Metastatic tumor cells – genotypes and phenotypes

doi:10.1007/s11515-018-1513-3

Front. Biol.

2018, Vol. 13

Issue (4) : 277-286 https://doi.org/10.1007/s11515-018-1513-3

REVIEW

Metastatic tumor cells – genotypes and phenotypes

Dingcheng Gao(

), Vivek Mittal, Yi Ban, Ana Rita Lourenco, Shira Yomtoubian, Sharrell Lee

Department of Cardiothoracic Surgery, Department of Cell and Developmental Biology, Neuberger Berman Lung Cancer Center, Weill Cornell Medicine, New York, NY10065, USA

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Abstract

BACKGROUND: Metastasis is the primary cause of mortality in cancer patients. Therefore, elucidating the genetics and epigenetics of metastatic tumor cells and the mechanisms by which tumor cells acquire metastatic properties constitute significant challenges in cancer research.

OBJECTIVE: To summarize the current understandings of the specific genotype and phenotype of the metastatic tumor cells.

METHOD and RESULT: In-depth genetic analysis of tumor cells, especially with advances in the next-generation sequencing, have revealed insights of the genotypes of metastatic tumor cells. Also, studies have shown that the cancer stem cell (CSC) and epithelial to mesenchymal transition (EMT) phenotypes are associated with the metastatic cascade.

CONCLUSION: In this review, we will discuss recent advances in the field by focusing on the genomic instability and phenotypic dynamics of metastatic tumor cells.

Keywords metastasis epithelial to mesenchymal transition (EMT) cancer stem cell circulating tumor cells cellular plasticity phenotype dynamics

Corresponding Author(s): Dingcheng Gao

Online First Date: 20 August 2018 Issue Date: 10 September 2018

Cite this article:

Dingcheng Gao,Vivek Mittal,Yi Ban, et al. Metastatic tumor cells – genotypes and phenotypes[J]. Front. Biol., 2018, 13(4): 277-286.

URL:

https://academic.hep.com.cn/fib/EN/10.1007/s11515-018-1513-3
https://academic.hep.com.cn/fib/EN/Y2018/V13/I4/277

Fig.1 The genotypic and phenotypic properties that define the metastatic tumor cells. The specific features of metastatic tumor cells could be defined on genomic and phenotypic levels. Both germline and somatic alterations including SNVs, CNAs, chromosome rearrangement and epigenetic modulations would lead to changes in the transcriptome of metastatic tumor cells. These genomic changes would not only serve as evolution markers in metastasis, but also manifest functions of cell proliferation, migration, invasion, anti-apoptosis and stemness that would be closely related to the CSC and EMT phenotypes.

Fig.2 The genotypic instability and phenotype dynamics of the metastatic tumor cells. A, Metastases could be derived from multiple subclones of the primary tumor cells. Genomic studies reveal a complicated phylogenetic relationship between the primary tumor and metastasis. Similar driving mutations and genetic alterations are shared between them, while additional passenger mutations are also detected in the metastases due to the genomic instability feature. B, The phenotype features of metastatic tumor cells could be transient, reversible between mesenchymal/stem like (Mes/CSC) and epithelial/non-stem like (Epi/non-CSC), and highly affected by microenvironment factors. It might not be the genotype or phenotype itself, but the genomic instability and phenotypic plasticity that determines the eventual survival of metastatic tumor cells.

