This document is an outline for a workshop presentation on colon carcinoma. It discusses the multistage theory of carcinogenesis, with mutations in genes like APC, KRAS, and TP53 driving progression. It describes the structure of the colon crypt and role of stem cells. Key pathways in colon cell growth and differentiation like Wnt and BMP signaling are disrupted in cancer. Tumor heterogeneity is high, with hundreds of mutations across dozens of pathways enabling metastasis.

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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5. Nature vs. Nurture
• Genetic: ~20-25% cases.
• Mutations in APC.
• Familial adenomatous polyposis (FAP): 1% of colon
carcinoma, Hereditary non-polyposis CRC (HNPCC)
• Environmental: diet, IBD…
• Renewal Rate
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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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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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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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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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16. Go the Whole
(Hedge)Hog
© SEGA/Sonic 2008-2012
Metastasis?
Medema and Vermeulen (Nature): 2011
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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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