to increased viral replication.
  • Systemic delivery of MSC-Ad.GS2 significantly reduced tumor growth and prolonged survival in metastatic bladder tumor models.

Conclusions:

  • MSCs effectively deliver and enhance the replication of telomerase-dependent oncolytic adenoviruses in metastatic tumors.
  • The tumor microenvironment, potentially via the SDF-1/STAT3/TERT axis, promotes viral replication within MSCs.
  • MSC-mediated delivery of oncolytic adenoviruses represents a promising and broadly applicable strategy for cancer therapy, particularly for metastatic disease.
Keywords:
SDF-1TERTbladder cancermesenchymal stem cellmetastasisoncolytic adenovirustelomerasetumor microenvironment

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