Cancer cell biology Flashcards
What is carcinogenesis?
Formation of cancer
By chemical, physical, viral carcinogens (mutagens)
mutagens can cause by cancer by damaging DNA= mutation
How do carcinogens cause DNA damage?
- Add chemically modified bases- point mutation
2. Strand breaks by deletion/translocation of chromosome
Risk factors of lung cancer
- Smoking tobacco
- Second hand smoke -those exposed to tobacco
- Asbestos
- Arsenic- in groundwater, human carcinogen
- radon
- Carcinogens- vehicle emissions and pollutants
- lung disease e.g TB and pneumonia leave scarring on lung tissue
How does asbestos contribute to lung cancer?
Naturally occurring minerals used in industries
Fibres easily shatter and suspend into the air and adhere to clothes
Particles can be inhaled and enter lungs
Damaging cells in lung
How does radon contribute to lung cancer?
Natural, radioactive gas found in soils and rocks
People who work in mines=exposed to radon
Example of a carcinogenic substance
Benzo-[A]-pyrene
How do carcinogens damage DNA? (3 steps)
1.Reacts with DNA
2. Forms an adduct with DNA
Adduct= formed when segment of chemical binds to DNA= distorts DNA double helix
3) Mutation
Why is it easy to study different stages of cancer in colorectal cancer?
Easy to get a biopsy
Where does colorectal cancer arise from?
Epithelium lining of colon and rectum
Where in the large intestine are stem cells that renew lining?
Intestinal crypts
Colorectal cancer
Small benign tumour (Adenoma) of gut epithelium
Form polyps (mass of abnormal tissue)
Polyps develop into carcinomas by mutations
Later stage- tumour cells break through epithelial basal lamina and spread through muscle of gut
Metastasize to lymph nodes via lymphatic vessels
And to liver, lungs and other organs
What is the most frequently mutated gene in colorectal cancer?
Ras (K-ras)
p53 (tumour suppressor gene)
K-Ras mutation in colorectal cancer
Point mutation
Activates it to become an oncogene
Cells found in colonic epithelium
Stem cells
Goblet cells
Enterocytes (absorb water and electrolytes)
Enteroendocrine cells (secrete hormones)
Cell renewal in colon epithelium?
Every 4-5 days
Continuous renewal= more susceptible to cancer forming
Role of Wnt signalling pathway
Highly conserved
Essential role in embryogenesis and cell growth (proliferation)
Wnt= glycoprotein
Produced by stromal cells at bottom of colonic crypts
Wnt acts locally- predominantly on intestinal cells
Drives proliferation
Wnt signalling pathway (presence of Wnt)
Destruction complex= GSK3, B-catenin, APC, AXIN
2 receptors- frizzled and LRP
1. Wnt binds to receptors
2. Dishevelled protein binds to frizzled receptor
3. Destruction complex moves towards receptor
4. Axin binds to dsh-receptor complex
5. Releases B-catenin which translocates to the nucleus= transcription factor
6. -catenin transcribes genes required for cell proliferation (MYC and Cyclin-D)
What happens when axin leaves the destruction complex?
Inactivates destruction complex
Blocks B-catenin phosphorylation and ubiquitylation
Allows unphopshorylated B-catenin to translocate to nucleus
Wnt signalling pathway- when Wnt is absent
Destruction complex stays together and (turns on itself)
GSK3 phosphorylates B-catenin
B-catenin undergoes ubiquitylation (degradation in proteasomes)= inhibits proliferation genes
So no proliferation= cells stop dividing and differentiating
groucho keep Wnt genes inactivated
Deregulated gene in colorectal cancers?
APC
APC= mutated/short protein formed by frameshift mutation (stop codon)
This deregulates destruction complex
So APC can’t bind to B-catenin
Meaning B-catenin is NOT degraded and functions as transcription factor= uncontrollable cell proliferation
In normal cells APC binds to B-catenin and deregulates it
What is the earliest mutation in colorectal cancer?
APC
Mutation of APC= creates polyps
What is familial adenomatous polyposis?
Autosomal dominant inherited condition
numerous adenomatous polyps form in the large intestine.
untreated= colorectal cancer
MAPK/ERK pathway
- Growth factor binds to receptor
- Ras activated (GDP to GTP)
- RAF-MEK-ERK
- Cell proliferation
What is the signalling pathway that activates oncogenic Ras?
MAPK/ERK pathway
What are E-Cadherins?
Proteins that allow epithelial cells of colon to attach to one another
What causes metastasis of colorectal cancer?
Breakdown of cell adhesion- loss of E cadherins
Increase levels of Matrix Metalloproteinases (MMPs) which help breakdown extracellular matrix (collagen and proteins)
What is a neoplasm?
Mass of abnormal cells (tumour)
Characteristics of malignant tumours
- Less differentiated cells (anaplastic)
- Pleomorphic=vary in shape and size
- High nuclear:cytoplasmic ratio
- Hyperchromatic (dark purple) nucleus (chrome= colour)
- Fast growing
- Many mitotic cells
What does cancer in-situ mean?
All mentioned for malignant tumours and entire epithelium replaced by dysplastic cells
Cancer?
Malignant tumour+cancer in-situ+ invasive and metastasizes to other places
Nomenclature for cancers
-sarcoma
chondrosarcoma (malignant tumours in cartilage)
Adenocarcinoma (epithelial cells of glands tumour)
cytic= cells
normocytic= normal cells
chrome= colour
Characteristics of benign tumours
- Differentiated cells
- Monomorphic cells- look the same
- Low nuclear:cytoplasmic ratio
- Normochromatic nucleus
- Slowly growing
- Few mitotic cells
- Not invasive
- Doesn’t metastasize
Nomenclature of benign tumours
-oma
chondroma
adenoma
