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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
RESEARCH ARTICLE |
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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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     
Corresponding Authors: Yixin Zeng   
Just Accepted Date: 28 January 2015   Online First Date: 10 February 2015    Issue Date: 02 March 2015
URL:  
http://academic.hep.com.cn/fmd/EN/10.1007/s11684-015-0389-8     OR     http://academic.hep.com.cn/fmd/EN/Y2015/V9/I1/57
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
1 Vogelstein B, Kinzler KW. Cancer genes and the pathways they control. Nat Med 2004; 10(8): 789-799
doi: 10.1038/nm1087 pmid: 15286780
2 Reya T, Morrison SJ, Clarke MF, Weissman IL. Stem cells, cancer, and cancer stem cells. Nature 2001; 414(6859): 105-111
doi: 10.1038/35102167 pmid: 11689955
3 Houghton J, Morozov A, Smirnova I, Wang TC. Stem cells and cancer. Semin Cancer Biol 2007; 17(3): 191-203
doi: 10.1016/j.semcancer.2006.04.003 pmid: 16762563
4 Liang Y, Zhong Z, Huang Y, Deng W, Cao J, Tsao G, Liu Q, Pei D, Kang T, Zeng YX. Stem-like cancer cells are inducible by increasing genomic instability in cancer cells. J Biol Chem 2010; 285(7): 4931-4940
doi: 10.1074/jbc.M109.048397 pmid: 20007324
5 Dean M, Fojo T, Bates S. Tumour stem cells and drug resistance. Nat Rev Cancer 2005; 5(4): 275-284
doi: 10.1038/nrc1590 pmid: 15803154
6 Scheel C, Weinberg RA. Cancer stem cells and epithelial-mesenchymal transition: concepts and molecular links. Semin Cancer Biol 2012; 22(5-6): 396-403
doi: 10.1016/j.semcancer.2012.04.001 pmid: 22554795
7 Chaffer CL, Weinberg RA. A perspective on cancer cell metastasis. Science 2011; 331(6024): 1559-1564
doi: 10.1126/science.1203543 pmid: 21436443
8 DiStefano V. Some Remarks on the Pharmacology of Radioprotectant Agents. Ann N Y Acad Sci 1964; 114(1): 588-596
doi: 10.1111/j.1749-6632.1964.tb53611.x pmid: 14125999
9 Carr CJ, Huff JE, Fisher KD, Huber TE. Protective agents modifying biological effects of radiation. A selective review. Arch Environ Health 1970; 21(1): 88-98
doi: 10.1080/00039896.1970.10667199 pmid: 4914546
10 Akoun G. Pharmacologic and clinical study of 2-amino-ethyl-isothiouronium hydrobromide: utilization in neurologic therapy. Psychiatr Neurol Neurochir 1964; 67: 278-288 (in French)
pmid: 14168887
11 Kidd JG, Rous P. A Transplantable Rabbit Carcinoma Originating in a Virus-Induced Papilloma and Containing the Virus in Masked or Altered Form. J Exp Med 1940; 71(6): 813-838
doi: 10.1084/jem.71.6.813 pmid: 19871000
12 Nishizaki T, Matsumata T, Kanematsu T, Yasunaga C, Sugimachi K. Surgical manipulation of VX2 carcinoma in the rabbit liver evokes enhancement of metastasis. J Surg Res 1990; 49(1): 92-97
doi: 10.1016/0022-4804(90)90116-J pmid: 2359299
13 Wang Z, Yang G, Nie P, Fu J, Wang X, Liu D. Dynamical observation on biological progression of VX2 liver tumors to identify the optimal time for intervention in animal models. PLoS ONE 2013; 8(8): e74327
doi: 10.1371/journal.pone.0074327 pmid: 23977399
14 Tomasz M. Mitomycin C: small, fast and deadly (but very selective). Chem Biol 1995; 2(9): 575-579
doi: 10.1016/1074-5521(95)90120-5 pmid: 9383461
15 Yu F, Yao H, Zhu P, Zhang X, Pan Q, Gong C, Huang Y, Hu X, Su F, Lieberman J, Song E. let-7 regulates self renewal and tumorigenicity of breast cancer cells. Cell 2007; 131(6): 1109-1123
doi: 10.1016/j.cell.2007.10.054 pmid: 18083101
16 Laborit H, Broussolle B, Jouany JM, Niaussat P, Reynier M, Weber B. Pharmacological study of 2-aminoethylisothiuronium hydrobromide (AET). Therapie 1959; 14: 1116-1135 (in French)
pmid: 14413213
17 Anderson DR. The radiation protective effects of AET on the enzyme creatine phosphokinase. Arch Biochem Biophys 1959; 81(2): 390-394
doi: 10.1016/0003-9861(59)90217-6 pmid: 13638001
18 Doherty DG, Burnett WT Jr. Protective effect of S, beta-aminoethylisothiuronium-Br-HBr and related compounds against x-radiation death in mice. Proc Soc Exp Biol Med 1955; 89(2): 312-314
doi: 10.3181/00379727-89-21795 pmid: 14395303
19 Crouch BG, Overman RR. Chemical protection against x-radiation death in primates: a preliminary report. Science 1957; 125(3257): 1092
doi: 10.1126/science.125.3257.1092 pmid: 13432770
20 Pritsos CA, Sartorelli AC. Generation of reactive oxygen radicals through bioactivation of mitomycin antibiotics. Cancer Res 1986; 46(7): 3528-3532
pmid: 3011250
[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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