1	Aceto N, Bardia A, Miyamoto D T, Donaldson MC, Wittner BS, Spencer JA, Yu M, Pely A, Engstrom A, Zhu H(2014). Circulating tumor cell clusters are oligoclonal precursors of breast cancer metastasis. Cell, 158:1110–1122
2	Al-Hajj M, Wicha M S, Benito-Hernandez A, Morrison S J, Clarke M F (2003). Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci U S A, 100:3983–3988
3	Boral D, Vishnoi M, Liu H N, Yin W, Sprouse M L, Scamardo A, Hong D S, Tan T Z, Thiery J P, Chang J C (2017). Molecular characterization of breast cancer CTCs associated with brain metastasis. Nat Commun, 8:196
4	Bos PD, Zhang X H F, Nadal C, Shu W, Gomis R R, Nguyen D X, Minn A J, Van de Vijver M, Gerald W, Foekens J A, Massagué J( 2009). Genes that mediate breast cancer metastasis to the brain. Nature, 459:1005–1009
5	Brabletz T 2012. To differentiate or not–routes towards metastasis. In: Nat Rev Cancer. England. p. 425–436.
6	Brastianos P K, Carter S L, Santagata S, Cahill D P, Taylor-Weiner A, Jones R T, Van Allen E M, Lawrence M S, Horowitz P M, Cibulskis K (2015). Genomic Characterization of Brain Metastases Reveals Branched Evolution and Potential Therapeutic Targets. Cancer Discov, 5:1164–1177
7	Cabrera M C, Hollingsworth R E, Hurt E M (2015). Cancer stem cell plasticity and tumor hierarchy. World J Stem Cells, 7:27–36
8	Campbell P J, Yachida S, Mudie L J, Stephens P J, Pleasance E D, Stebbings L A, Morsberger L A, Latimer C, McLaren S, Lin M L (2010). The patterns and dynamics of genomic instability in metastatic pancreatic cancer. Nature, 467:1109–1113
9	Carmody L, Germain A, Morgan B, VerPlank L, Fernandez C, Forbeck E, Ting A, Feng Y, Perez J, Dandapani S (2010). Identification of a Selective Small-Molecule Inhibitor of Breast Cancer Stem Cells- Probe 1. In: Probe Reports from the NIH Molecular Libraries Program. Bethesda (MD): National Center for Biotechnology Information (US).
10	Chaffer C L, Marjanovic N D, Lee T, Bell G, Kleer C G, Reinhardt F, D'Alessio A C, Young R A, Weinberg R A (2013). Poised chromatin at the ZEB1 promoter enables breast cancer cell plasticity and enhances tumorigenicity. Cell, 154:61–74
11	Chen D, Wu M, Li Y, Chang I, Yuan Q, Ekimyan-Salvo M, Deng P, Yu B, Yu Y, Dong J (2017). Targeting BMI1(+) Cancer Stem Cells Overcomes Chemoresistance and Inhibits Metastases in Squamous Cell Carcinoma. Cell Stem Cell, 20:621–634
12	Chiou SH, Risca VI, Wang GX, Yang D, Gruner BM, Kathiria AS, Ma RK, Vaka D, Chu P, Kozak M (2017). BLIMP1 Induces Transient Metastatic Heterogeneity in Pancreatic Cancer. Cancer Discov, 7:1184–1199
13	Chuang C H, Greenside P G, Rogers Z N, Brady J J, Yang D, Ma R K, Caswell D R, Chiou S H, Winters A F, Gruner B M (2017). Molecular definition of a metastatic lung cancer state reveals a targetable CD109-Janus kinase-Stat axis. Nat Med, 23:291–300
14	Chui M H (2013). Insights into cancer metastasis from a clinicopathologic perspective: Epithelial-Mesenchymal Transition is not a necessary step. Int J Cancer, 132:1487–1495
15	Davis F M, Stewart T A, Thompson E W, Monteith G R (2014). Targeting EMT in cancer: opportunities for pharmacological intervention. Trends Pharmacol Sci, 35: 479–488
16	de Sousa e Melo F, Kurtova A V, Harnoss J M, Kljavin N, Hoeck J D, Hung J, Anderson J E, Storm E E, Modrusan Z, Koeppen H (2017). A distinct role for Lgr5(+) stem cells in primary and metastatic colon cancer. Nature, 543:676–680
17	Dragu D L, Necula L G, Bleotu C, Diaconu C C, Chivu-Economescu M (2015). Therapies targeting cancer stem cells: Current trends and future challenges. World J Stem Cells, 7:1185–1201
