1. Stem Cells and Hepatocarcinogenesis Neil Theise, MD Depts. of Pathology and Medicine Beth Israel Medical Center – Albert Einstein College of Medicine New York City www.neiltheise.com

2. Differentiation-Inducing Activity of Hydroxycamptothecin on Cancer Stem-Like Cells Derived from Hepatocellular Carcinoma. Zhang Y, Song WJ, Zhang FQ, Liu WH, Dou KF. Dig Dis Sci. 2011 Immunohistochemical study of hepatocyte, cholangiocyte and stem cell markers of hepatocellular carcinoma. Shibuya M, Kondo F, Sano K, Takada T, Asano T. J Hepatobiliary Pancreat Sci. 2011 MicroRNAs involved in neoplastic transformation of liver cancer stem cells. Li R, Qian N, Tao K, You N, Wang X, Dou K. J Exp Clin Cancer Res. 2010 Dec 23;29:169. Complete response in 5 out of 38 patients with advanced hepatocellular carcinoma treated with stem cell differentiation stage factors: case reports from a single centre. Livraghi T, Ceriani R, Palmisano A, Pedicini V, Pich MG, Tommasini MA, Torzilli G. Curr Pharm Biotechnol. 2011 Lupeol targets liver tumor-initiating cells through phosphatase and tensin homolog modulation. Lee TK, Castilho A, Cheung VC, Tang KH, Ma S, Ng IO. Hepatology. 2011 Jan;53(1):160-70. The cyclin E regulator cullin 3 prevents mouse hepatic progenitor cells from becoming tumor-initiating cells. Kossatz U, Breuhahn K, Wolf B, Hardtke-Wolenski M, Wilkens L, Steinemann D, Singer S, Brass F, Kubicka S, Schlegelberger B, Schirmacher P, Manns MP, Singer JD, Malek NP. J Clin Invest. 2010 Nov 1;120(11):3820-33 Invasion and EMT-associated genes are up-regulated in B viral hepatocellular carcinoma with high expression of CD133-human and cell culture study. Na DC, Lee JE, Yoo JE, Oh BK, Choi GH, Park YN. Exp Mol Pathol. 2011 Feb;90(1):66-73 Characterization of the epithelial cell adhesion molecule (EpCAM)+ cell population in hepatocellular carcinoma cell lines. Kimura O, Takahashi T, Ishii N, Inoue Y, Ueno Y, Kogure T, Fukushima K, Shiina M, Yamagiwa Y, Kondo Y, Inoue J, Kakazu E, Iwasaki T, Kawagishi N, Shimosegawa T, Sugamura K. Cancer Sci. 2010 Oct;101(10):2145-5 Cytoplasmic expression of CD133 is an important risk factor for overall survival in hepatocellular carcinoma. Sasaki A, Kamiyama T, Yokoo H, Nakanishi K, Kubota K, Haga H, Matsushita M, Ozaki M, Matsuno Y, Todo S. Oncol Rep. 2010 Aug;24(2):537-46. Collecting evidence for a stem cell hypothesis in HCC. Teufel A, Galle PR. Gut. 2010 Jul;59(7):870-1Expression of Oct4 in HCC and modulation to wnt/βcatenin and TGF-β signal pathways. Yuan F, Zhou W, Zou C, Zhang Z, Hu H, Dai Z, Zhang Y. Mol Cell Biochem. 2010 Oct;343(1-2):155-62Characterization of the epithelial cell adhesion molecule (EpCAM)+ cell population in hepatocellular carcinoma cell lines. Kimura O, Takahashi T, Ishii N, Inoue Y, Ueno Y, Kogure T, Fukushima K, Shiina M, Yamagiwa Y, Kondo Y, Inoue J, Kakazu E, Iwasaki T, Kawagishi N, Shimosegawa T, Sugamura K Cancer Sci. 2010 Oct;101(10):2145-55Oncostatin m renders epithelial cell adhesion molecule-positive liver cancer stem cells sensitive to 5-Fluorouracil by inducing hepatocytic differentiation. Yamashita T, Honda M, Nio K, Nakamoto Y, Yamashita T, Takamura H, Tani T, Zen Y, Kaneko S. Cancer Res. 2010 Jun 1;70(11):4687-97EpCAM, a new marker for cancer stem cells in hepatocellular carcinoma. Terris B, Cavard C, Perret C. J Hepatol. 2010 Feb;52(2):280-1. What is the relationship among microRNA-181, epithelial cell-adhesion molecule (EpCAM) and beta-catenin in hepatic cancer stem cells. Li JP, Zheng JY, Du JJ, Zhang R, Yang AG. Hepatology. 2009 Dec;50(6):2047-Hepatic progenitor cells in liver cancers from Asian children. Ward SC, Thung SN, Lim KH, Tran TT, Hong TK, Hoang PL, Jang JJ, Park YN, Abe K. Liver Int. 2010 Jan;30(1):102-11EpCAM-positive hepatocellular carcinoma cells are tumor-initiating cells with stem/progenitor cell features. Yamashita T, Ji J, Budhu A, Forgues M, Yang W, Wang HY, Jia H, Ye Q, Qin LX, Wauthier E, Reid LM, Minato H, Honda M, Kaneko S, Tang ZY, Wang XW. Gastroenterology. 2009 Mar;136(3):1012-24Immunohistochemical staining of cancer stem cell markers in hepatocellular carcinoma. Lingala S, Cui YY, Chen X, Ruebner BH, Qian XF, Zern MA, Wu J. Exp Mol Pathol. 2010 Aug;89(1):27-35.

