Effect of Tumor Initiating Cells and Epithelial-Mesenchymal Transition in Tumor Metastasis and Drug Resistance_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

CAI Cheng , YU Jiwei ,  JIANG Bojian

First Department of General Surgery， Third People’s Hospital， Shanghai Jiao-Tong University School of Medicine， Shanghai 201900， China;

Corresponding author：

JIANG Bojian, Email: Jiang_md@hotmail.com

Keywords：

Epithelial-mesenchymal transition; Tumor initiating cells; Tumor; Metastasis; Drug resistance

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Abstract Full text Figures/Tables Video References Cited by

Objective 　To summarize the roles of tumor initiating cells （TICs） and epithelial-mesenchymal transition （EMT） in tumor metastasis and drug resistance.
Methods 　Domestic and international publications online which involving TICs，EMT，and its roles in tumor metastasis and drug resistance in recent years were reviewed.
Results 　TICs were self-renewal cells and had the ability to give rise to more differentiated cell types，and played an important role in tumor metastasis and drug resistance. Various markers had been used to identify TICs，such as CD133，CD44，and so on. EMT was the process by which epithelial cells losed polarity and detach from the epithelial sheet， and acquired a motile mesenchymal phenotype，usually observed in embryo development and wound healing. It also could promote tumor progression and metastasis，and may also be responsible for the ability of tumors to evade the body’s immune response. EMT may be the reasons of TICs that drived tumor metastasis and recurrence. TICs or EMT as a target for treatments may effectively prevent tumor recurrence and improve patient’s survival.
Conclusions 　EMT is probably the mechanism that TICs promote tumor metastasis and drug resistance. More effective target therapies for cancer may be found if we know more about TICs and EMT.

Citation： CAI Cheng,YU Jiwei,JIANG Bojian. Effect of Tumor Initiating Cells and Epithelial-Mesenchymal Transition in Tumor Metastasis and Drug Resistance. CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY, 2013, 20(1): 99-103. doi: Copy