18	DuPage M, Dooley A L, Jacks T (2009). Conditional mouse lung cancer models using adenoviral or lentiviral delivery of Cre recombinase. Nat Protoc, 4(7): 1064–1072 https://doi.org/10.1038/nprot.2009.95 pmid: 19561589
19	Fischer KR, Durrans A, Lee S, Sheng J, Li F, Wong ST, Choi H, El Rayes T, Ryu S, Troeger J (2015). Epithelial-to-mesenchymal transition is not required for lung metastasis but contributes to chemoresistance. Nature. Nov 26;527:472–476. Epub 2015/11/13.
20	Fishbein L, Leshchiner I, Walter V, Danilova L, Robertson A G, Johnson A R, Lichtenberg T M, Murray B A, Ghayee H K, Else T(2017). Comprehensive Molecular Characterization of Pheochromocytoma and Paraganglioma. Cancer Cell, 31:181–193
21	Fraser M, Sabelnykova V Y, Yamaguchi T N, Heisler L E, Livingstone J, Huang V, Shiah Y J, Yousif F, Lin X, Masella A P(2017). Genomic hallmarks of localized, non-indolent prostate cancer. Nature, 541: 359–364
22	George J T, Jolly M K, Xu S, Somarelli J A, Levine H (2017). Survival Outcomes in Cancer Patients Predicted by a Partial EMT Gene Expression Scoring Metric. Cancer Res, 77: 6415–6428
23	Giannelli G, Villa E, Lahn M (2014). Transforming growth factor-beta as a therapeutic target in hepatocellular carcinoma. Cancer Res, 74:1890–1894
24	Goossens N, Hoshida Y, Aguirre-Ghiso J A(2015). Origin and interpretation of cancer transcriptome profiling: the essential role of the stroma in determining prognosis and drug resistance. EMBO Mol Med, 7:1385–1387
25	Grigore A D, Jolly M K, Jia D, Farach-Carson M C, Levine H (2016). Tumor Budding: The Name is EMT. Partial EMT. J Clin Med, 29:5
26	Gupta P B, Chaffer C L, Weinberg R A (2009). Cancer stem cells: mirage or reality? Nat Med, 15:1010–1012
27	Gupta P B, Onder T T, Jiang G, Tao K, Kuperwasser C, Weinberg R A, Lander E S (2009). Identification of selective inhibitors of cancer stem cells by high-throughput screening. Cell, 138:645–659
28	Hecht I, Natan S, Zaritsky A, Levine H, Tsarfaty I, Ben-Jacob E(2015). The motility-proliferation-metabolism interplay during metastatic invasion. Sci Rep, 5:13538
29	Hoadley K A, Siegel M B, Kanchi K L, Miller C A, Ding L, Zhao W, He X, Parker J S, Wendl M C, Fulton R S(2016). Tumor Evolution in Two Patients with Basal-like Breast Cancer: A Retrospective Genomics Study of Multiple Metastases. PLoS Med, e1002174
30	Jaggupilli A, Elkord E (2012). Significance of CD44 and CD24 as cancer stem cell markers: an enduring ambiguity. Clin Dev Immunol, 2012: 708036 https://doi.org/10.1155/2012/708036 pmid: 22693526
31	Kalluri R, Weinberg R A (2009). The basics of epithelial-mesenchymal transition. J Clin Invest, 119:1420–1428
32	Kang Y, Siegel P M, Shu W, Drobnjak M, Kakonen S M, Cordon-Cardo C, Guise T A, Massague J (2003). A multigenic program mediating breast cancer metastasis to bone. Cancer Cell, 3:537–549
33	Ku S Y, Rosario S, Wang Y, Mu P, Seshadri M, Goodrich Z W, Goodrich M M, Labbe D P, Gomez E C, Wang J, Long H W, Xu B, Brown M, Loda M, Sawyers C L, Ellis L, Goodrich D W (2017). Rb1 and Trp53 cooperate to suppress prostate cancer lineage plasticity, metastasis, and antiandrogen resistance. Science, 355:78–83
34	Labib M, Mohamadi R M, Poudineh M, Ahmed S U, Ivanov I, Huang C L, Moosavi M, Sargent E H, Kelley S O (2018). Single-cell mRNA cytometry via sequence-specific nanoparticle clustering and trapping. Nat Chem, 10:489–495
35	Lambert A W, Pattabiraman D R, Weinberg R A (2017). Emerging Biological Principles of Metastasis. Cell, 168:670–691