3. Neil Theise, MD Depts. of Pathology and Medicine Beth Israel Medical Center – Albert Einstein College of Medicine New York City www.neiltheise.com Cancer and Stem Cells and Stem Cell-derived Cancer and Cancer-derived Stem Cells and… and… and… and…

4. This talk has been posted on: www.slideshare.net Search: “Neil Theise”

7. stem cell

8. stem cell “ assymetric division”

9. stem cell

10. stem cell

11. stem cell transit amplifying cells

12. stem cell transit amplifying cells ductular reactions (humans) oval cells (rodents)

13. stem cell transit amplifying cells drug resistant hypoxia resistant radio-resistant

14. stem cell transit amplifying cells drug resistant hypoxia resistant radio-resistant i.e. resistant to mutations

15. stem cell transit amplifying cells drug resistant hypoxia resistant radio-resistant telomerase

16. stem cell transit amplifying cells Keratin 19 CD117 (c-kit) CD90 (thy-1) EpCAM CD 133 (prominin-1) ABC-G2

17. Keratin 19 CD117 (c-kit) CD90 (thy-1) EpCAM CD 133 (prominin-1) ABC-G2 stem cell transit amplifying cells “ Side Population”

22. 1. Combined HCC-ChC 2. Combined HCC-ChC with stem cell features A. typical subtype B. intermediate cell subtype C. cholangiocellular subtype Chapter 10-4, N. D. Theise, O. Nakashima, Y. N. Park, Y. Nakanuma

24. Stem Cell Niche

25. Stem Cell Stromal Cell

26. Immortal Strand Hypothesis Stem cell retention of original DNA template after replication and division

27. Immortal Strand Hypothesis Stem cell retention of original DNA template after replication and division SO: STEM CELLS SHOULD REMAIN FREE OF MUTATIONS

28. Disordered stem cell retention of original DNA template in chronic disease e.g. inflammatory bowel disease primary sclerosing cholangitis mammary fibrocystic disease chronic viral hepatitis H. pylori gastritis

29. Disordered stem cell retention of original DNA template in chronic disease

30. Disordered stem cell retention of original DNA template in chronic disease

31. Disordered stem cell retention of original DNA template in chronic disease

32. Disordered stem cell retention of original DNA template in chronic disease MUTATION!!

34. Carcinogenesis

37. Cancer Stem Cell EpCAM CD133 ABC-G2 CD90 tumor

38. Cancer Stem Cell EpCAM CD133 ABC-G2 CD90 Often tumor initiating… tumor

42. cancer stem cell drug resistant hypoxia resistant radio-resistant tumor

43. Anti-tumor therapy cancer stem cell drug resistant hypoxia resistant radio-resistant tumor

44. Anti-tumor therapy cancer stem cell drug resistant hypoxia resistant radio-resistant tumor

45. Anti-tumor therapy cancer stem cell drug resistant hypoxia resistant radio-resistant tumor

46. Anti-tumor therapy cancer stem cell drug resistant hypoxia resistant radio-resistant tumor

47. Anti-tumor therapy cancer stem cell drug resistant hypoxia resistant radio-resistant

48. cancer stem cell drug resistant hypoxia resistant radio-resistant

49. cancer stem cell

50. cancer stem cell

51. cancer stem cell

52. cancer stem cell

53. cancer stem cell So: successful treatments will depend on new therapies that can successively eradicate tumor stem cells.

54. In summary: Cancers can arise from stem cells

55. In summary: Cancers can arise from stem cells or Cancers can arise from differentiated cells

56. In summary: Cancers can arise from stem cells or Cancers can arise from differentiated cells “ Cancer stem cells” may refer to the stem cells from which cancers start, BUT generally refer to:

57. In summary: Cancers can arise from stem cells or Cancers can arise from differentiated cells “ Cancer stem cells” can refer to the stem cells from which some cancers start, BUT generally refer to the: cells within a tumor that have stem cell-like properties :

58. In summary: Cancers can arise from stem cells or Cancers can arise from differentiated cells “ Cancer stem cells” can refer to the stem cells from which some cancers start, BUT generally refer to the: cells within a tumor that have stem cell like properties: i.e. slow cycling self-renewal multidrug resistance hypoxia resistant radio-insensitive

59. In summary: Cancers can arise from stem cells or Cancers can arise from differentiated cells “ Cancer stem cells” can refer to the stem cells from which some cancers start, BUT generally refer to the: cells within a tumor that have stem cell like properties: i.e. slow cycling self-renewal multidrug resistance hypoxia resistant radio-insensitive and therefore are resistant to therapy and responsible for tumor recurrence…

60. cells within a tumor that have stem cell like properties: i.e. slow cycling self-renewal multidrug resistance hypoxia resistant radio-insensitive and therefore are resistant to therapy and responsible for tumor recurrence… Antigenic Markers : CD133 c-kit EpCAM Keratin 19 Functional Markers : Side population Label retaining cells

61. Epigenetic regulation of cancer stem cells in liver cancer: current concepts and clinical implications. Marquardt JU, Factor VM, Thorgeirsson SS. J Hepatol. 2010; 53: 568. Stem cell plasticity: recapping the decade, mapping the future. Theise ND. Exp Hematol. 2010; 38: 529. FURTHER READING