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Frontiers of Medicine

ISSN 2095-0217

ISSN 2095-0225(Online)

CN 11-5983/R

Postal Subscription Code 80-967

2018 Impact Factor: 1.847

Front. Med.    2015, Vol. 9 Issue (1) : 57-62     DOI: 10.1007/s11684-015-0389-8
Tumor growth and metastasis can be inhibited by maintaining genomic stability in cancer cells
Yi Liang1,2,Qisheng Feng1,2,Jian Hong1,4,Futuo Feng1,2,Yi Sang1,2,Wenrong Hu1,2,Miao Xu1,2,Roujun Peng1,3,Tiebang Kang1,2,Jinxin Bei1,2,Yixin Zeng1,2,5,*()
1. Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine
2. Department of Experimental Research
3. Department of Medical Oncology, Sun Yat-sen University Cancer Center, Guangzhou 510060, China
4. Department of Hepatobiliary Oncology, Affiliated Tumor Hospital, Guangzhou Medical University, Guangzhou 510095, China
5. Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100730, China
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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     
Corresponding Authors: Yixin Zeng   
Just Accepted Date: 28 January 2015   Online First Date: 10 February 2015    Issue Date: 02 March 2015
URL:     OR
Fig.1  MMC alone disadvantages outcome, but the combination of MMC and AET prolongs overall survival. (A) Overall survival (OS) curves for the VX2-tumor-bearing rabbits treated with vehicle (NS), MMC, or the combination of MMC and AET, respectively. (B) The median OS of the VX2-tumor-bearing rabbits treated with vehicle (NS), MMC, or the combination of MMC and AET, respectively. The P values of pairwise multiple comparisons are indicated.
Fig.2  MMC alone promotes lung metastases, but MMC and AET reverse this effect. (A) Representative photograph of the VX2 primary liver tumors and lung metastases from the rabbits treated with vehicle (NS), MMC or the combination of MMC and AET, respectively. (B) Statistical analysis for the size of primary liver tumors. (C) Statistical analysis for the wet weight of entire lungs. Data are represented as mean±SD. The P values are indicated in the figure.
Primary liver tumor cells Tumor incidence after subcutaneous transplantation (6 weeks)
3×106 cells 1×106 cells 3×105 cells
NS 3/8 0/8 0/8
MMC 5/8 3/8 2/8
MMC+ AET 0/8 0/8 0/8
Tab.1  Tumorigenic assays of primary VX2 liver tumor cells treated with vehicle (NS), MMC, or the combination of MMC and AET
Fig.3  Differences and similarities of CN-altered loci among vehicle control (NS), MMC, and MMC+ AET groups.
No. of amplificated loci No. of deleted loci Total No. of altered loci No. of amplificated segments No. of deleted segments Total No. of altered segments
NS 366 669 1035 192 164 356
MMC 611 785 1396 213 263 476
MMC+ AET 300 514 814 156 103 259
Tab.2  Copy number variation (CNV) assays of primary VX2 tumor cells treated with vehicle (NS), MMC, or combination of MMC and AET
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[1] Supplementary Material Download
[1] Zhangguo Chen,Jing H. Wang. Generation and repair of AID-initiated DNA lesions in B lymphocytes[J]. Front. Med., 2014, 8(2): 201-216.
[2] Jing H. Wang. Mechanisms and impacts of chromosomal translocations in cancers[J]. Front Med, 2012, 6(3): 263-274.
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