36	Lapidot T, Sirard C, Vormoor J, Murdoch B, Hoang T, Caceres-Cortes J, Minden M, Paterson B, Caligiuri M A, Dick J E (1994). A cell initiating human acute myeloid leukaemia after transplantation into SCID mice. Nature, 367:645–648
37	Lawson D A, Bhakta N R, Kessenbrock K, Prummel K D, Yu Y, Takai K, Zhou A, Eyob H, Balakrishnan S, Wang C Y, Yaswen P, Goga A, Werb Z (2015). Single-cell analysis reveals a stem-cell program in human metastatic breast cancer cells. Nature, 526:131–135
38	Lim J, Thiery J P 2012. Epithelial-mesenchymal transitions: insights from development. In: Development. England. p. 3471–3486.
39	Liu H, Patel M R, Prescher J A, Patsialou A, Qian D, Lin J, Wen S, Chang Y F, Bachmann M H, Shimono Y, Dalerba P, Adorno M, Lobo N, Bueno J, Dirbas F M, Goswami S, Somlo G, Condeelis J, Contag C H, Gambhir S S, Clarke M F (2010). Cancer stem cells from human breast tumors are involved in spontaneous metastases in orthotopic mouse models. Proc Natl Acad Sci U S A, 107:18115–18120
40	Liu Y, Cao X (2016). Characteristics and Significance of the Pre-metastatic Niche. Cancer Cell, 30:668–681
41	Luzzi K J, MacDonald I C, Schmidt E E, Kerkvliet N, Morris V L, Chambers A F, Groom A C (1998). Multistep nature of metastatic inefficiency: dormancy of solitary cells after successful extravasation and limited survival of early micrometastases. Am J Pathol. 153:865–873
42	Magnani L, Frige G, Gadaleta R M, Corleone G, Fabris S, Kempe H, Verschure P J, Barozzi I, Vircillo V, Hong S P, Perone Y, Saini M, Trumpp A, Viale G, Neri A, Ali S, Colleoni M A, Pruneri G, Minucci S (2017). Acquired CYP19A1 amplification is an early specific mechanism of aromatase inhibitor resistance in ERalpha metastatic breast cancer. Nat Genet,49:444–450
43	Makohon-Moore A, Iacobuzio-Donahue C A (2016). Pancreatic cancer biology and genetics from an evolutionary perspective. Nat Rev Cancer,16:553–565
44	Makohon-Moore A P, Zhang M, Reiter J G, Bozic I, Allen B, Kundu D, Chatterjee K, Wong F, Jiao Y, Kohutek Z A, Hong J, Attiyeh M, Javier B, Wood L D, Hruban R H, Nowak M A, Papadopoulos N, Kinzler K W, Vogelstein B, Iacobuzio-Donahue C A (2017). Limited heterogeneity of known driver gene mutations among the metastases of individual patients with pancreatic cancer. Nat Genet, 49:358–366
45	Mani S A, Guo W, Liao M J, Eaton E N, Ayyanan A, Zhou A Y, Brooks M, Reinhard F, Zhang C C, Shipitsin M, Campbell L L, Polyak K, Brisken C, Yang J, Weinberg R A (2008). The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell, 133:704–715
46	Martinez-Cardus A, Moran S, Musulen E, Moutinho C, Manzano J L, Martinez-Balibrea E, Tierno M, Elez E, Landolfi S, Lorden P, Arribas C, Müller F, Bock C, Tabernero J, Esteller M (2016). Epigenetic homogeneity within colorectal tumors predicts shorter relapse-free and overall survival times for patients with locoregional cancer. Gastroenterology, 151:961–972
47	McCauley HA, Chevrier V, Birnbaum D, Guasch G (2017). De-repression of the RAC activator ELMO1 in cancer stem cells drives progression of TGFbeta-deficient squamous cell carcinoma from transition zones. Elife, 21:6
48	McDonald O G, Li X, Saunders T, Tryggvadottir R, Mentch S J, Warmoes M O, Word A E, Carrer A, Salz T H, Natsume S, Stauffer K M, Makohon-Moore A, Zhong Y, Wu H, Wellen K E, Locasale J W, Iacobuzio-Donahue C A, Feinberg A P (2017). Epigenomic reprogramming during pancreatic cancer progression links anabolic glucose metabolism to distant metastasis. Nat Genet, 49:367–376
