Cancer Cell Biology

Question 1

What are the basic stages of colorectal cancer development?

Answer 1

-Normal cell
-Mutated cell
-Small polyp = small adenoma
-Large polyp = large adenoma
-Carcinoma (cancer)

Question 2

What is the colonic crypt cell hierarchy?

Answer 2

Stem cells at bottom -> then start to proliferate (migrate up) -> then start differentiating into specific cells (migrate up) -> then die (apoptosis)
-THEN GET RENEWAL OF EP

Question 3

Role of stem cells (e.g., in colonic crypts)?

Answer 3

-Are where all other cells come from - will proliferate & differentiate from these
-Can self-renew

Question 4

4 cell types in colonic crypts, & their roles?

Answer 4

-Enterocytes = absorb H2O & electrolytes
-Goblet = secrete mucus - lubrication, neut?
-Enteroendocrine = secrete hormones
-Tuft = like brush cells - act as antimicrobial defence

Question 5

How do stem cells (SC) divide systematically to give rise to specialised cell types?

Answer 5

-1st SC divides symmetrically = x2 SCs
-Each x2SCs divide asymmetrically = x1SC + x1progenitor/transit amplifying cell - PC (pluripotent)
-PC divides (symmetrical) = x2 PCs
-PC divide - fully differentiated = specific colonic cells x2

Question 6

How to identify SCs of colon?

Answer 6

Have specific marker protein - LGR5

Question 7

How do cells become differentiated?

Answer 7

-As divide have different proteins, TFs activated
-Diff TFs activated at diff times along maturation = diff genes expressed = become more & more specific

Question 8

What causes initial SC pop to begin proliferation & division?

Answer 8

-Proteins e.g., Wnt
= glycoprotein (sugar attached) - produced by stromal cells (bottom colonic crypts)

Question 9

How does Wnt cause SCs to start proliferating & dividing?

Answer 9

-Stromal cells = Wnt = acts locally - so on SCs
(both at bottom of crypts)
-Wnt binds Fz rec (transmemb) = activates Fz
–> recruits LRP5/6
-Activates Dsh (from cytoplasm)
-Dsh activates dissoc of destruction complex - as recruits Axin to rec complex
= this releases B-catenin
-B-catenin (TF) - binds/transcribes spec promotors of genes that activate cell prolif - e.g., c-myc

Question 10

How is cell prolif prevented in SCs when is no Wnt?

Answer 10

-Destruction complex - B-catenin phosphorylated by GSK3 (kinase)
-B-catenin = ubiutination & degraded by proteosome

Question 11

Why is it important that B-catenin is degraded?

Answer 11

-To stop cell prolif & differentiation - so cells can undergo apoptosis

Question 12

How does prolif only occur at bottom of colonic crypts & not at top where apoptosis needs to occur?

Answer 12

-Wnt acts locally from stromal cells at bottom
-Is a Wnt gradient
= highest at bottom & gradually gets lower as rise up crypt
–> as Wnt is used up
-No more signalling for prolif

Question 13

What happens in colorectal cancers to cause continued/deregulated cell prolif?

Answer 13

-APC (part dest complex) = deregulated gene
-So = truncated = nonsense mutation
-APC = deactivated
-APC not bind B-catenin = no dest complex
-B-catenin free to bind to promotors (can’t degrade)
-Wnt now = no role (will prolif anyway)

Question 14

What is a nonsense mutation?

Answer 14

Premature stop codon = gives rise to shorter protein

Question 15

How do polyps form from APC mutation?

Answer 15

-Continued cell prolif
-Cells not differentiated = unspecialised
-no apoptosis (as continue to prolif)
=polyp (lump of undifferentiated cells)

Question 16

What type of gene is APC?

Answer 16

TSG (when functions normally) - as keeps B-catenin in dest complex so not free

Question 17

How can cells prevent polyp development once APC mutation occurred?

Answer 17

-Genomic instability –> DNA damage
-DNA repair mechs identify
-Stop division of cells with APC mutation (apoptosis?)

Question 18

What type of gene is APC?

Answer 18

-TSG (when functions normally) - as keeps B-catenin in dest complex so not free
-So most commonly mutated in colorectal cancer

Question 19

How can small polyp lead to larger polyp to cancer?

Answer 19

-Accumulation of mutations (as faster prolif if APC mutated = genetic instability inc)
-If Ras (oncogene) mutated = inc cell prolif
(APC = inactive, Ras - activated)
-p53 TSG also lost
-Metastasis to liver, lungs, brain

Question 20

Role of p53 & how can further lead to colorectal cancer development once is deleted?

Answer 20

= TSG
-Stops CDK inhibitors - no cell cycle checkpoints = muts not recognised to stop & repair
-Stops apoptosis (won’t be induced)

Question 21

How would you know where cancer started - once metastasised?

Answer 21

Markers on cells

Question 22

How does metastasis of cancer occur?

Answer 22

-E-cadherin proteins loss = cell’s epithelia detach from each other
-Matrix metalloproteinases inc = more ext matrix of cells degraded (collagen & prots)
= cells move around to other tissues

Question 23

Role of ext matrix?

Answer 23

Holds cells together

Question 24

Benign tumour 8 features?

Answer 24

-Differentiated cells (normal)
-Monomorphic cells (look normal)
-Smaller nucleus
-Normochromic nuclei (normal chromosome no.)
-Grow slowly
-Low mitotic index
-Non-invasive & localised
-No metastasis

Question 25

Malignant tumour 9 features?

Answer 25

-Less differentiated cells (anaplastic - less normal)
-Pleomorphic cells (various cells)
-Large nuclei
-Hyperchromatic cells (higher chromosome no.)
-Grow fast
-High mitotic index
-All ep = dysplastic cells
-Invasive
-Metastasise

Question 26

Nomenclature suffix of benign tumours?

Answer 26

-oma

Question 27

Nomenclature suffix of malignant tumours?

Answer 27

-sarcoma

Question 28

Why do malignant tumour cells have larger nuclei?

Answer 28

Cells not divide correctly - so continue to enter subsequent cell cycle stages without halving chromosome number (so inc in no. chromosomes)

Question 29

What is a neoplasm?

Answer 29

Mass of abnormal cells (tumour)