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Colon carcinoma: A Life Story
1. Colon
Carcinoma:
A Life Story
Khalil Abou-El-Ardat
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2. Outline
1. General Introduction: Cancer
2. Introduction: Colon Carcinoma
1. Multistep Theory of Carcinogenesis
2. The colon crypt
3. Stem Cancer Cells
4. Disrupted Pathways
3. Out of one many
4. Conclusions
5. Further Reading
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3. Long is the Road…
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4. A Gut Feeling
• Colon carcinoma: one of earliest models of
multistage progression.
• Due to genetic and environmental factors.
• 1.2 million new cases worldwide.
• Key players identified:
o APC: in ~80% of colon carcinomas; risk increase.
o KRAS
o TP53
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6. Multistep Theory of
Carcinogenesis
• Four to five hits required.
• Progression time: 2-10 years
• APC as initiating.
Fearon and Vogelstein (Cell) 1990
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7. Fearon and Vogelstein
1990
• Translocations and amplifications of oncogenes not
common.
• Mutations in TSG.
• Losses of 17p (p53), 5q, and 18q
• TSGs could exert effect even if heterozygous.
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8. The Crypt Keeper
• The intestinal crypt as functional unit:
o Layer of columnar epithelial cells.
o Connective tissue of the lamina propria
• Four types of cells:
o Endocrine cells
o Goblet cells
o Colonocytes
o Paneth cells
• Stem cells in ‘bottom’ of crypt
• Clonal population
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9. There Goes the
Neighborhood
Humphries and Wright (Nat. Rev. Cancer) 2008
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10. Humphries and Wright (Nat. Rev. Cancer) 2008
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11. Stem Cells Gone Wild
• Stem cells already have cancerous properties:
o Proliferative potential
o Different stages of differentiation
o In colon, the only cells that persist long enough
• Every crypt has several types of stem cells.
• Some stem cells can occupy a crypt (‘niche’
succession).
• Microenvironment plays a role in ‘stemness’.
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and Mathematical Models
12. Home Sweet Home
• TOFT: Tissue Organization Field Theory.
• The microenvironment of the cancer has gained
more prominence in recent years.
• Hallmark of Cancer.
Hanahan and Weinberg (Cell) 2011
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and Mathematical Models
13. Gone with the Wnt
• Wnt signaling in stem cells.
• APC mutation: appearance of adenomas.
Medema and Vermeulen (Nature): 2011
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14. A NOTCH Further
• Goblet cell maintenance
Medema and Vermeulen (Nature): 2011
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and Mathematical Models
15. A BMP in the Road
• Differentiation.
• Mutations in SMAD4 render cell unresponsive to
BMP.
• Inhibition leads to hyperproliferation and crypt
fission.
Medema and Vermeulen (Nature): 2011
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and Mathematical Models
17. Greaves and Maley (Nature) 2012
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18. Many Roads, One Goal
• Tumor heterogeneity.
• Hundreds of mutations!
• Dozen of Pathways
• Mimic original heterogeneity of tissue
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19. The Rise and Fall
• Size restriction due to limited nutrient and oxygen
supply.
• Unless…
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20. Stem Cells Revisited
• Stem cancer cell vs. cancer stem cell.
• Markers: CD133, CD166, CD44, CD24
• Case of Avastin
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21. Further Reading
• Greaves, M and Maley, CC (2012) Clonal Evolution in
Cancer
• Humphries, A and Wright, NA (2008) Colonic Crypt
Organization and Tumorigenesis
• Medema, JP and Vermeulen, L (2011)
Microenvironmental Regulation of Stem Cells in Intestinal
Homeostasis and Cancer
• Fearon, ER and Vogelstein, B (1990) A Genetic Model for
Colorectal Tumorigenesis
• De la Chapelle, A (2004) Genetic Predisposition to
Colorectal Cancer
• Bozic, I et al. (2010) Accumulation of Driver and
Passenger Mutations During Tumor Progression
• Hanahan, D and Weinberg, RA (2011) Hallmarks of
Cancer: The Next Generation
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