49	Minn AJ, Gupta GP, Siegel PM, Bos PD, Shu W, Giri DD, Viale A, Olshen AB, Gerald WL, Massagué J ( 2005). Genes that mediate breast cancer metastasis to lung. Nature, 436:518–524.
50	Nagare R P, Sneha S, Priya S K, Ganesan T S (2017). Cancer Stem Cells- Are Surface Markers Alone Sufficient? Curr Stem Cell Res Ther, 12(1): 37–44 https://doi.org/10.2174/1574888X11666160607211436 pmid: 27280437
51	Navin N, Kendall J, Troge J, Andrews P, Rodgers L, McIndoo J, Cook K, Stepansky A, Levy D, Esposito D, Muthuswamy L, Krasnitz A, McCombie W R, Hicks J, Wigler M (2011). Tumour evolution inferred by single-cell sequencing. Nature, 472:90–94
52	Navin N E (2015). The first five years of single-cell cancer genomics and beyond. Genome Res, 25:1499–1507
53	Nguyen D X, Massague J (2007). Genetic determinants of cancer metastasis. Nat Rev Genet, 8:341–352
54	Olsen S N, Wronski A, Castano Z, Dake B, Malone C, De Raedt T, Enos M, DeRose YS, Zhou W, Guerra S, Loda M, Welm A, Partridge A H, McAllister S S, Kuperwasser C, Cichowski K (2017). Loss of RasGAP tumor suppressors underlies the aggressive nature of luminal b breast cancers. Cancer Discov, 7:202–217
55	Patel A P, Tirosh I, Trombetta J J, Shalek A K, Gillespie S M, Wakimoto H, Cahill D P, Nahed B V, Curry W T, Martuza R L, Louis D N, Rozenblatt-Rosen O, Suvà M L, Regev A, Bernstein B E (2014). Single-cell RNA-seq highlights intratumoral heterogeneity in primary glioblastoma. Science, 344:1396–1401
56	Patel S A, Vanharanta S (2016). Epigenetic determinants of metastasis. Mol Oncol, 11(1): 79–96
57	Peitzsch C, Tyutyunnykova A, Pantel K, Dubrovska A (2017). Cancer stem cells: The root of tumor recurrence and metastases. Semin Cancer Biol, 44(Feb): 10–24 https://doi.org/10.1016/j.semcancer.2017.02.011 pmid: 28257956
58	Pon J R, Marra M A (2015). Driver and passenger mutations in cancer. Annu Rev Pathol, 10(1): 25–50 https://doi.org/10.1146/annurev-pathol-012414-040312 pmid: 25340638
59	Poudineh M, Aldridge P M, Ahmed S, Green B J, Kermanshah L, Nguyen V, Tu C, Mohamadi R M, Nam R K, Hansen A (2017). Tracking the dynamics of circulating tumour cell phenotypes using nanoparticle-mediated magnetic ranking. Nat Nanotechnol, 12:274–281
60	Puram S V, Tirosh I, Parikh A S, Patel A P, Yizhak K, Gillespie S, Rodman C, Luo C L, Mroz E A, Emerick K S (2017). Single-cell transcriptomic analysis of primary and metastatic tumor ecosystems in head and neck cancer. Cell, 171:1611–1624
61	Rinaldi L, Avgustinova A, Martin M, Datta D, Solanas G, Prats N, Benitah S A (2017). Loss of Dnmt3a and Dnmt3b does not affect epidermal homeostasis but promotes squamous transformation through PPAR-gamma. Elife, 20:6
62	Robinson D R, Wu Y M, Lonigro R J, Vats P, Cobain E, Everett J, Cao X, Rabban E, Kumar-Sinha C, Raymond V (2017). Integrative clinical genomics of metastatic cancer. Nature, 548: 297–303
63	Rodon J, Carducci M A, Sepulveda-Sanchez J M, Azaro A, Calvo E, Seoane J, Brana I, Sicart E, Gueorguieva I, Cleverly A L(2015). First-in-human dose study of the novel transforming growth factor-beta receptor I kinase inhibitor LY2157299 monohydrate in patients with advanced cancer and glioma. Clin Cancer Res, 21:553–560
64	Roe J S, Hwang C I, Somerville T D D, Milazzo J P, Lee E J, Da Silva B, Maiorino L, Tiriac H, Young C M, Miyabayashi K (2017). Enhancer reprogramming promotes pancreatic cancer metastasis. Cell, 170:875–888
65	Shackleton M, Quintana E, Fearon E R, Morrison S J (2009). Heterogeneity in cancer: cancer stem cells versus clonal evolution. Cell, 138:822–829
