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
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
Differentiated cells
Definition of cancer stem cell Tumor initiating cell: mother cell make two different daughter
Tumor-initiating cell
Transitamplifying cells
Normal stem cell In the context of cancer tissue CSC : cancer stem cell This cell is qualified to seed a new tumor
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
Marcus M. Monroe et al
CSC
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
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
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
TGF1, Snail, Twist, TGF and mutation in oncogenic Ras cooperate to promote the CD24+ to CD24 cellsand tumorigenic characters.
invasive tumor
Frequent Cancer Recurrence May Be due to the Preferential Killing of Differentiated Cells While Leaving CSCs behind
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
Apoptosis inhibit
In order to more effectively target CSCs, molecular proliferation and survival mechanisms of CSCs must be better understood
Pathway 1
Pathway 2
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.
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
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.
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
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