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

作者：Park Geon Tae; Kim Seung U; Choi Kyung Chul^*

来源：Cancer Research and Treatment, 2017, 49(1): 79-91.

DOI：10.4143/crt.2015.503

• Colorectal neoplasms
• Lymphatic metastasis
• Neural stem cells
• Flucytosine
• Interferon-beta

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 coil cytosine deaminase (CD) (HB1.F3.CD) and human interferon-beta (IFN-beta) (HB1.F3.CD.IFN-beta) 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-beta also strongly inhibits tumor growth by inducingthe 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-beta cells expressed both CD and IFN-beta genes.
Results
In results of a modified trans-well migration assay, HB1.F3.CD and HB1.F3.CD.IFN-beta 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 HBIF3.CD.IFN-beta 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.

• 出版日期2017-1