apasl 1000 1030 n.theise

Stem Cells andHepatocarcinogenesis

Neil Theise, MDDepts. of Pathology and Medicine

Beth Israel Medical Center – Albert Einstein College of MedicineNew York City

www.neiltheise.com

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.

Neil Theise, MDDepts. of Pathology and Medicine

Beth Israel Medical Center – Albert Einstein College of MedicineNew York City

www.neiltheise.com

Cancer and Stem Cells

and Stem Cell-derived Cancer and Cancer-derived Stem Cells

and… and… and… and…

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1. Are there hepatobiliary stem cells?

2. Is there evidence that hepatobiliary cancers arise fromstem cells?

3. How can hepatobiliary carcinomas arise from stem cells?

4. Do all hepatobiliary tumors, then, start from stem cells?

5. Do all hepatobiliary tumors have stem cells?

1. Are there hepatobiliary stem cells?

Yes, in the: canals of Heringbile ductsbone marrow

Perhaps also:peribiliary “null cell” monocytesperibiliary hepatocytes

stem cell

stem cell

“assymetric division”

stem cell

stem cell

stem cell

transit amplifying cells

stem cell

transit amplifying cells

ductular reactions (humans)oval cells (rodents)

stem cell

transit amplifying cells

drug resistanthypoxia resistant

radio-resistant

stem cell

transit amplifying cells

drug resistanthypoxia resistant

radio-resistanti.e. resistant to

mutations

stem cell

transit amplifying cells

drug resistanthypoxia resistant

radio-resistanttelomerase

stem cell

transit amplifying cells

Keratin 19CD117 (c-kit)CD90 (thy-1)

EpCAMCD 133 (prominin-1)

ABC-G2

Keratin 19CD117 (c-kit)CD90 (thy-1)

EpCAMCD 133 (prominin-1)

ABC-G2

stem cell

transit amplifying cells

“Side Population”

1. Are there hepatobiliary stem cells?

2. Is there evidence that hepatobiliary cancers arise fromstem cells?

Combined hepatocellular/cholangiocarcinomas

Is there evidence that hepatobiliary cancers arise from stem cells?

Combined hepatocellular/cholangiocarcinomas

Combined HCC/ChC arising in a dysplastic nodule

Harada K, Terada T, Nakanuma Y, Furukawa Y, Kurumaya H.

A case of small combined hepatocellular and cholangiocellular carcinoma arising in a nodule of atypical adenomatous hyperplasia of the liver.

Am. J. Gastroenterol. 1993; 88; 1968–1969.

Is there evidence that hepatobiliary cancers arise from stem cells?

Combined hepatocellular/cholangiocarcinomas

Combined HCC/ChC arising in a dysplastic nodule

“Stem cell tumors” of the liver

Is there evidence that hepatobiliary cancers arise from stem cells?

1. Combined HCC-ChC2. Combined HCC-ChC with stem cell features

A. typical subtypeB. intermediate cell subtype C. cholangiocellular subtype

Chapter 10-4, N. D. Theise, O. Nakashima, Y. N. Park, Y. Nakanuma

1. Are there hepatobiliary stem cells?

2. Is there evidence that hepatobiliary cancers arise fromstem cells?

3. How can hepatobiliary carcinomas arise from stem cells?

Stem Cell Niche

Stem Cell

Stromal Cell

Immortal Strand Hypothesis

Stem cell retention of original DNA template

after replication and division

Immortal Strand Hypothesis

Stem cell retention of original DNA template

after replication and division

SO: STEM CELLS SHOULDREMAIN FREE OF MUTATIONS

Disordered stem cell retention of original DNA template

in chronic disease

e.g. inflammatory bowel diseaseprimary sclerosing cholangitismammary fibrocystic disease

chronic viral hepatitisH. pylori gastritis

Disordered stem cell retention of original DNA template

in chronic disease

Disordered stem cell retention of original DNA template

in chronic disease

Disordered stem cell retention of original DNA template

in chronic disease

Disordered stem cell retention of original DNA template

in chronic disease

MUTATION!!

