• 上海交通大學(xué)醫(yī)學(xué)院附屬第三人民醫(yī)院普外一科（上海 201900）;

目的 　總結(jié)目前胃腸道干細(xì)胞及其在胃腫瘤中的作用的研究進(jìn)展。
方法 　通過(guò)查詢PubMed，檢索胃腸道干細(xì)胞微環(huán)境、標(biāo)志物和胃腫瘤干細(xì)胞理論相關(guān)的文獻(xiàn)，對(duì)關(guān)于胃腸道干細(xì)胞以及腫瘤干細(xì)胞的研究文獻(xiàn)進(jìn)行分析。
結(jié)果 　腫瘤的干細(xì)胞起源理論10年來(lái)發(fā)展十分迅速，胃腸道干細(xì)胞與胃腫瘤關(guān)系密切，自身具有特定的標(biāo)志物，生長(zhǎng)的微環(huán)境包含多種組織因子。胃腸道干細(xì)胞受到炎癥刺激誘導(dǎo)出現(xiàn)異常增殖，轉(zhuǎn)變?yōu)槟[瘤干細(xì)胞，從而促進(jìn)胃腫瘤的生長(zhǎng)、侵襲和轉(zhuǎn)移。
結(jié)論 　胃腫瘤干細(xì)胞可作為治療胃腫瘤的有效靶點(diǎn)之一，可為人類胃腫瘤的治療提供新的突破口。

引用本文： 王嘉,俞繼衛(wèi),姜波健. 胃腸道干細(xì)胞及其在胃腫瘤中的作用的研究進(jìn)展△. 中國(guó)普外基礎(chǔ)與臨床雜志, 2013, 20(2): 221-226. doi: 復(fù)制

1. van der Flier LG， van Gijn ME， Hatzis P， et al. Transcription factor achaete scute-like 2 controls intestinal stem cell fate[J]. Cell， 2009， 136(5)：903-912.
2. McNairn AJ， Guasch G. Epithelial transition zones：mergingmicroenvironments， niches， and cellular transformation[J]. Eur J Dermatol， 2011， 21 Suppl 2：21-28.
3. Levin DE， Grikscheit TC. Tissue-engineering of the gastrointestinal tract[J]. Curr Opin Pediatr， 2012， 24(3)：365-370.
4. Haegebarth A， Clevers H. Wnt signaling， Lgr5， and stem cells in the intestine and skin[J]. Am J Pathol， 2009， 174(3)：715-721.
5. Neal MD， Richardson WM， Sodhi CP， et al. Intestinal stem cells and their roles during mucosal injury and repair[J]. J Surg Res， 2011， 167(1)：1-8.
6. Sato T， Vries RG， Snippert HJ， et al. Single Lgr5 stem cells build crypt-villus structures in vitro without a mesenchymal niche[J]. Nature， 2009， 459(7244)：262-265.
7. Sato T， van Es JH， Snippert HJ， et al. Paneth cells constitute the niche for Lgr5 stem cells in intestinal crypts[J]. Nature， 2011， 469(7330)：415-418.
8. Kim TH， Escudero S， Shivdasani RA. Intact function of Lgr5 receptor-expressing intestinal stem cells in the absence of Paneth cells[J]. Proc Natl Acad Sci USA， 2012， 109(10)：3932-3937.
9. Saikawa Y， Fukuda K， Takahashi T， et al. Gastric carcinogenesis and the cancer stem cell hypothesis[J]. Gastric Cancer， 2010， 13(1)：11-24.
10. Karam SM. A focus on parietal cells as a renewing cell population[J]. World J Gastroenterol， 2010， 16(5)：538-546.
11. Bredemeyer AJ， Geahlen JH， Weis VG， et al. The gastric epithelialprogenitor cell niche and differentiation of the zymogenic (chief) cell lineage[J]. Dev Biol， 2009， 325(1)：211-224.
12. Nam KT， Lee HJ， Sousa JF， et al. Mature chief cells are cryptic progenitors for metaplasia in the stomach[J]. Gastroenterology， 2010， 139(6)：2028-2037.
13. Goldenring JR， Nam KT， Mills JC. The origin of pre-neoplastic metaplasia in the stomach：chief cells emerge from the Mist[J]. Exp Cell Res， 2011， 317(19)：2759-2764.
