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

Frontiers of Medicine 2015年第1期9卷 57-62页

作者： Yi Liang Sun Yat-sen University cancer Center State Key Laboratory of Oncology in South China ' Collaborative Innovation Center for CancerMedicine Department of Experimental Research Department of Medical Oncology Sun Yat-sen University Cancer Center Guangzhou 510060 China Department of Hepatobiliary Oncology Affiliated Tumor Hospital Guangzhou Medical University Guangzhou 510095 China Peking Union Medical College Chinese Academy of Medical Sciences Beijing 100730 China

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.

关键词： rabbit VX2 liver tumor mitomycin C AET stem-like cancer cells genomic instability

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