The problem

Cancer is a leading cause of death worldwide and accounted for 7.6 million deaths (around 13% of all deaths) in 2008.

The main types of cancer are: lung (1.37 million deaths) stomach (736 000 deaths) liver (695 000 deaths) colorectal (608 000 deaths) breast (458 000 deaths) cervical cancer (275 000 deaths) About 70% of all cancer deaths occurred in low- and middleincome countries. Deaths from cancer worldwide are projected to continue to rise to over 13.1 million in 2030.

University of Science

Cancer Stem Cell

Nguyn Trng Sinh

Definition of cancer stem cell Minority of tumor cells: unlimited ability to proliferate and seed new tumor Bulk of tumor cells: little if any ability to proliferate and seed new tumor

Evidence of heterogenity in tumor

Definition of cancer stem cell

Single cell New tumor

Single cell New tumor

Phenotype of second tumor is the same as primary tumor

Definition of cancer stem cell

Definition of all cells in a tumor are equal is an illusion

Definition of cancer stem cell

The reality looks more like this

Definition of cancer stem cell This seems to be how tumors organized

The tumor initiating cell

Non tumor-initiaiting cells

Definition of cancer stem cell Arrangement of tumor

Tumor-initiating cells

Differentiated cells

The mother cell creates two different cell daughter

Definition of cancer stem cell Tumor initiating cell: mother cell make two different daughter

Tumor-initiating cell

Non tumor-initiating cells

The behavior of stem cell

Same organization of normal stem cell

Normal stem cell

Normal stem cell

Normal stem cell

The ground rule: stem cells can do two things

1. They can make copy of themself 2. They can diferentiate

Normal stem cell The arrangment of normal tissue

Self-renewal stem cell

Transitamplifying cells

Post-mitotic differentiated stem cell

Normal stem cell In the context of cancer tissue CSC : cancer stem cell This cell is qualified to seed a new tumor

These cell is not qualified to seed a new tumor

Post-mitotic differentiated stem cell

Definition of cancer stem cell

What are Cancer Stem Cells?

Cells that have properties of normal stem cells: 1) The abilities to self-renew.

2) The ability to differentiate into multiple cell types. 3) These CSCs cells persist in tumors as a distinct population that likely causes relapses and metastasis

The origin of cancer stem cell

Origin of cancer stem cell

SC: stem cell; TA: transit amplification; Diff: differentiation

Marcus M. Monroe et al

CSC

Origin of cancer stem cell Hypothesis 1

Only stem cells have the ability to self renew and neoplasia is essentially dysregulated self renewal Stem cells are long-lived cells which can acquire the necessary number of sequential mutation Surface marker phenotype can be similar to normal stem cells (eg. AML)

Green: CSC, Red: Transit amplifying population, Pink: differentiated cell population

Origin of cancer stem cell Hypothesis 2

Origin of cancer stem cell Hypothesis 3

Origin of cancer stem cell

Metastasis and Cancer Stem Cell

Metastasis and Cancer Stem Cell

EMT ( epithelial mesenchymal transition)

Epithelial Cells Junctions Complex, stable Tissue Uniform array, continuous layer Polarity Apical vs. Basal Motility Lack of mobility by individual cells

Mesenchymal Cells: Looser or none No uniform tissue structure Leading vs. Trailing edge Motile, potentially invasive

Metastasis and Cancer Stem Cell

EMT ( epithelial mesenchymal transition)

H. Peinado et al., Nature Rev. Cancer 7:415-428, 2007

1. Complete EMT
A process wherein static epithelial cells: 1. Loose cell-cell contacts 2. Acquire mesenchymal morphology 3. Manifest a migratory phenotype 4. Increases in extracellular proteolytic activity 5. Proliferative

Metastasis and Cancer Stem Cell

Cancer cell can borrow EMT process to increase tumorgenicity

Metastasis and Cancer Stem Cell

TGF1, Snail, Twist, TGF and mutation in oncogenic Ras cooperate to promote the CD24+ to CD24 cellsand tumorigenic characters.

Cancer cells are invasive

normal tissue

invasive tumor

Figure 20-17 Molecular Biology of the Cell ( Garland Science 2008)

Are we targeting the right cell ?

Frequent Cancer Recurrence May Be due to the Preferential Killing of Differentiated Cells While Leaving CSCs behind

Mechanisms of CSC Resistance to Chemotherapy and Radiation

Mechanisms of CSC Resistance

Resistance to Drug Penetration into CSCs

Mechanisms of CSC Resistance

Resistance to Drug Penetration into CSCs

Mechanisms of CSC Resistance

Alter the cell cycle checkpoint

Mechanisms of CSC Resistance

Resistance to DNA Damage within CSCs

Ensure entegrity of the genome

Block of chromosome segregation until chromosomes are correctly aligned on the mitotic spindle

Block of mitosis entry until DNA replication is complete and DNA damage is repair

Mechanisms of CSC Resistance

Resistance to DNA Damage within CSCs

Chk: checkpoint kinases

Mechanisms of CSC Resistance

Apoptosis inhibit

Mechanisms of CSC Resistance

Resistance to Apoptosis within CSCs

Mechanisms of CSC Resistance

Resistance to Apoptosis within CSCs

Mechanisms of CSC Resistance

Resistance to Apoptosis within CSCs

In order to more effectively target CSCs, molecular proliferation and survival mechanisms of CSCs must be better understood

Cancer stem cell pathway

Cancer stem cell pathway

Pathway 1

Cancer stem cell pathway

Pathway 2

Cancer stem cell pathway

Pathway 3

Wnt pathway

In the normal Wnt pathway the levels of the transcription factor -catenin mediates self-renewal.
In cancer the control process is circumvented and catenin levels constantly thrive, hence causing continual proliferation and self- renewal.

Promoting genomic instabil-ity and DNA damage tolerance

Targeting cancer stem cell

Targeting Wnt pathway

Wnt/-catenin pathway may promote genomic instability after irradiation, allowing tumor cells to both survive after irradiation and develop additional adaptive mutations. Anticancer drugs in development should target the Wnt signaling pathway

Targeting Hedgehoh pathway

The hedgehog signaling pathway is a potential modulator of cancer stem cell carcinogenesis with significant therapeutic implications. GDC-0449, XL-139, and IPI926 are drugs under development targeting this signaling pathway.

Targeting Notch pathway

The Notch/-secretase/Jagged signaling pathway is an important regulator of differentiation and helps specify cell fate. Notch signaling pathways have been shown to be activated in both breast CSCs and in endothelial cells in response to radiation. MK-0752 and R4733 are drugs under development targeting -secretase in this signaling pathway

Targeting resistance mechanism

Targeting the ABC transporters

Targeting the key elements of apoptosis signalling directly influences therapy-induced tumour-cell death

Targeting the different surface markers

Identify cancer stem cell

Identify cancer stem cell

Good Lifestyle Choices Can Limit Cancer Risk

Avoid tobacco completely

Maintain a desirable weight; eat a low-fat diet with plenty of fruits and vegetables Drink alcohol in moderation Make sure your living and work environment is safe from carcinogens Protect your skin from the suns UV rays

Thank you for your attention