1. Are there hepatobiliary stem cells?

2. Is there evidence that hepatobiliary cancers arise fromstem cells?

3. How can hepatobiliary carcinomas arise from stem cells?

4. Do all hepatobiliary tumors, then, start from stem cells?

Carcinogenesis

1. Are there hepatobiliary stem cells?

2. Is there evidence that hepatobiliary cancers arise fromstem cells?

3. How can hepatobiliary carcinomas arise from stem cells?

4. Do all hepatobiliary tumors, then, start from stem cells? No. Mutations can probably happen in all cell types:

Stem cellsProgenitor cells (ductular reactions!)Fully differentiated cells

1. Are there hepatobiliary stem cells?

2. Is there evidence that hepatobiliary cancers arise fromstem cells?

3. How can hepatobiliary carcinomas arise from stem cells?

4. Do all hepatobiliary tumors, then, start from stem cells?

5. Do all hepatobiliary tumors have stem cells?

CancerStem CellEpCAMCD133

ABC-G2CD90

tumor

CancerStem CellEpCAMCD133

ABC-G2CD90

tumor

Often tumor initiating…

1. Are there hepatobiliary stem cells?

2. Is there evidence that hepatobiliary cancers arise fromstem cells?

3. How can hepatobiliary carcinomas arise from stem cells?

4. Do all hepatobiliary tumors, then, start from stem cells?

5. Do all hepatobiliary tumors have stem cells?

1. Are there hepatobiliary stem cells?

2. Is there evidence that hepatobiliary cancers arise fromstem cells?

3. How can hepatobiliary carcinomas arise from stem cells?

4. Do all hepatobiliary tumors, then, start from stem cells?

5. Do all hepatobiliary tumors have stem cells?

Many do, though not necessarily all…

1. Are there hepatobiliary stem cells?

2. Is there evidence that hepatobiliary cancers arise fromstem cells?

3. How can hepatobiliary carcinomas arise from stem cells?

4. Do all hepatobiliary tumors, then, start from stem cells?

5. Do all hepatobiliary tumors have stem cells?

So what…?

cancerstem cell

drug resistanthypoxia resistant

radio-resistant

tumor

tumor

Anti-tumor therapy

cancerstem cell

drug resistanthypoxia resistant

radio-resistant

tumor

Anti-tumor therapy

cancerstem cell

drug resistanthypoxia resistant

radio-resistant

tumor

Anti-tumor therapy

cancerstem cell

drug resistanthypoxia resistant

radio-resistant

tumor

Anti-tumor therapy

cancerstem cell

drug resistanthypoxia resistant

radio-resistant

Anti-tumor therapy

cancerstem cell

drug resistanthypoxia resistant

radio-resistant

cancerstem cell

drug resistanthypoxia resistant

radio-resistant

cancerstem cell

cancerstem cell

cancerstem cell

cancerstem cell

cancerstem cell

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

In summary: Cancers can arise from stem cells

In summary: Cancers can arise from stem cells

orCancers can arise from differentiated cells

In summary: Cancers can arise from stem cells

orCancers can arise from differentiated cells

“Cancer stem cells” may refer to the stem cells from which cancers start,BUT generally refer to:

In summary: Cancers can arise from stem cells

orCancers 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:

In summary: Cancers can arise from stem cells

orCancers 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 cyclingself-renewalmultidrug resistancehypoxia resistantradio-insensitive

In summary: Cancers can arise from stem cells

orCancers 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 cyclingself-renewalmultidrug resistancehypoxia resistantradio-insensitive

and therefore are resistant to therapy and responsible fortumor recurrence…

cells within a tumor that have stem cell like properties:i.e. slow cycling

self-renewalmultidrug resistancehypoxia resistantradio-insensitive

and therefore are resistant to therapy and responsible fortumor recurrence…

Antigenic Markers: CD133c-kitEpCAMKeratin 19

Functional Markers: Side populationLabel retaining cells

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