Anti-proliferative Effect of Engineered Neural Stem Cells Expressing Cytosine Deaminase and Interferon-β against Lymph Node-Derived Metastatic Colorectal Adenocarcinoma in Cellular and Xenograft Mouse Models.

Abstract

PURPOSE:

Genetically engineered stem cells may be advantageous for gene therapy against various human cancers due to their inherent tumor-tropic properties. In this study, genetically engineered human neural stem cells (HB1.F3) expressing Escherichia coli cytosine deaminase (CD) (HB1.F3.CD) and human interferon-β (IFN-β) (HB1.F3.CD.IFN-β) were employed against lymph node-derived metastatic colorectal adenocarcinoma.

MATERIALS AND METHODS:

CD can convert a prodrug, 5-fluorocytosine (5-FC), to active 5-fluorouracil, which inhibits tumor growth through the inhibition of DNA synthesis,while IFN-β also strongly inhibits tumor growth by inducing the apoptotic process. In reverse transcription polymerase chain reaction analysis, we confirmed that HB1.F3.CD cells expressed the CD gene and HB1.F3.CD.IFN-β cells expressed both CD and IFN-β genes.

RESULTS:

In results of a modified trans-well migration assay, HB1.F3.CD and HB1.F3.CD.IFN-β cells selectively migrated toward SW-620, human lymph node-derived metastatic colorectal adenocarcinoma cells. The viability of SW-620 cells was significantly reduced when co-cultured with HB1.F3.CD or HB1.F3.CD.IFN-β cells in the presence of 5-FC. In addition, it was found that the tumor-tropic properties of these engineered human neural stem cells (hNSCs) were attributed to chemoattractant molecules including stromal cell-derived factor 1, c-Kit, urokinase receptor, urokinase-type plasminogen activator, and C-C chemokine receptor type 2 secreted by SW-620 cells. In a xenograft mouse model, treatment with hNSC resulted in significantly inhibited growth of the tumor mass without virulent effects on the animals.

CONCLUSION:

The current results indicate that engineered hNSCs and a prodrug treatment inhibited the growth of SW-620 cells. Therefore, hNSC therapy may be a clinically effective tool for the treatment of lymph node metastatic colorectal cancer.

• Authors: Geon-Tae Park, Seung U Kim, Kyung-Chul Choi
• Journal: Cancer research and treatment (Cancer Res Treat) Vol. 49 Issue 1 Pg. 79-91 (Jan 2017) ISSN: 2005-9256 [Electronic] Korea (South)
• PMID: 27188205 (Publication Type: Journal Article)

Chemical References

• Interferon-beta
• Flucytosine
• Cytosine Deaminase

Topics

• Animals
• Cell Line, Tumor
• Cell Proliferation
• Cell Survival
• Cell- and Tissue-Based Therapy
• Colorectal Neoplasms (genetics, secondary, therapy)
• Combined Modality Therapy
• Cytosine Deaminase (genetics, metabolism)
• Disease Models, Animal
• Female
• Flucytosine (pharmacology)
• Gene Expression
• Genetic Engineering
• Genetic Therapy
• Humans
• Interferon-beta (genetics, metabolism)
• Mice
• Neural Stem Cells (metabolism)
• Tumor Burden
• Xenograft Model Antitumor Assays