Stem Cell Theory of Carcinogenesis -Classical and Most Recent Evidence Stem Cell Theory of Carcinogenesis -Classical and Most Recent Evidence Chia-Cheng Chang, Ph.D. Dept. Pediatrics and Human Development Michigan State University
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Stem Cell Theory of Carcinogenesis-Classical and
Most Recent Evidence
Stem Cell Theory of Carcinogenesis-Classical and
Most Recent Evidence
Chia-Cheng Chang, Ph.D.
Dept. Pediatrics and Human Development Michigan State University
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The Origin of Undifferentiated State of Tumor Cells
The re la t ively undif ferent ia ted s ta te of certain tumor cells is reminiscent of the stateof embryonic cells prior to theirspecialization during development.
Gene and the Biology of CancerHarold Varmus and Robert A. Weinberg
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1.Dedifferentiation2.Blocked differentiation of stem cells
The Origin of Undifferentiated State of Tumor Cells
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◇ Cancer is :
◇ a disease of cell differentiation(Markert, 1968).
◇ oncogeny as blocked or partially blockedontogeny (Potter, 1978).
◇ a disease of the pluripotent stem cell(Sawyers et al., 1991).
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Chronic Myelogenous Leukemia (CML)
◇ t(9:22) Philadelphia chromosome
◇ hybrid mRNA and protein with tyrosinekinase activity (bcr-abl, p210)
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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 64:337-350, 1991
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Acute Myeloid Leukaemia (AML)•The most frequent chromosomal abnormalities in
AML involve the 8; 21 translocation, which results in AML1-ETO chimaeric transcripts in leukaemiacells.
•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: 7521-7526, 2000.
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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)
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Cancer Instances in Large and Small Intestines
◇ Small Intestines 350 new cases/year◇ Large Intestines 28,600 new cases/year
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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. 108:2261-2271, 1995
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Location of apoptotic cells following cytotoxic exposure
Small intestine---At stem cell positionHigh frequency (altruistic suicide)
Large intestine---Not limited to stem cell positionLow frequency
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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)
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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. RussoEnviron. Health Perspectives 104:938-967, 1996
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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 : 6118-6123, 1999.
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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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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.
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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: 2991-3003, 2002.
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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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Anchorage Independent Growth of HL1-1 Cell Line
AIG = 4.6% Colony forming efficiency on plastic = 11%
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Similarity Between Putative Human Liver Stem Cells and
Hepatocellular Carcinoma
Deficient in gap junctional intercellular communicatioonExpression of VimentinExpression alpha foetoproteinAbility of anchorage independent growth
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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+).
Similarity of Stem Cells and Tumor Cells
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Similarity of Stem Cells and Tumor Cells
4.Nucleostemin, a novel protein found in thenucleoli of CNS stem cells, embryonic stemcells and several cancer cell lines.When stem cells differentiate, nucleosteminexpression 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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These results are consistent with “Oncogeny as blocked or partially
blocked ontogeny” theory -------by Van R. Potter
and The stem cell theory of carcinogenesis
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Paradoxical effects of phenobarbital on mouse
hepatocarcinogenesis
G.H. LeeToxicologic Pathology 28 :
215-225, 2000
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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 andimmortalization.
•Stem cells of large intestine have higher thresholdfor apoptosis ( bcl-2 expression).
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Two Types of Target Cells for Carcinogenesis
Liver : Basophilic tumors – inhibition by phenobarbitalEosinophilic tumors – promotion byphenobarbital
Breast : Hormone dependent (ER+) – Vimentin+
Cytokeratin 19-
Hormone independent (ER-) – Vimentin-(50%)Cytokeratin 19+(50%)
Prostate : Androgen dependentAndrogen independent
Skin : Basal cell carcinomaSquamous cell carcinoma