colon carcinoma: a life story
TRANSCRIPT
04/13/2023 1Workshop Brain Tumors: Mechanisms and Mathematical Models
Colon Carcinoma: A Life Story
Khalil Abou-El-Ardat
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Outline1. General Introduction: Cancer2. Introduction: Colon Carcinoma
1. Multistep Theory of Carcinogenesis2. The colon crypt3. Stem Cancer Cells4. Disrupted Pathways
3. Out of one many4. Conclusions5. Further Reading
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Long is the Road…
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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 KRASo TP53
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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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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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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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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 cellso Goblet cellso Colonocyteso Paneth cells
• Stem cells in ‘bottom’ of crypt• Clonal population
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There Goes the Neighborhood
Humphries and Wright (Nat. Rev. Cancer) 2008
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Humphries and Wright (Nat. Rev. Cancer) 2008
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Stem Cells Gone Wild• Stem cells already have cancerous properties:
o Proliferative potentialo Different stages of differentiationo 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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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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Gone with the Wnt• Wnt signaling in stem cells.• APC mutation: appearance of adenomas.
Medema and Vermeulen (Nature): 2011
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A NOTCH Further• Goblet cell maintenance
Medema and Vermeulen (Nature): 2011
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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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Go the Whole (Hedge)Hog
© SEGA/Sonic 2008-2012
Medema and Vermeulen (Nature): 2011
Metastasis?
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Greaves and Maley (Nature) 2012
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Many Roads, One Goal• Tumor heterogeneity.• Hundreds of mutations!• Dozen of Pathways• Mimic original heterogeneity of tissue
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The Rise and Fall• Size restriction due to limited nutrient and oxygen
supply.• Unless…
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Stem Cells Revisited• Stem cancer cell vs. cancer stem cell.• Markers: CD133, CD166, CD44, CD24• Case of Avastin
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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