66	Sheffield N C, Pierron G, Klughammer J, Datlinger P, Schonegger A, Schuster M, Hadler J, Surdez D, Guillemot D, Lapouble E (2017). DNA methylation heterogeneity defines a disease spectrum in Ewing sarcoma. Nat Med, 23:386–395
67	Sinkala E, Sollier-Christen E, Renier C, Rosas-Canyelles E, Che J, Heirich K, Duncombe T A, Vlassakis J, Yamauchi K A, Huang H ( 2017) . Profiling protein expression in circulating tumour cells using microfluidic western blotting. Nat Commun, 8:14622
68	Tan TZ, Miow Q H, Miki Y, Noda T, Mori S, Huang R Y, Thiery J P (2014). Epithelial-mesenchymal transition spectrum quantification and its efficacy in deciphering survival and drug responses of cancer patients. EMBO Mol Med, 6:1279–1293
69	Thiery J P, Acloque H, Huang R Y, Nieto M A (2009). Epithelial-mesenchymal transitions in development and disease. In: Cell. United States. p. 871–890.
70	Tran H D, Luitel K, Kim M, Zhang K, Longmore G D, Tran D D (2014). Transient SNAIL1 expression is necessary for metastatic competence in breast cancer. Cancer Res, 74:6330–6340
71	Tsai J H, Donaher J L, Murphy D A, Chau S, Yang J (2012). Spatiotemporal regulation of epithelial-mesenchymal transition is essential for squamous cell carcinoma metastasis. Cancer Cell, 22:725–736
72	Valastyan S, Weinberg R A (2011). Tumor metastasis: molecular insights and evolving paradigms. Cell, 147:275–292
73	Wishart D S (2015). Is Cancer a Genetic Disease or a Metabolic Disease? In: EBioMedicine. p. 478–479.
74	Yates L R, Knappskog S, Wedge D, Farmery J H R, Gonzalez S, Martincorena I, Alexandrov L B, Van Loo P, Haugland H K, Lilleng P K, ( 2017). Genomic Evolution of Breast Cancer Metastasis and Relapse. Cancer Cell, 32:169–184.e167
75	Ye X, Brabletz T, Kang Y, Longmore G D, Nieto M A, Stanger B Z, Yang J, Weinberg R A (2017). Upholding a role for EMT in breast cancer metastasis. Nature, 547:E1–e3
76	Ye X, Tam W L, Shibue T, Kaygusuz Y, Reinhardt F, Ng Eaton E, Weinberg R A (2015). Distinct EMT programs control normal mammary stem cells and tumour-initiating cells. Nature, 525: 256–260. Epub 2015/09/04.
77	Yeung KT, Yang J. 2017. Epithelial-mesenchymal transition in tumor metastasis. Mol Oncol, 11:28–39
78	Yu M, Bardia A, Wittner B S, Stott S L, Smas M E, Ting D T, Isakoff S J, Ciciliano J C, Wells M N, Shah A M (2013). Circulating breast tumor cells exhibit dynamic changes in epithelial and mesenchymal composition. Science, 339:580–584
79	Zehir A, Benayed R, Shah R H, Syed A, Middha S, Kim H R, Srinivasan P, Gao J, Chakravarty D, Devlin SM (2017). Mutational landscape of metastatic cancer revealed from prospective clinical sequencing of 10,000 patients. Nat Med, 23:703–713
80	Zheng X, Carstens J L, Kim J, Scheible M, Kaye J, Sugimoto H, Wu C C, LeBleu V S, Kalluri R (2015). Epithelial-to-mesenchymal transition is dispensable for metastasis but induces chemoresistance in pancreatic cancer. Nature, 527:525–530
81	Zhu S, Zhang X, Weichert-Leahey N, Dong Z, Zhang C, Lopez G, Tao T, He S, Wood A C, Oldridge D (2017). LMO1 Synergizes with MYCN to Promote Neuroblastoma Initiation and Metastasis. Cancer Cell, 32:310–323.e315

[1]	Yanan Sun,Jie Yang,Zhenyi Ma. Functions of the adaptor protein p66^Shc in solid tumors[J]. Front. Biol., 2015, 10(6): 487-494.
[2]	Mahandranauth A. CHETRAM, Cimona V. HINTON. ROS-mediated regulation of CXCR4 in cancer[J]. Front Biol, 2013, 8(3): 273-278.
[3]	Yinghui HUANG, Xiaoxue QIU, Ji-Long CHEN. Identification of cancer stem cells: from leukemia to solid cancers[J]. Front Biol, 2010, 5(5): 407-416.

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