Download Colorectal cancer

Colorectal cancer
• Incidence:
– 2nd most common cancer
– 60-80 years of age
• DK 2002 - 3516 new cases
– Colon cancer: 67%
– Recal cancer: 33%
• Stage at time of diagnosis:
– 45% localized disease
– 55 advanced disease with
metastases
• Treatment:
– Surgical and adjuvant therapy
Hanahan and Weinberg (2000)
Colorectal neoplasia
Colorectal neoplasia
Adenomas:
Adenomas:
• Benign tumors
• Malignant risk depending on size,
architecture, dysplasia
Tubular adenomas ~90%
Villous adenomas 5-10%
Tubulovillous adenomas ~1%
• Benign tumors
• Malignant risk depending on size,
architecture, dysplasia
Tubular adenomas ~90%
Villous adenomas 5-10%
Tubulovillous adenomas ~1%
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Colorectal cancer
Colorectal carcinoma
Etiology:
Life style - dietary factors
1-3% occur in patients with familial
syndromes:
FAP: mutations in APC (adenomatous polyposis coli)
HNPCC: mutations in mismatch repair genes
Ulceration
Colorectal carcinogenesis
2 pathways.
APC/β-catenin pathway
APC/β-catenin pathway
Mikrosatellite Instability pathway
Voutsadakis, J Cell. Mol. Med. 2007
β-catenin pathway
Voutsadakis, J Cell. Mol. Med. 2007
Cox-2 – a β-catenin target
Voutsadakis, J Cell. Mol. Med. 2007
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Prostaglandin production and action
K-ras pathway
Voutsadakis, J Cell. Mol. Med. 2007
TGFβ pathway in colorectal cancer
Loss of smad4 function in
>30% of sporadic human
colon cancer
TGFβRII mutations in 90%
of MSI colon cancers
Massague et al. FEBS letter 2006
p53 pathway
Voutsadakis, J Cell. Mol. Med. 2007
TGFβ pathway
Voutsadakis, J Cell. Mol. Med. 2007
APC/β-catenin pathway
Voutsadakis, J Cell. Mol. Med. 2007
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Clonal evolution
Colon cancer stem cells
Key properties of stem cells:
• Capacity for self- renewal
• Asymmetric cells division
• Long-lived
• Down-stream differentiation
• Active telomerase expression
• Anti-apoptotic pathways
• Anoikis resistance
• Ability to migrate
Metastasis
Invasion
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Epithelial-Mesenchymal Transition
Stem cell – and EMT markers in colorectal cancer progression
Invasion
Matrix metalloproteinases
Noel et al., Cell & Developmental Biology 2007
Metalloproteinases
Subclan MA(M)
Metzincin
Family M12
Family M10
Serralysin
MMP
SVMP
Adamlysin
ADAM
Astacin
ADAMTS
Adopted from
http://merops.sanger.ac.uk
Seals & Courtneidge, Genes & Dev. 2003
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Invasion
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