Stem Cell Theory of Carcinogenesis

8/7/2019 Stem Cell Theory of Carcinogenesis

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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 DevelopmentMichigan State University


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The Origin of Undifferentiated

State of Tumor Cells

The rela t ively undifferent ia ted s ta te ofcertain 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


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1.Dedifferentiation

2.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 blocked

ontogeny (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 tyrosine

kinase 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 transcriptswere found in a fraction of normal HSCs in themarrow, indicating that the translocation occurredoriginally in normal HSC and that additionalmutations subsequently lead to leukaemia.

(CD34Cd38Thy-1 CD34Cd38Thy-1)

Miyamoto, T et al, Proc . Natl. Acad. Sci. USA 97:7521-7526, 2000.


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B-Cell Non-Hodgkins

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 andSmall 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 position

High frequency (altruistic suicide)

Large intestine---Not limited to stem cell position

Low 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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Lobule 1 Lobule 2 Lobule 3

Three Lobule Types of Breast Tissue


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Terminal End Buds of Mammary Gland

as Major Target for Carcinogenesis

Carcinogen acts on the TEB and thatthis structure is the one that evolves to

intraductal proliferation, carcinoma in

situ, and invasive carcinoma.

I.H. Russo and J. Russo

Environ. Health Perspectives 104:938-967, 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, thymidine kinase etc.


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Major Events in

Carcinogenesis

(1) Altered cell cycle regulation bypassingcellular 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-dependentmanner.

Found in the nucleoli of CNS stem cells,embryonic stem cells and several cancer celllines. When stem cells differentiate,

nucleostemin expression decreases rapidly.


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Gap Junctional IntercellularCommunication of HL1-1 Cell Line


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GJIC in L1SV1 Cells


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GJIC in Heptoma Cells


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Current Opinion in Cell Biology 1998; 10:710


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Vimentin and -foetoproteinare collectively termed the

oval cell phenotype


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Expression of Vimentin in HL1-1 Cell Line


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Expression of Vimentin in L1SV1 Cells


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Expression of Alpha Foetoproteinin HL1-1 Cell Line


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Expression of Alpha Foetoproteinin L1SV1 Cells


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Anchorage Independent Growthof HL1-1 Cell Line

AIG = 4.6%

Colony forming efficiency on plastic = 11%


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Similarity Between PutativeHuman Liver Stem Cells and

Hepatocellular Carcinoma

Deficient in gap junctional intercellular

communicatioon

Expression of Vimentin

Expression alpha foetoprotein

Ability 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,-6 integrin, maspin, estrogen

receptor (ER).

Similarity of Stem Cells and

Tumor Cells


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Similarity of Stem Cells and

Tumor Cells4.Nucleostemin, a novel protein found in the

nucleoli of CNS stem cells, embryonic stem

cells and several cancer cell lines.

When stem cells differentiate, nucleosteminexpression decrease rapidly prior to cell-cycle exitboth in vitro and in vivo.

5.Expression of alpha foetoprotein and vimetin inliver stem cells and liver tumor cells

6..Contact-insensitive growth (e.g. kidneyepithelial 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. Lee

Toxicologic Pathology 28 :

215-225, 2000


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Protocol One--Postweaning


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Protocol Two--Postweaning


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Protocol Three--Preweaning


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Discussion


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Discussion


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Two Types of Target Cells for

CarcinogenesisLiver : 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 independentSkin : Basal cell carcinoma

Squamous cell carcinoma


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Acknowledgement of

Co-Workers

Chien-Yuan Kao Koichiro Nomata

Ikue Morita Angela Cruz

Ching-Yi Hsieh Wei Sun

Maki Saitoh James E. Trosko

Jin Lian Tsai

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Stem Cell Theory of Carcinogenesis

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