1.	Charafe-Jauffret E， Ginestier C， Iovino F， et al. Aldehyde dehyd-rogenase 1-positive cancer stem cells mediate metastasis and poor clinical outcome in inflammatory breast cancer[J]. Clin Cancer Res， 2010， 16(1)：45-55.
2.	Gjerdrum C， Tiron C， Høiby T， et al. Axl is an essential epithelial-to-mesenchymal transition-induced regulator of breast cancer metastasis and patient survival[J]. Proc Natl Acad Sci U S A， 2010， 107(3)：1124-1129.
3.	Hoshino H， Miyoshi N， Nagai K， et al. Epithelial-mesenchymal transition with expression of SNAI1-induced chemoresistance in colorectal cancer[J]. Biochem Biophys Res Commun， 2009， 390(3)：1061-1065.
4.	Li X， Lewis MT， Huang J， et al. Intrinsic resistance of tumorigenic breast cancer cells to chemotherapy[J]. J Natl Cancer Inst， 2008， 100(9)：672-679.
5.	Yang L， Ping YF， Yu X， et al. Gastric cancer stem-like cells possess higher capability of invasion and metastasis in association with a mesenchymal transition phenotype[J]. Cancer Lett， 2011， 310(1)：46-52.
6.	Scatena R， Bottoni P， Pontoglio A， et al. Cancer stem cells：the development of new cancer therapeutics[J]. Expert Opin Biol Ther， 2011， 11(7)：875-892.
7.	Mackenzie IC. Cancer stem cells[J]. Ann Oncol， 2008， 19 Suppl 5：v40-v43.
8.	Mackenzie IC. Stem cell properties and epithelial malignancies[J]. Eur J Cancer， 2006， 42(9)：1204-1212.
9.	Stingl J. Detection and analysis of mammary gland stem cells[J].J Pathol， 2009， 217(2)：229-241.
10.	Vries RG， Huch M， Clevers H. Stem cells and cancer of the stom-ach and intestine[J]. Mol Oncol， 2010， 4(5)：373-384.
11.	Jason CM， Shivdasani RA. Gastric epithelial stem cells[J]. Gastroenterology， 2011， 140(2)：412-424.
12.	Kassem NM. Review article：cancer stem cells：from identification to eradication[J]. J Egypt Natl Canc Inst， 2008， 20(3)：209-215.
13.	Yu SP， Yang XJ， Zhang B， et al. Enhanced invasion in vitro and the distribution patterns in vivo of CD133+ glioma stem cells[J]. Chin Med J， 2011， 124(17)：2599-2604.
14.	Catalano V， Di Franco S， Iovino F， et al. CD133 as a target for colon cancer[J]. Expert Opin Ther Targets， 2012， 16(3)： 259-267.
15.	陆瑞祺，吴巨钢，周国才，等. 胃癌CD133阳性细胞的纯化及其生物学特性研究[J]. 中国普外基础与临床杂志， 2011， 18(12)：1265-1270.
16.	Ricardo S， Vieira AF， Gerhard R， et al. Breast cancer stem cellmarkers CD44， CD24 and ALDH1：expression distribution withinintrinsic molecular subtype[J]. J Clin Pathol， 2011， 64(11)：937-946.
17.	Faber A， Barth C， Hörmann K， et al. CD44 as a stem cell markerin head and neck squamous cell carcinoma[J]. Oncol Rep， 2011， 26(2)：321-326.
18.	Liu C， Kelnar K， Liu B， et al. The microRNA miR-34a inhibits prostate cancer stem cells and metastasis by directly repressing CD44[J]. Nat Med， 2011， 17(2)：211-215.
19.	Williams JL. Cancer stem cells[J]. Clin Lab Sci， 2012， 25(1)：50-57.
20.	Hotz B， Visekruna A， Buhr HJ， et al. Beyond epithelial to mesenchymal transition：a novel role for the transcription factor Snail in inflammation and wound healing[J]. J Gastrointest Surg， 2010， 14(2)：388-397.
21.	Weber CE， Li NY， Wai PY， et al. Epithelial-mesenchymal transition， TGF-β， and osteopontin in wound healing and tissue remodeling after injury[J]. J Burn Care Res， 2012， 33(3)：311-318.
22.	Kalluri R， Weinberg RA. The basics of epithelial-mesenchymal transition[J]. J Clin Invest， 2009， 119(6)：1420-1428.
23.	Fuchs BC， Fujii T， Dorfman JD， et al. Epithelial-to-mesenchymal transition and integrin-linked kinase mediate sensitivity to epidermal growth factor receptor inhibition in human hepatoma cells[J]. Cancer Res， 2008， 68(7)：2391-2399.
24.	Kudo-Saito C， Shirako H， Takeuchi T， et al. Cancer metastasis is accelerated through immunosuppression during Snail-induced EMT of cancer cells[J]. Cancer Cell， 2009， 15(3)：195-206.
25.	Ru GQ， Wang HJ， Xu WJ， et al. Upregulation of twist in gastriccarcinoma associated with tumor invasion and poor prognosis[J]. Pathol Oncol Res， 2011， 17(2)：341-347.
26.	Siemens H， Jackstadt R， Hünten S， et al. miR-34 and SNAIL form a double-negative feedback loop to regulate epithelial-mesenchymal transitions[J]. Cell Cycle， 2011， 10(24)：4256-4271.