14. Qiao XT， Gumucio DL. Current molecular markers for gastric progenitor cells and gastric cancer stem cells[J]. J Gastroenterol， 2011， 46(7)：855-865.
15. Barker N， Huch M， Kujala P， et al. Lgr5+ve stem cells drive self-renewal in the stomach and build long-lived gastric units in vitro[J]. Cell Stem Cell， 2010， 6(1)：25-36.
16. Fan XS， Wu HY， Yu HP， et al. Expression of Lgr5 in human colorectal carcinogenesis and its potential correlation with beta-catenin[J]. Int J Colorectal Dis， 2010， 25(5)：583-590.
17. Leushacke M， Barker N. Lgr5 and Lgr6 as markers to study adult stem cell roles in self-renewal and cancer[J]. Oncogene， 2012， 31(25)：3009-3022.
18. Simon E， Petke D， Böger C， et al. The spatial distribution of LGR5+ cells correlates with gastric cancer progression[J]. PLoS One， 2012， 7(4)：e35486.
19. Quante M， Marrache F， Goldenring JR， et al. TFF2 mRNA transcript expression marks a gland progenitor cell of the gastric oxyntic mucosa[J]. Gastroenterology， 2010， 139(6)：2018-2027.
20. Huh WJ， Esen E， Geahlen JH， et al. XBP1 controls maturation of gastric zymogenic cells by induction of MIST1 and expansion of the rough endoplasmic reticulum[J]. Gastroenterology， 2010， 139(6)：2038-2049.
21. Tian X， Jin RU， Bredemeyer AJ， et al. RAB26 and RAB3D are direct transcriptional targets of MIST1 that regulate exocrine granulematuration[J]. Mol Cell Biol， 2010， 30(5)：1269-1284.
22. Lennerz JK， Kim SH， Oates EL， et al. The transcription factor MIST1 is a novel human gastric chief cell marker whose expression is lost in metaplasia， dysplasia， and carcinoma[J]. Am J Pathol， 2010， 177(3)：1514-1533.
23. Zhang Y， Huang X. Investigation of doublecortin and calcium/calmodulin-dependent protein kinase-like-1-expressing cells in the mouse stomach[J]. J Gastroenterol Hepatol， 2010， 25(3)：576-582.
24. Kikuchi M， Nagata H， Watanabe N， et al. Altered expression of a putative progenitor cell marker DCAMKL1 in the rat gastric mucosa in regeneration， metaplasia and dysplasia[J]. BMC Gastroenterol， 2010， 10：65.
25. Snippert HJ， van Es JH， van den Born M， et al. Prominin-1/CD133 marks stem cells and early progenitors in mouse smallintestine[J]. Gastroenterology， 2009， 136(7)：2187-2194.
26. Zhu L， Gibson P， Currle DS， et al. Prominin 1 marks intestinal stem cells that are susceptible to neoplastic transformation[J]. Nature， 2009， 457(7229)：603-607.
27. Fukamachi H， Shimada S， Ito K， et al. CD133 is a marker of gland-forming cells in gastric tumors and Sox17 is involved in its regulation[J]. Cancer Sci， 2011， 102(7)：1313-1321.
28. Cao L， Hu X， Zhang Y， et al. Omental milky spots in screening gastric cancer stem cells[J]. Neoplasma， 2011， 58(1)：20-26.
29. Yasui W， Sentani K， Sakamoto N， et al. Molecular pathology of gastric cancer：research and practice[J]. Pathol Res Pract， 2011， 207(10)：608-612.
30. Matkar SS， Durham A， Brice A， et al. Systemic activation of K-ras rapidly induces gastric hyperplasia and metaplasia in mice[J]. Am J Cancer Res， 2011， 1(4)：432-445.
31. da Cunha CB， Oliveira C， Wen X， et al. De novo expression of CD44 variants in sporadic and hereditary gastric cancer[J]. Lab Invest， 2010， 90(11)：1604-1614.
32. Palagani V， El Khatib M， Krech T， et al. Decrease of CD44-positive cells correlates with tumor response to chemotherapy in patients with gastrointestinal cancer[J]. Anticancer Res， 2012， 32(5)：1747-1755.
