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BMW UvA molecular oncology summary
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A summary of molecular oncology.
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Stem cells in the intestine – Jan Paul MedemaWhat is a stem cell?
- A non-specialized cell
Where can you find stem cells?
- In virtually all organs
Why do we have stem cells?
- Regeneration; to provide the body new cells
Stem cells
- Non-specialized
- Can divide asymmetrically (stem cell vs progenitor)
- Unlimited division capacity
- Generate a specific subset of differentiated cells
De definition
- Self-renewal cells
- Heterogeny
What is the total surface area of the intestinal wall?
- 250 m2
Marked DNA from the stem cells
- Doorgegeven aan daughter cells
- Lineage tracing
Morphogens
- Wnt
o Wnt regulates proliferation in the crypt
o Less crypts when downregulation of Wnt
o Stem cell marker has an CreER GFP instead of Igr5
o When the stem cell becomes a progenitor
ROSA26 stays but the CreER and GFP not
o When you want stem cells, you need to add Wnt3A
- Bmp
o Bone morphogenetic protein
o Blocks crypt proliferation and allows for differentiation
o Produced by mesenchyme
o Regulated by the level of noggin
o Facilitates differentiation
- Notch
o Transmembrane receptor in the crypt
o Ligands are expressed in crypt as well
o Notch blocks differentiation into secretory cells
o Goblet differentiation
, o More notch than more differentiation in cells close to them
o Bmi1 marks a different stem cell in the crypt
What happens if you would delete the stem cells from the crypt?
- New stem cells are generated
Stem cells who are not fully differentiated can go back to Paneth cells
- Dedifferentiation
Tumour describes the size of the tumour
- Tis means carcinoma in situ. The cancer is at its earliest stage and only in
the mucosa.
- T1 means the tumour is only in the inner layer of the bowel.
- T2 means the tumour has grown into the muscle layer of the bowel wall.
- T3 means the tumour has grown into the outer lining of the bowel wall but
has not grown through it
- T4 is split into 2 stages, T4a and T4b:
o T4a means the tumour has grown through the outer lining of the
bowel wall and has spread into the tissue layer (peritoneum)
covering the organs in the tummy (abdomen)
o T4b means the tumour has grown through the bowel wall into
nearby organs
Node (N) describes whether the cancer has spread to the lymph nodes.
- N0 means there are no lymph nodes containing cancer cells.
- N1 is split into 3 stages – N1a, N1b and N1c:
o N1a means there are cancer cells in 1 nearby lymph nod
o N1b means there are cancer cells in 2 or 3 nearby lymph nodes
o N1c means the nearby lymph nodes don’t contain cancer, but there
are cancer cells in the tissue near the tumour
- N2 is split into 2 stages – N2a and N2b:
o N2a means there are cancer cells in 4 to 6 nearby lymph nodes
o N2b means there are cancer cells in more than 7 nearby lymph
nodes
Metastasis (M) describes whether the cancer has spread to a different part of the
body.
- M0 means the cancer has not spread to other organs.
- M1 means the cancer has spread to other parts of the body such as the
lung or liver. It is split into 3 stages, M1a, M1b and M1c:
o M1a means the cancer has spread to 1 distant site or organ, for
example the liver, but it hasn’t spread to the tissue lining your
tummy (peritoneum)
o M1b means the cancer has spread to 2 or more distant sites or
organs, but it hasn’t spread to the tissue lining your peritoneum
o M1c means the cancer may have spread to distant organs and it has
spread to your peritoneum
hERT (telomerase) maintains telomere length
Only RAS transformed cells grow in vivo
,Adenomas
- Activation of KRAS
o Self-sufficiency in growth signals
- Loss of p53
o Evading
- Loss of APC
o Self-sufficiency in growth signals
- Loss of Smad4
Familial adenomatous polyposis
- Genetic disease characterized by multiple adenomas
Identification of APC
- APC gene = adenomatous polyposis coli
Juvenile polyposis
- Early onset of polyp formation
- Familial syndrome
- Caused in some patients by mutation in BMPR1
, Genomic defects in cancer – Nicolas Leveille
How do we detect chromosomal changes and mutations?
- G banding
- Comparative genomic hybridization (CGH)
- Whole exome sequencing (WES)
o Fragment genome, wash genome, capture DNA and DNA sequencing
Chromosomal changes
- Deletions
- Insertions
- Translocations
- Inversion
- Extrachromosomal DNA
- Isochromosome
Chromosome inversion
(paracentric)
Translocation
- Gene fusion
- TCF7L1 is a repressor of beta catenin
Duplication and deletion
- More material is more expression
- Two copies of EGFR and MET
Loss of Smad4
- No differentiation
- Loss of Smad4 changes the function of the BMP signalling (tumour
suppressive pro-metastatic)
Extrachromosomal DNA
- ecDNA can amplify and drive higher expression
of oncogenes in cancer cells
Mutations
Stepwise accumulation of mutations in CRC
- Inactivation mutation (tumour suppressor)
o APC mutation will lose the ability to
breakdown b-catenin, what results in
proliferation
- Activation mutation (oncogene)
o KRAS mutation in MAPK will promote
cell proliferation
o P53 mutation P53 will be inactivated and the cell will escape the
cell cycle and apoptosis
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