27.	Liu YN， Abou-Kheir W， Yin JJ， et al. Critical and reciprocal regulation of KLF4 and SLUG in transforming growth factor β-initiated prostate cancer epithelial-mesenchymal transition[J]. Mol Cell Biol， 2012， 32(5)：941-953.
28.	Wu KJ， Yang MH. Epithelial-mesenchymal transition and cancer stemness：the Twist1-Bmi1 connection[J]. Biosci Rep， 2011， 31(6)：449-455.
29.	Mani SA， Guo W， Liao MJ， et al. The epithelial-mesenchymal transition generates cells with properties of stem cells[J]. Cell， 2008， 133(4)：704-715.
30.	Ryu HS， Park do J， Kim HH， et al. Combination of epithelial-mesenchymal transition and cancer stem cell-like phenotypes has independent prognostic value in gastric cancer[J]. Hum Pathol， 2012， 43(4)：520-528.
31.	Hwang WL， Yang MH， Tsai ML， et al. SNAIL regulates interleukin-8 expression， stem cell-like activity， and tumorigenicity of human colorectal carcinoma cells[J]. Gastroenterology， 2011， 141(1)：279-291.
32.	Burk U， Schubert J， Wellner U， et al. A reciprocal repression between ZEB1 and members of the miR-200 family promotes EMT and invasion in cancer cells[J]. EMBO Rep， 2008， 9(6)：582-589.
33.	Chaffer CL， Brueckmann I， Scheel C， et al. Normal and neoplastic nonstem cells can spontaneously convert to a stem-like state[J]. Proc Natl Acad Sci U S A， 2011， 108(19)：7950-7955.
34.	Yang MH， Wu MZ， Chiou SH， et al. Direct regulation of TWIST by HIF-1alpha promotes metastasis[J]. Nat Cell Biol， 2008， 10(3)：295-305.
35.	Gaggioli C， Hooper S， Hidalgo-Carcedo C， et al. Fibroblast-ledcollective invasion of carcinoma cells with differing roles for RhoGTPases in leading and following cells[J]. Nat Cell Biol， 2007， 9(12)：1392-1400.
36.	Giampieri S， Manning C， Hooper S， et al. Localized and reve-rsible TGFbeta signalling switches breast cancer cells from cohe-sive to single cell motility[J]. Nat Cell Biol， 2009， 11(11)：1287-1296.
37.	Brabletz T， Jung A， Spaderna S， et al. Opinion：migrating cancerstem cells-an integrated concept of malignant tumour progression[J]. Nat Rev Cancer， 2005， 5(9)：744-749.
38.	Asiedu MK， Ingle JN， Behrens MD， et al. TGFbeta/TNF (alpha)-mediated epithelial-mesenchymal transition generates breast cancer stem cells with a claudin-low phenotype[J]. CancerRes， 2011， 71(13)：4707-4719.
39.	Biddle A， Liang X， Gammon L， et al. Cancer stem cells in squamous cell carcinoma switch between two distinct phenotypes that are preferentially migratory or proliferative[J]. Cancer Res， 2011， 71(15)：5317-5326.
40.	Chaffer CL， Brennan JP， Slavin JL， et al. Mesenchymal-to-epithelial transition facilitates bladder cancer metastasis：role of fibroblast growth factor receptor-2[J]. Cancer Res， 2006， 66(23)：11271-11278.
41.	Korpal M， Ell BJ， Buffa FM， et al. Direct targeting of Sec23a by miR-200s influences cancer cell secretome and promotes metastatic colonization[J]. Nat Med， 2011， 17(9)：1101-1108.
42.	Vinogradov S， Wei X. Cancer stem cells and drug resistance：the potential of nanomedicine[J]. Nanomedicine (Lond)， 2012， 7(4)：597-615.
43.	Skvortsova I， Skvortsov S， Raju U， et al. Epithelial-to-mesenchymal transition and c-myc expression are the determinants of cetuximab-induced enhancement of squamous cell carcinoma radioresponse[J]. Radiother Oncol， 2010， 96(1)：108-115.
44.	Wang XQ， Ongkeko WM， Chen L， et al. Octamer 4 (Oct4) mediates chemotherapeutic drug resistance in liver cancer cells through a potential Oct4-AKT-ATP-binding cassette G2 pathway[J]. Hepatology， 2010， 52(2)：528-539.
45.	Cheung ST， Cheung PF， Cheng CK， et al. Granulin-epithelin precursor and ATP-dependent binding cassette (ABC) B5 regulate liver cancer cell chemoresistance[J]. Gastroenterology， 2011， 140(1)：344-355.
46.	Pang R， Law WL， Chu AC， et al. A subpopulation of CD26＋cancer stem cells with metastatic capacity in human colorectal cancer[J]. Cell Stem Cell， 2010， 6(6)：603-615.
47.	Marsh D， Suchak K， Moutasim KA， et al. Stromal features are predictive of disease mortality in oral cancer patients[J]. J Pathol， 2011， 223(4)：470-481.