33. Takaishi S， Okumura T， Tu S， et al. Identification of gastric cancer stem cells using the cell surface marker CD44[J]. Stem Cells， 2009， 27(5)：1006-1020.
34. Dhingra S， Feng W， Brown RE， et al. Clinicopathologic significance of putative stem cell markers， CD44 and nestin， in gastric adenocarcinoma[J]. Int J Clin Exp Pathol， 2011， 4(8)：733-741.
35. Arnold K， Sarkar A， Yram MA， et al. Sox2+ adult stem andprogenitor cells are important for tissue regeneration and survival of mice[J]. Cell Stem Cell， 2011， 9(4)：317-329.
36. Honda A， Hirose M， Hatori M， et al. Generation of induced pluripotent stem cells in rabbits：potential experimental models for human regenerative medicine[J]. J Biol Chem， 2010， 285(41)：31362-31369.
37. Kirchner T， Muller S， Hattori T， et al. Metaplasia， intraepithelialneoplasia and early cancer of the stomach are related to dedifferentiated epithelial cells defined by cytokeratin-7 expression in gastritis[J]. Virchows Arch， 2001， 439(4)：512-522.
38. Karam SM. Mouse models demonstrating the role of stem/progenitor cells in gastric carcinogenesis[J]. Front Biosci， 2010， 15：595-603.
39. Houghton J， Stoicov C， Nomura S， et al. Gastric cancer originating from bone marrowderived cells[J]. Science， 2004， 306(5701)：1568-1571.
40. Quante M， Tu SP， Tomita H， et al. Bone marrow-derivedmyofibroblasts contribute to the mesenchymal stem cell niche and promote tumor growth[J]. Cancer Cell， 2011， 19(2)：257-272.
41. Shibata W， Ariyama H， Westphalen CB， et al. Stromal cell-derived factor-1 overexpression induces gastric dysplasia through expansion of stromal myofibroblasts and epithelial progenitors[J]. Gut， 2012 Feb 23. [Epub ahead of print].
42. Pilpilidis I， Kountouras J， Zavos C， et al. Upper gastrointestinal carcinogenesis：H. pylori and stem cell cross-talk[J]. J Surg Res， 2011， 166(2)：255-264.
43. Varon C， Dubus P， Mazurier F， et al. Helicobacter pylori infectionrecruits bone marrow-derived cells that participate in gastric prene-oplasia in mice[J]. Gastroenterology， 2012， 142(2)：281-291.
44. Kouznetsova I， Kalinski T， Meyer F， et al. Self-renewal of the human gastric epithelium：new insights from expression profiling using laser microdissection[J]. Mol Biosyst， 2011， 7(4)：1105-1112.
45. Polk DB， Peek RM Jr. Helicobacter pylori：gastric cancer and beyond[J]. Nat Rev Cancer， 2010， 10(6)：403-414.
46. Ding SZ， Goldberg JB， Hatakeyama M. Helicobacter pyloriinfection， oncogenic pathways and epigenetic mechanisms in gastriccarcinogenesis[J]. Future Oncol， 2010， 6(5)：851-862.
47. Seoane J. NO signals from the cancer stem cell niche[J]. Cell Stem Cell， 2010， 6(2)：97-98.
48. Takebe N， Harris PJ， Warren RQ， et al. Targeting cancer stem cells by inhibiting Wnt， Notch， and Hedgehog pathways[J]. Nat Rev Clin Oncol， 2011， 8(2)：97-106.
49. Takebe N， Ivy SP. Controversies in cancer stem cells：targetingembryonic signaling pathways[J]. Clin Cancer Res， 2010， 16(12)：3106-3112.
50. Martelli AM， Evangelisti C， Follo MY， et al. Targeting the phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin signaling network in cancer stem cells[J]. Curr Med Chem， 2011， 18(18)：2715-2726.
51. Thiel A， Mrena J， Ristimäki A. Cyclooxygenase-2 and gastric cancer[J]. Cancer Metastasis Rev， 2011， 30(3-4)：387-395.
52. Futagami S， Hamamoto T， Shimpuku M， et al. Celecoxib inhibitsCD133-positive cell migration via reduction of CCR2 in Helicobacter pylori-infected Mongolian gerbils[J]. Digestion， 2010， 81(3)：193-203.
