Stem Cell Theory of Carcinogenesis -Classical and Most Recent Evidence

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1 Stem Cell Theory of Carcinogenesis -Classical and Most Recent Evidence Chia-Cheng Chang, Ph.D. Dept. Pediatrics and Human Development Michigan State University

2 The Origin of Undifferentiated State of Tumor Cells The relatively undifferentiated state of certain tumor cells is reminiscent of the state of embryonic cells prior to their specialization during development. Gene and the Biology of Cancer Harold Varmus and Robert A. Weinberg

3 The Origin of Undifferentiated State of Tumor Cells 1.Dedifferentiation 2.Blocked differentiation of stem cells

4 Cancer is : a disease of cell differentiation (Markert, 1968). oncogeny as blocked or partially blocked ontogeny (Potter, 1978). a disease of the pluripotent stem cell (Sawyers et al., 1991).

5 Chronic Myelogenous Leukemia (CML) t(9:22) Philadelphia chromosome hybrid mrna and protein with tyrosine kinase activity (bcr-abl, p210)

6 CML is a disease of the pluripotent stem cell The Philadelphia chromosome is found in all hematopoietic lineages in patients with this malignancy, but not in skin fibroblasts or bone marrow stromal cells. Sawyers et al. Cell 64: , 1991

7 Acute Myeloid Leukaemia (AML) The most frequent chromosomal abnormalities in AML involve the 8; 21 translocation, which results in AML1-ETO chimaeric transcripts in leukaemia cells. In patients in remission, the AML1-ETO transcripts were found in a fraction of normal HSCs in the marrow, indicating that the translocation occurred originally in normal HSC and that additional mutations subsequently lead to leukaemia. (CD34 + Cd38 - Thy-1 + CD34 + Cd38 - Thy-1 - ) Miyamoto, T et al, Proc. Natl. Acad. Sci. USA 97: , 2000.

8 B-Cell Non-Hodgkin s Lymphoma t (14:18) translocation in all hematopoietic cell lineage S. Yarkoni et al. (J. Nat. Cancer Inst., 88: 973-9, 1996)

9 Cancer Instances in Large and Small Intestines Small Intestines Large Intestines 350 new cases/year 28,600 new cases/year

10 The Role of Bcl-2 in Maintaining Stem Cell Integrity The anti-apoptotic gene bcl-2 is expressed at the base of murine and human colonic crypts, whereas expression is not seen in the small intestine, supporting the view that bcl-2 increases the apoptotic threshold of colonic stem cells. Merritt et al., J. Cell Sci. 108: , 1995

11 Location of apoptotic cells following cytotoxic exposure Small intestine---at stem cell position High frequency (altruistic suicide) Large intestine---not limited to stem cell position Low frequency

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13 Pregnancy and Reduced Risk of Breast Cancer 1. Decreased stem cell multiplication (John Cairns,1975) 2. Induced differentiation of mammary gland (L.H. Russo et al., 1990)

14 Three Lobule Types of Breast Tissue Lobule 1 Lobule 2 Lobule 3

15 Terminal End Buds of Mammary Gland as Major Target for Carcinogenesis Carcinogen acts on the TEB and that this structure is the one that evolves to intraductal proliferation, carcinoma in situ, and invasive carcinoma. I.H. Russo and J. Russo Environ. Health Perspectives 104: , 1996

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30 High susceptibility of a human breast epithelial cell type with stem cell characteristics to telomerase activation and immortalization W. Sun, K.S. Kang, I. Morita, J.E. Trosko and C.C. Chang Cancer Res. 59 : , 1999.

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34 Function of SV40 Large T-antigen 1.Inactivating p53 and prb. 2.Inducing a CCAAT box binding factor which transactivates cyclin A, cdc2, DNA polymerase α, thymidine kinase etc.

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36 Major Events in Carcinogenesis (1) Altered cell cycle regulation bypassing cellular senescence. (2) Telomerase activation immortalization (3) Activation of a growth-promoting pathway tumorigenic (4) Altered cell adhesion, mobility and protease/collagenase activity invasion and metastasis.