1. Charafe-Jauffret E， Ginestier C， Iovino F， et al. Aldehyde dehyd-rogenase 1-positive cancer stem cells mediate metastasis and poor clinical outcome in inflammatory breast cancer[J]. Clin Cancer Res， 2010， 16(1)：45-55.
2. Gjerdrum C， Tiron C， Høiby T， et al. Axl is an essential epithelial-to-mesenchymal transition-induced regulator of breast cancer metastasis and patient survival[J]. Proc Natl Acad Sci U S A， 2010， 107(3)：1124-1129.
3. Hoshino H， Miyoshi N， Nagai K， et al. Epithelial-mesenchymal transition with expression of SNAI1-induced chemoresistance in colorectal cancer[J]. Biochem Biophys Res Commun， 2009， 390(3)：1061-1065.
4. Li X， Lewis MT， Huang J， et al. Intrinsic resistance of tumorigenic breast cancer cells to chemotherapy[J]. J Natl Cancer Inst， 2008， 100(9)：672-679.
5. Yang L， Ping YF， Yu X， et al. Gastric cancer stem-like cells possess higher capability of invasion and metastasis in association with a mesenchymal transition phenotype[J]. Cancer Lett， 2011， 310(1)：46-52.
6. Scatena R， Bottoni P， Pontoglio A， et al. Cancer stem cells：the development of new cancer therapeutics[J]. Expert Opin Biol Ther， 2011， 11(7)：875-892.
7. Mackenzie IC. Cancer stem cells[J]. Ann Oncol， 2008， 19 Suppl 5：v40-v43.
8. Mackenzie IC. Stem cell properties and epithelial malignancies[J]. Eur J Cancer， 2006， 42(9)：1204-1212.
9. Stingl J. Detection and analysis of mammary gland stem cells[J].J Pathol， 2009， 217(2)：229-241.
10. Vries RG， Huch M， Clevers H. Stem cells and cancer of the stom-ach and intestine[J]. Mol Oncol， 2010， 4(5)：373-384.
11. Jason CM， Shivdasani RA. Gastric epithelial stem cells[J]. Gastroenterology， 2011， 140(2)：412-424.
12. Kassem NM. Review article：cancer stem cells：from identification to eradication[J]. J Egypt Natl Canc Inst， 2008， 20(3)：209-215.
13. Yu SP， Yang XJ， Zhang B， et al. Enhanced invasion in vitro and the distribution patterns in vivo of CD133+ glioma stem cells[J]. Chin Med J， 2011， 124(17)：2599-2604.
14. Catalano V， Di Franco S， Iovino F， et al. CD133 as a target for colon cancer[J]. Expert Opin Ther Targets， 2012， 16(3)： 259-267.
15. 陆瑞祺，吴巨钢，周国才，等. 胃癌CD133阳性细胞的纯化及其生物学特性研究[J]. 中国普外基础与临床杂志， 2011， 18(12)：1265-1270.
16. Ricardo S， Vieira AF， Gerhard R， et al. Breast cancer stem cellmarkers CD44， CD24 and ALDH1：expression distribution withinintrinsic molecular subtype[J]. J Clin Pathol， 2011， 64(11)：937-946.
17. Faber A， Barth C， Hörmann K， et al. CD44 as a stem cell markerin head and neck squamous cell carcinoma[J]. Oncol Rep， 2011， 26(2)：321-326.
18. Liu C， Kelnar K， Liu B， et al. The microRNA miR-34a inhibits prostate cancer stem cells and metastasis by directly repressing CD44[J]. Nat Med， 2011， 17(2)：211-215.
19. Williams JL. Cancer stem cells[J]. Clin Lab Sci， 2012， 25(1)：50-57.
20. Hotz B， Visekruna A， Buhr HJ， et al. Beyond epithelial to mesenchymal transition：a novel role for the transcription factor Snail in inflammation and wound healing[J]. J Gastrointest Surg， 2010， 14(2)：388-397.
21. Weber CE， Li NY， Wai PY， et al. Epithelial-mesenchymal transition， TGF-β， and osteopontin in wound healing and tissue remodeling after injury[J]. J Burn Care Res， 2012， 33(3)：311-318.
22. Kalluri R， Weinberg RA. The basics of epithelial-mesenchymal transition[J]. J Clin Invest， 2009， 119(6)：1420-1428.
23. Fuchs BC， Fujii T， Dorfman JD， et al. Epithelial-to-mesenchymal transition and integrin-linked kinase mediate sensitivity to epidermal growth factor receptor inhibition in human hepatoma cells[J]. Cancer Res， 2008， 68(7)：2391-2399.
24. Kudo-Saito C， Shirako H， Takeuchi T， et al. Cancer metastasis is accelerated through immunosuppression during Snail-induced EMT of cancer cells[J]. Cancer Cell， 2009， 15(3)：195-206.
25. Ru GQ， Wang HJ， Xu WJ， et al. Upregulation of twist in gastriccarcinoma associated with tumor invasion and poor prognosis[J]. Pathol Oncol Res， 2011， 17(2)：341-347.
26. Siemens H， Jackstadt R， Hünten S， et al. miR-34 and SNAIL form a double-negative feedback loop to regulate epithelial-mesenchymal transitions[J]. Cell Cycle， 2011， 10(24)：4256-4271.