53. Stoicov C， Li H， Cerny J， et al. How the study of Helicobacter infection can contribute to the understanding of carcinoma development[J]. Clin Microbiol Infect， 2009， 15(9)：813-822.
54. Cukierman E， Bassi DE. The mesenchymal tumor microenvironment：a drug-resistant niche[J]. Cell Adh Migr， 2012， 6(3)：285-296.
55. Cabarcas SM， Mathews LA， Farrar WL. The cancer stem cell niche-there goes the neighborhood?[J]. Int J Cancer， 2011， 129(10)：2315-2327.
  1. 1. van der Flier LG， van Gijn ME， Hatzis P， et al. Transcription factor achaete scute-like 2 controls intestinal stem cell fate[J]. Cell， 2009， 136(5)：903-912.
  2. 2. McNairn AJ， Guasch G. Epithelial transition zones：mergingmicroenvironments， niches， and cellular transformation[J]. Eur J Dermatol， 2011， 21 Suppl 2：21-28.
  3. 3. Levin DE， Grikscheit TC. Tissue-engineering of the gastrointestinal tract[J]. Curr Opin Pediatr， 2012， 24(3)：365-370.
  4. 4. Haegebarth A， Clevers H. Wnt signaling， Lgr5， and stem cells in the intestine and skin[J]. Am J Pathol， 2009， 174(3)：715-721.
  5. 5. Neal MD， Richardson WM， Sodhi CP， et al. Intestinal stem cells and their roles during mucosal injury and repair[J]. J Surg Res， 2011， 167(1)：1-8.
  6. 6. Sato T， Vries RG， Snippert HJ， et al. Single Lgr5 stem cells build crypt-villus structures in vitro without a mesenchymal niche[J]. Nature， 2009， 459(7244)：262-265.
  7. 7. Sato T， van Es JH， Snippert HJ， et al. Paneth cells constitute the niche for Lgr5 stem cells in intestinal crypts[J]. Nature， 2011， 469(7330)：415-418.
  8. 8. Kim TH， Escudero S， Shivdasani RA. Intact function of Lgr5 receptor-expressing intestinal stem cells in the absence of Paneth cells[J]. Proc Natl Acad Sci USA， 2012， 109(10)：3932-3937.
  9. 9. Saikawa Y， Fukuda K， Takahashi T， et al. Gastric carcinogenesis and the cancer stem cell hypothesis[J]. Gastric Cancer， 2010， 13(1)：11-24.
  10. 10. Karam SM. A focus on parietal cells as a renewing cell population[J]. World J Gastroenterol， 2010， 16(5)：538-546.
  11. 11. Bredemeyer AJ， Geahlen JH， Weis VG， et al. The gastric epithelialprogenitor cell niche and differentiation of the zymogenic (chief) cell lineage[J]. Dev Biol， 2009， 325(1)：211-224.
  12. 12. Nam KT， Lee HJ， Sousa JF， et al. Mature chief cells are cryptic progenitors for metaplasia in the stomach[J]. Gastroenterology， 2010， 139(6)：2028-2037.
  13. 13. Goldenring JR， Nam KT， Mills JC. The origin of pre-neoplastic metaplasia in the stomach：chief cells emerge from the Mist[J]. Exp Cell Res， 2011， 317(19)：2759-2764.
  14. 14. Qiao XT， Gumucio DL. Current molecular markers for gastric progenitor cells and gastric cancer stem cells[J]. J Gastroenterol， 2011， 46(7)：855-865.
  15. 15. Barker N， Huch M， Kujala P， et al. Lgr5+ve stem cells drive self-renewal in the stomach and build long-lived gastric units in vitro[J]. Cell Stem Cell， 2010， 6(1)：25-36.
  16. 16. Fan XS， Wu HY， Yu HP， et al. Expression of Lgr5 in human colorectal carcinogenesis and its potential correlation with beta-catenin[J]. Int J Colorectal Dis， 2010， 25(5)：583-590.
  17. 17. Leushacke M， Barker N. Lgr5 and Lgr6 as markers to study adult stem cell roles in self-renewal and cancer[J]. Oncogene， 2012， 31(25)：3009-3022.
