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Metastatic Ovarian Cancer Can Be Efficiently Treated by Genetically Modified Mesenchymal Stromal Cells

Lenka Toro1, Roman Bohovic1, Miroslava Matuskova1

  • 11 Laboratory of Molecular Oncology, Cancer Research Institute , Biomedical Research Center, Slovak Academy of Sciences, Bratislava, Slovakia .

Stem Cells and Development
|August 20, 2016
PubMed

Insights

Engineered adipose tissue-derived mesenchymal stromal cells (AT-MSC) expressing cytosine deaminase::uracil phosphoribosyltransferase (CD::UPRT-MSC) effectively treated ovarian carcinoma in 3D models and mouse xenografts. This gene-modified cell therapy shows promise for treating this deadly cancer.

Area of Science:

  • Oncology
  • Biotechnology
  • Cell Therapy

Background:

  • Human ovarian carcinoma is a deadly disease with high mortality due to late diagnosis, recurrence, metastasis, and chemotherapy resistance.
  • Adipose tissue-derived mesenchymal stromal cells (AT-MSC) are being explored as therapeutic gene delivery vehicles.
  • Engineered AT-MSC expressing Herpes simplex virus thymidine kinase (HSVtk-MSC) or yeast fused cytosine deaminase::uracil phosphoribosyltransferase (CD::UPRT-MSC) offer novel treatment strategies.

Purpose of the Study:

  • To evaluate the differential cytotoxicity of CD::UPRT-MSC/5-fluorocytosine (5-FC) treatment on human ovarian carcinoma cell lines (SKOV-3 and A2780) in 2D and 3D cultures.
  • To assess the predictive potential of 3D cell culture models for in vivo therapeutic outcomes.
  • To determine the efficacy of CD::UPRT-MSC/5-FC treatment in reducing tumor volume and prolonging tumor-free survival in a mouse xenograft model of ovarian carcinoma.

Main Methods:

  • Engineered AT-MSC to express either HSVtk or CD::UPRT.
  • Treated human ovarian carcinoma cell lines (SKOV-3 and A2780) with CD::UPRT-MSC/5-FC in adherent (2D) and three-dimensional (3D) cultures.
  • Assessed cell viability and cytotoxicity in both culture models.
  • Evaluated the efficacy of CD::UPRT-MSC/5-FC treatment in subcutaneous xenografts of A2780 cells in nude mice.

Main Results:

  • Both SKOV-3 and A2780 cells showed high chemosensitivity in 2D culture.
  • The 3D model revealed significant differences: 36% of SKOV-3 cells and 90% of A2780 cells were eliminated.
  • CD::UPRT-MSC/5-FC treatment significantly decreased tumor volumes in A2780 xenografts.
  • Tumor-free survival was prolonged in 33% of animals with highly metastatic ovarian carcinoma.

Conclusions:

  • The 3D cell culture model accurately predicts in vivo therapeutic responses for ovarian carcinoma.
  • CD::UPRT-MSC/5-FC gene-modified cell therapy demonstrates significant anti-tumor efficacy against ovarian carcinoma.
  • This approach holds potential for treating recurrent and metastatic ovarian cancer, improving patient outcomes.
Keywords:
5-fluorocytosineadipose tissue-derived mesenchymal stromal cellscancer gene therapycytosine deaminaseovarian carcinoma

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