37 A Nucleolar mechanism controlling cell proliferation in stem cells and cancer cells. R.Y.L. Tsai and R. D.G. McKay Genes and Development 16: , 2002.

38 Nucleostemin A novel protein containing an N-terminal basic domain and two GTP-binding domain. Function : regulate cell proliferation, differentiation, apoptosis in a p53-dependent manner. Found in the nucleoli of CNS stem cells, embryonic stem cells and several cancer cell lines. When stem cells differentiate, nucleostemin expression decreases rapidly.

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43 Gap Junctional Intercellular Communication of HL1-1 Cell Line

44 GJIC in L1SV1 Cells

45 GJIC in Heptoma Cells

46 Current Opinion in Cell Biology 1998; 10:710

47 Vimentin and α-foetoprotein are collectively termed the oval cell phenotype

48 Expression of Vimentin in HL1-1 Cell Line

49 Expression of Vimentin in L1SV1 Cells

50 Expression of Alpha Foetoprotein in HL1-1 Cell Line

51 Expression of Alpha Foetoprotein in L1SV1 Cells

52 Anchorage Independent Growth of HL1-1 Cell Line AIG = 4.6% Colony forming efficiency on plastic = 11%

53 Similarity Between Putative Human Liver Stem Cells and Hepatocellular Carcinoma Deficient in gap junctional intercellular communicatioon Expression of Vimentin Expression alpha foetoprotein Ability of anchorage independent growth

54 Similarity of Stem Cells and Tumor Cells 1.Deficient in gap junctional intercellular communication. 2.Ability of anchorage independent growth. 3.Similar phenotypes of human breast epithelial stem cells and breast cancer cells CX26 -, α-6 integrin -, maspin -, estrogen receptor (ER + ).

55 Similarity of Stem Cells and Tumor Cells 4.Nucleostemin, a novel protein found in the nucleoli of CNS stem cells, embryonic stem cells and several cancer cell lines. When stem cells differentiate, nucleostemin expression decrease rapidly prior to cell-cycle exit both in vitro and in vivo. 5.Expression of alpha foetoprotein and vimetin in liver stem cells and liver tumor cells 6..Contact-insensitive growth (e.g. kidney epithelial stem cells)

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57 These results are consistent with Oncogeny as blocked or partially blocked ontogeny theory by Van R. Potter and The stem cell theory of carcinogenesis

58 Paradoxical effects of phenobarbital on mouse hepatocarcinogenesis G.H. Lee Toxicologic Pathology 28 : , 2000

59 Protocol One--Postweaning

60 Protocol Two--Postweaning

61 Protocol Three--Preweaning

62 Discussion

63 Discussion

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65 Why Stem Cells Are Key Target Cells for Carcinogenesis 1.Stem cells express many tumor cell phenotypes, fewer mutations or epigenetic alterations may be required for tumor progression. Human embryonic stem cells are immortal and tumorigenic (teratoma) 2.Stem cells have unlimited or extended lifespan, there is a much greater opportunity for mutations to accumulate. Human breast epithelial stem cells are more susceptible to telomerase activation and immortalization. Stem cells of large intestine have higher threshold for apoptosis ( bcl-2 expression).

66 Two Types of Target Cells for Carcinogenesis Liver : Basophilic tumors inhibition by phenobarbital Eosinophilic tumors promotion by phenobarbital Breast : Hormone dependent (ER + ) Vimentin + Cytokeratin 19 - Hormone independent (ER - ) Vimentin - (50%) Cytokeratin 19 + (50%) Prostate : Androgen dependent Androgen independent Skin : Basal cell carcinoma Squamous cell carcinoma

67 Acknowledgement of Co-Workers Chien-Yuan Kao Ikue Morita Ching-Yi Hsieh Maki Saitoh Jin Lian Tsai Koichiro Nomata Angela Cruz Wei Sun James E. Trosko