  18. 18. Simon E， Petke D， Böger C， et al. The spatial distribution of LGR5+ cells correlates with gastric cancer progression[J]. PLoS One， 2012， 7(4)：e35486.
  19. 19. Quante M， Marrache F， Goldenring JR， et al. TFF2 mRNA transcript expression marks a gland progenitor cell of the gastric oxyntic mucosa[J]. Gastroenterology， 2010， 139(6)：2018-2027.
  20. 20. Huh WJ， Esen E， Geahlen JH， et al. XBP1 controls maturation of gastric zymogenic cells by induction of MIST1 and expansion of the rough endoplasmic reticulum[J]. Gastroenterology， 2010， 139(6)：2038-2049.
  21. 21. Tian X， Jin RU， Bredemeyer AJ， et al. RAB26 and RAB3D are direct transcriptional targets of MIST1 that regulate exocrine granulematuration[J]. Mol Cell Biol， 2010， 30(5)：1269-1284.
  22. 22. Lennerz JK， Kim SH， Oates EL， et al. The transcription factor MIST1 is a novel human gastric chief cell marker whose expression is lost in metaplasia， dysplasia， and carcinoma[J]. Am J Pathol， 2010， 177(3)：1514-1533.
  23. 23. Zhang Y， Huang X. Investigation of doublecortin and calcium/calmodulin-dependent protein kinase-like-1-expressing cells in the mouse stomach[J]. J Gastroenterol Hepatol， 2010， 25(3)：576-582.
  24. 24. Kikuchi M， Nagata H， Watanabe N， et al. Altered expression of a putative progenitor cell marker DCAMKL1 in the rat gastric mucosa in regeneration， metaplasia and dysplasia[J]. BMC Gastroenterol， 2010， 10：65.
  25. 25. Snippert HJ， van Es JH， van den Born M， et al. Prominin-1/CD133 marks stem cells and early progenitors in mouse smallintestine[J]. Gastroenterology， 2009， 136(7)：2187-2194.
  26. 26. Zhu L， Gibson P， Currle DS， et al. Prominin 1 marks intestinal stem cells that are susceptible to neoplastic transformation[J]. Nature， 2009， 457(7229)：603-607.
  27. 27. Fukamachi H， Shimada S， Ito K， et al. CD133 is a marker of gland-forming cells in gastric tumors and Sox17 is involved in its regulation[J]. Cancer Sci， 2011， 102(7)：1313-1321.
  28. 28. Cao L， Hu X， Zhang Y， et al. Omental milky spots in screening gastric cancer stem cells[J]. Neoplasma， 2011， 58(1)：20-26.
  29. 29. Yasui W， Sentani K， Sakamoto N， et al. Molecular pathology of gastric cancer：research and practice[J]. Pathol Res Pract， 2011， 207(10)：608-612.
  30. 30. Matkar SS， Durham A， Brice A， et al. Systemic activation of K-ras rapidly induces gastric hyperplasia and metaplasia in mice[J]. Am J Cancer Res， 2011， 1(4)：432-445.
  31. 31. da Cunha CB， Oliveira C， Wen X， et al. De novo expression of CD44 variants in sporadic and hereditary gastric cancer[J]. Lab Invest， 2010， 90(11)：1604-1614.
  32. 32. Palagani V， El Khatib M， Krech T， et al. Decrease of CD44-positive cells correlates with tumor response to chemotherapy in patients with gastrointestinal cancer[J]. Anticancer Res， 2012， 32(5)：1747-1755.
  33. 33. Takaishi S， Okumura T， Tu S， et al. Identification of gastric cancer stem cells using the cell surface marker CD44[J]. Stem Cells， 2009， 27(5)：1006-1020.
  34. 34. Dhingra S， Feng W， Brown RE， et al. Clinicopathologic significance of putative stem cell markers， CD44 and nestin， in gastric adenocarcinoma[J]. Int J Clin Exp Pathol， 2011， 4(8)：733-741.
  35. 35. Arnold K， Sarkar A， Yram MA， et al. Sox2+ adult stem andprogenitor cells are important for tissue regeneration and survival of mice[J]. Cell Stem Cell， 2011， 9(4)：317-329.
  36. 36. Honda A， Hirose M， Hatori M， et al. Generation of induced pluripotent stem cells in rabbits：potential experimental models for human regenerative medicine[J]. J Biol Chem， 2010， 285(41)：31362-31369.