27. Liu YN， Abou-Kheir W， Yin JJ， et al. Critical and reciprocal regulation of KLF4 and SLUG in transforming growth factor β-initiated prostate cancer epithelial-mesenchymal transition[J]. Mol Cell Biol， 2012， 32(5)：941-953.
28. Wu KJ， Yang MH. Epithelial-mesenchymal transition and cancer stemness：the Twist1-Bmi1 connection[J]. Biosci Rep， 2011， 31(6)：449-455.
29. Mani SA， Guo W， Liao MJ， et al. The epithelial-mesenchymal transition generates cells with properties of stem cells[J]. Cell， 2008， 133(4)：704-715.
30. Ryu HS， Park do J， Kim HH， et al. Combination of epithelial-mesenchymal transition and cancer stem cell-like phenotypes has independent prognostic value in gastric cancer[J]. Hum Pathol， 2012， 43(4)：520-528.
31. Hwang WL， Yang MH， Tsai ML， et al. SNAIL regulates interleukin-8 expression， stem cell-like activity， and tumorigenicity of human colorectal carcinoma cells[J]. Gastroenterology， 2011， 141(1)：279-291.
32. Burk U， Schubert J， Wellner U， et al. A reciprocal repression between ZEB1 and members of the miR-200 family promotes EMT and invasion in cancer cells[J]. EMBO Rep， 2008， 9(6)：582-589.
33. Chaffer CL， Brueckmann I， Scheel C， et al. Normal and neoplastic nonstem cells can spontaneously convert to a stem-like state[J]. Proc Natl Acad Sci U S A， 2011， 108(19)：7950-7955.
34. Yang MH， Wu MZ， Chiou SH， et al. Direct regulation of TWIST by HIF-1alpha promotes metastasis[J]. Nat Cell Biol， 2008， 10(3)：295-305.
35. Gaggioli C， Hooper S， Hidalgo-Carcedo C， et al. Fibroblast-ledcollective invasion of carcinoma cells with differing roles for RhoGTPases in leading and following cells[J]. Nat Cell Biol， 2007， 9(12)：1392-1400.
36. Giampieri S， Manning C， Hooper S， et al. Localized and reve-rsible TGFbeta signalling switches breast cancer cells from cohe-sive to single cell motility[J]. Nat Cell Biol， 2009， 11(11)：1287-1296.
37. Brabletz T， Jung A， Spaderna S， et al. Opinion：migrating cancerstem cells-an integrated concept of malignant tumour progression[J]. Nat Rev Cancer， 2005， 5(9)：744-749.
38. Asiedu MK， Ingle JN， Behrens MD， et al. TGFbeta/TNF (alpha)-mediated epithelial-mesenchymal transition generates breast cancer stem cells with a claudin-low phenotype[J]. CancerRes， 2011， 71(13)：4707-4719.
39. Biddle A， Liang X， Gammon L， et al. Cancer stem cells in squamous cell carcinoma switch between two distinct phenotypes that are preferentially migratory or proliferative[J]. Cancer Res， 2011， 71(15)：5317-5326.
40. Chaffer CL， Brennan JP， Slavin JL， et al. Mesenchymal-to-epithelial transition facilitates bladder cancer metastasis：role of fibroblast growth factor receptor-2[J]. Cancer Res， 2006， 66(23)：11271-11278.
41. Korpal M， Ell BJ， Buffa FM， et al. Direct targeting of Sec23a by miR-200s influences cancer cell secretome and promotes metastatic colonization[J]. Nat Med， 2011， 17(9)：1101-1108.
42. Vinogradov S， Wei X. Cancer stem cells and drug resistance：the potential of nanomedicine[J]. Nanomedicine (Lond)， 2012， 7(4)：597-615.
43. Skvortsova I， Skvortsov S， Raju U， et al. Epithelial-to-mesenchymal transition and c-myc expression are the determinants of cetuximab-induced enhancement of squamous cell carcinoma radioresponse[J]. Radiother Oncol， 2010， 96(1)：108-115.
44. Wang XQ， Ongkeko WM， Chen L， et al. Octamer 4 (Oct4) mediates chemotherapeutic drug resistance in liver cancer cells through a potential Oct4-AKT-ATP-binding cassette G2 pathway[J]. Hepatology， 2010， 52(2)：528-539.
45. Cheung ST， Cheung PF， Cheng CK， et al. Granulin-epithelin precursor and ATP-dependent binding cassette (ABC) B5 regulate liver cancer cell chemoresistance[J]. Gastroenterology， 2011， 140(1)：344-355.
46. Pang R， Law WL， Chu AC， et al. A subpopulation of CD26＋cancer stem cells with metastatic capacity in human colorectal cancer[J]. Cell Stem Cell， 2010， 6(6)：603-615.
47. Marsh D， Suchak K， Moutasim KA， et al. Stromal features are predictive of disease mortality in oral cancer patients[J]. J Pathol， 2011， 223(4)：470-481.

CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Effect of Tumor Initiating Cells and Epithelial-Mesenchymal Transition in Tumor Metastasis and Drug Resistance

Abstract Full text Figures/Tables Video References Cited by

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