Tumor growth and metastasis can be inhibited by maintaining genomic stability in cancer cells

Abstract

The existence of cancer stem cells, stem-like cancer cells (SLCCs), or tumor-initiating cells is considered as the cause of tumor formation and recurrence, indicating the importance of studying novel therapy that targets SLCCs. The origin of SLCCs is controversial because of two competing hypotheses: SLCCs are either transformed from tissue adult stem cells or dedifferentiated from transformed progenitor cells. Our previous research demonstrates that SLCCs are inducible by increasing genomic instability in cancer cells. In this study, to block the emergence of SLCCs, aminoethyl isothiourea (AET), a compound that clears free radicals and is used to protect patients from radioactive exposure, was used as an agent that maintains genomic stability in combination with mitomycin C (MMC), a commonly used chemotherapeutic drug that damages DNA. Using a rabbit tumor model with VX2 hepatic carcinoma, we found that MMC alone increased lung metastases and disadvantaged survival outcome, but the combination of MMC and AET reversed this effect and even prolonged overall survival. Moreover, in a VX2 xenograft model by immunocompromised mice, MMC alone enriched tumor-initiating cells, but the administration of MMC in combination with AET eliminated tumor cells effectively. Furthermore, MMC alone enhanced genomic instability, but MMC combined with AET attenuated the extent of genomic instability in primary VX2 tumor tissue. Taken together, our data suggest that the genomic protector AET can inhibit the induction of SLCCs, and this combination treatment by AET and cytotoxic agents should be considered as a promising strategy for future clinical evaluation.

Keywords

rabbit VX2 liver tumor / mitomycin C / AET / stem-like cancer cells / genomic instability

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Acknowledgements

This work was supported by the National Basic Research Program of China (973 Program, 2012CB967000), the National High Technology Research and Development Program of China (863 Program, 2012AA02A501 and 2012AA02A206), and the Ministry of Education of China (Academic Award for Excellent Doctoral Student, 2010).

Compliance with ethics guidelines

Yi Liang, Qisheng Feng, Jian Hong, Futuo Feng, Yi Sang, Wenrong Hu, Miao Xu, Roujun Peng, Tiebang Kang, Jinxin Bei, and Yixin Zeng declare that they have no conflict of interest. All institutional and national guidelines for the care and use of laboratory animals were followed.

Electronic Supplementary Material

Supplementary material is available in the online version of this article at http://dx.doi.org/ 10.1007/s11684-015-0389-8 and is accessible for authorized users.

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2014 Higher Education Press and Springer-Verlag Berlin Heidelberg