  37. 37. Kirchner T， Muller S， Hattori T， et al. Metaplasia， intraepithelialneoplasia and early cancer of the stomach are related to dedifferentiated epithelial cells defined by cytokeratin-7 expression in gastritis[J]. Virchows Arch， 2001， 439(4)：512-522.
  38. 38. Karam SM. Mouse models demonstrating the role of stem/progenitor cells in gastric carcinogenesis[J]. Front Biosci， 2010， 15：595-603.
  39. 39. Houghton J， Stoicov C， Nomura S， et al. Gastric cancer originating from bone marrowderived cells[J]. Science， 2004， 306(5701)：1568-1571.
  40. 40. Quante M， Tu SP， Tomita H， et al. Bone marrow-derivedmyofibroblasts contribute to the mesenchymal stem cell niche and promote tumor growth[J]. Cancer Cell， 2011， 19(2)：257-272.
  41. 41. Shibata W， Ariyama H， Westphalen CB， et al. Stromal cell-derived factor-1 overexpression induces gastric dysplasia through expansion of stromal myofibroblasts and epithelial progenitors[J]. Gut， 2012 Feb 23. [Epub ahead of print].
  42. 42. Pilpilidis I， Kountouras J， Zavos C， et al. Upper gastrointestinal carcinogenesis：H. pylori and stem cell cross-talk[J]. J Surg Res， 2011， 166(2)：255-264.
  43. 43. Varon C， Dubus P， Mazurier F， et al. Helicobacter pylori infectionrecruits bone marrow-derived cells that participate in gastric prene-oplasia in mice[J]. Gastroenterology， 2012， 142(2)：281-291.
  44. 44. Kouznetsova I， Kalinski T， Meyer F， et al. Self-renewal of the human gastric epithelium：new insights from expression profiling using laser microdissection[J]. Mol Biosyst， 2011， 7(4)：1105-1112.
  45. 45. Polk DB， Peek RM Jr. Helicobacter pylori：gastric cancer and beyond[J]. Nat Rev Cancer， 2010， 10(6)：403-414.
  46. 46. Ding SZ， Goldberg JB， Hatakeyama M. Helicobacter pyloriinfection， oncogenic pathways and epigenetic mechanisms in gastriccarcinogenesis[J]. Future Oncol， 2010， 6(5)：851-862.
  47. 47. Seoane J. NO signals from the cancer stem cell niche[J]. Cell Stem Cell， 2010， 6(2)：97-98.
  48. 48. Takebe N， Harris PJ， Warren RQ， et al. Targeting cancer stem cells by inhibiting Wnt， Notch， and Hedgehog pathways[J]. Nat Rev Clin Oncol， 2011， 8(2)：97-106.
  49. 49. Takebe N， Ivy SP. Controversies in cancer stem cells：targetingembryonic signaling pathways[J]. Clin Cancer Res， 2010， 16(12)：3106-3112.
  50. 50. Martelli AM， Evangelisti C， Follo MY， et al. Targeting the phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin signaling network in cancer stem cells[J]. Curr Med Chem， 2011， 18(18)：2715-2726.
  51. 51. Thiel A， Mrena J， Ristimäki A. Cyclooxygenase-2 and gastric cancer[J]. Cancer Metastasis Rev， 2011， 30(3-4)：387-395.
  52. 52. Futagami S， Hamamoto T， Shimpuku M， et al. Celecoxib inhibitsCD133-positive cell migration via reduction of CCR2 in Helicobacter pylori-infected Mongolian gerbils[J]. Digestion， 2010， 81(3)：193-203.
  53. 53. Stoicov C， Li H， Cerny J， et al. How the study of Helicobacter infection can contribute to the understanding of carcinoma development[J]. Clin Microbiol Infect， 2009， 15(9)：813-822.
  54. 54. Cukierman E， Bassi DE. The mesenchymal tumor microenvironment：a drug-resistant niche[J]. Cell Adh Migr， 2012， 6(3)：285-296.
  55. 55. Cabarcas SM， Mathews LA， Farrar WL. The cancer stem cell niche-there goes the neighborhood?[J]. Int J Cancer， 2011， 129(10)：2315-2327.

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