• 上海交通大學附屬第三人民醫(yī)院普外一科（上海 201900）;

目的 　總結腫瘤起始細胞（tumor initiating Cells，TICs）和上皮-間質(zhì)轉(zhuǎn)化（epithelial-mesenchymal transition，EMT）及其在腫瘤轉(zhuǎn)移和耐藥中的研究現(xiàn)狀。
方法 　檢索近年來國內(nèi)外有關TICs和EMT及其與腫瘤轉(zhuǎn)移和耐藥關系的文獻并做綜述。
結果 　TICs是腫瘤細胞中一小群具有自我更新、高度增殖及多向分化能力的細胞，表達多種表面標志物，如CD133、CD44等，在腫瘤的侵襲、轉(zhuǎn)移和耐藥中起著重要的作用。EMT是腫瘤上皮細胞失去極性轉(zhuǎn)變?yōu)殚g質(zhì)細胞的一種現(xiàn)象，常見于胚胎發(fā)育及組織修復，能夠促進腫瘤的侵襲、轉(zhuǎn)移以及逃避宿主的免疫反應，EMT可能是TICs所致腫瘤轉(zhuǎn)移和復發(fā)的根源。靶向TICs或EMT的治療可能有效預防腫瘤的復發(fā)及改善患者的預后。
結論 　EMT是TICs致腫瘤轉(zhuǎn)移及耐藥的重要機理，對于TICs和EMT的研究可用于探索更有效的針對腫瘤的靶向治療策略。

引用本文： 蔡成,俞繼衛(wèi),姜波健. 腫瘤起始細胞及上皮-間質(zhì)轉(zhuǎn)化在腫瘤轉(zhuǎn)移及耐藥中的作用△. 中國普外基礎與臨床雜志, 2013, 20(1): 99-103. doi: 復制

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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. 陸瑞祺， 吳巨鋼， 周國才， 等. 胃癌CD133陽性細胞的純化及其生物學特性研究[J]. 中國普外基礎與臨床雜志， 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. 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. 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. 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. 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. 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. 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. 7. Mackenzie IC. Cancer stem cells[J]. Ann Oncol， 2008， 19 Suppl 5：v40-v43.
  8. 8. Mackenzie IC. Stem cell properties and epithelial malignancies[J]. Eur J Cancer， 2006， 42(9)：1204-1212.
  9. 9. Stingl J. Detection and analysis of mammary gland stem cells[J].J Pathol， 2009， 217(2)：229-241.
  10. 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. 11. Jason CM， Shivdasani RA. Gastric epithelial stem cells[J]. Gastroenterology， 2011， 140(2)：412-424.
  12. 12. Kassem NM. Review article：cancer stem cells：from identification to eradication[J]. J Egypt Natl Canc Inst， 2008， 20(3)：209-215.
  13. 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. 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. 15. 陸瑞祺， 吳巨鋼， 周國才， 等. 胃癌CD133陽性細胞的純化及其生物學特性研究[J]. 中國普外基礎與臨床雜志， 2011， 18(12)：1265-1270.
  16. 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. 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. 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. 19. Williams JL. Cancer stem cells[J]. Clin Lab Sci， 2012， 25(1)：50-57.
  20. 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. 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. 22. Kalluri R， Weinberg RA. The basics of epithelial-mesenchymal transition[J]. J Clin Invest， 2009， 119(6)：1420-1428.
  23. 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. 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. 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. 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. 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. 28. Wu KJ， Yang MH. Epithelial-mesenchymal transition and cancer stemness：the Twist1-Bmi1 connection[J]. Biosci Rep， 2011， 31(6)：449-455.
  29. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 42. Vinogradov S， Wei X. Cancer stem cells and drug resistance：the potential of nanomedicine[J]. Nanomedicine (Lond)， 2012， 7(4)：597-615.
  43. 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. 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. 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. 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. 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.