Colon carcinoma: A Life Story
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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.
Colon carcinoma: A Life Story
- 1. Colon Carcinoma: A Life Story Khalil Abou-El-Ardat Workshop Brain Tumors: Mechanisms 11/27/2012 1 and Mathematical Models
- 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 Workshop Brain Tumors: Mechanisms 11/27/2012 2 and Mathematical Models
- 3. Long is the Road¡ Workshop Brain Tumors: Mechanisms 11/27/2012 3 and Mathematical Models
- 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 Workshop Brain Tumors: Mechanisms 11/27/2012 4 and Mathematical Models
- 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 Workshop Brain Tumors: Mechanisms 11/27/2012 5 and Mathematical Models
- 6. Multistep Theory of Carcinogenesis ? Four to five hits required. ? Progression time: 2-10 years ? APC as initiating. Fearon and Vogelstein (Cell) 1990 Workshop Brain Tumors: Mechanisms 11/27/2012 6 and Mathematical Models
- 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. Workshop Brain Tumors: Mechanisms 11/27/2012 7 and Mathematical Models
- 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 Workshop Brain Tumors: Mechanisms 11/27/2012 8 and Mathematical Models
- 9. There Goes the Neighborhood Humphries and Wright (Nat. Rev. Cancer) 2008 Workshop Brain Tumors: Mechanisms 11/27/2012 9 and Mathematical Models
- 10. Humphries and Wright (Nat. Rev. Cancer) 2008 Workshop Brain Tumors: Mechanisms 11/27/2012 10 and Mathematical Models
- 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¡¯. Workshop Brain Tumors: Mechanisms 11/27/2012 11 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 Workshop Brain Tumors: Mechanisms 11/27/2012 12 and Mathematical Models
- 13. Gone with the Wnt ? Wnt signaling in stem cells. ? APC mutation: appearance of adenomas. Medema and Vermeulen (Nature): 2011 Workshop Brain Tumors: Mechanisms 11/27/2012 13 and Mathematical Models
- 14. A NOTCH Further ? Goblet cell maintenance Medema and Vermeulen (Nature): 2011 Workshop Brain Tumors: Mechanisms 11/27/2012 14 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 Workshop Brain Tumors: Mechanisms 11/27/2012 15 and Mathematical Models
- 16. Go the Whole (Hedge)Hog ? SEGA/Sonic 2008-2012 Metastasis? Medema and Vermeulen (Nature): 2011 Workshop Brain Tumors: Mechanisms 11/27/2012 16 and Mathematical Models
- 17. Greaves and Maley (Nature) 2012 Workshop Brain Tumors: Mechanisms 11/27/2012 17 and Mathematical Models
- 18. Many Roads, One Goal ? Tumor heterogeneity. ? Hundreds of mutations! ? Dozen of Pathways ? Mimic original heterogeneity of tissue Workshop Brain Tumors: Mechanisms 11/27/2012 18 and Mathematical Models
- 19. The Rise and Fall ? Size restriction due to limited nutrient and oxygen supply. ? Unless¡ Workshop Brain Tumors: Mechanisms 11/27/2012 19 and Mathematical Models
- 20. Stem Cells Revisited ? Stem cancer cell vs. cancer stem cell. ? Markers: CD133, CD166, CD44, CD24 ? Case of Avastin Workshop Brain Tumors: Mechanisms 11/27/2012 20 and Mathematical Models
- 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 Workshop Brain Tumors: Mechanisms 11/27/2012 21 and Mathematical Models