Colorectal cancer Flashcards
What causes colorectal cancer and how does it develop?
Genomic instability leads to DNA damage
Defects in DNA repair mechanisms gives rise to mutations including APC
- APC is inactivated forming a truncated protein or mutation
- This regulates destruction complex - APC cannot bind to B-catenin
- B-catenin cannot be degraded and acts a transcription factor for proliferation genes - even in the absence of Wnt signalling
- Cell proliferation continues
- Cells don’t undergo apoptosis
- Gives rise to polyps
- Polyps left untreated eventually become malignant after accumulation of mutations
- Angiogenesis and metastasis
What is Wnt signalling in the proliferation of intestinal stem cells?
Wnt = secreted glycoprotein from stromal cells at base of colonic crypts
> Wnt binds to transmembrane protein receptor - Frizzled - Fz
> Activation of Wnt-Fz complex requires LRP5/6 receptor > Wnt signalling
> Activates Dsh
> Dsh causes Axon recruitment (part of the destruction complex)
> causes B-catenin release which translocates to nucleus and acts as TF for proliferation genes
What occurs in the absence of Wnt signaling?
Destruction complex stays together
GSK3 phosphorylates B-catenin
B-catenin undergoes ubiutination (ub) and subsequent proteasomal degradation
Results in inhibition of proliferation signal
What are the types of bowel cancer?
Adenocarcinoma: starts in gland cells in epithelial cells
Rare types:
- Squamous cell tumours: skin cells and gland cells
- Carcinoid tumours: neuroendocrine tumour
- Sarcoma: in the smooth muscle
- Lymphomas: cancers of lymphatic system
- Melanoma: in the rectum/anus
What is the grading of bowel cancer?
Low grade: similar to healthy tissue
- Grade 1 - cells look normal
- Grade 2 - moderately differentiated
High grade: very different to healthy tissue
- Grade 3 - poorly differentiated
- Grade 4 - undifferentiated - completely different from normal
How are bowel cancers staged?
TNM staging system
T - Primary tumour: T0 cannot be found, TX cannot be measured, T1,2,3,4
N - regional lymph nodes: NX cancer near LN cannot be measured, N0 no cancer LN, N1,2,3,4 - location and number of lymph nodes
M - MX cannot be measured, M0 not spread, M1 has spread
Numerical number staging system
Stage 0 - CIS
Stage 1 - cancer growth through inner lining
Stage 2 - local spread no lymph nodes
Stage 3 - lymph node involvement
Stage 4 - cancer spread to other organs and tissues
Adenoma
Neoplastic polyps
Precursor lesions to colorectal adenocarcinomas
Precancerous
Neoplasm
Rapid and autonomous growth
Polyp
Small non-cancerous growth protruding from tissue surface
Adenomas are therefore a type of polyp
Hyperchromasia
Increased staining nucleus - due to increased replications and growth
Dysplasia
Abnormal cellular growth and maturation
What are the two types of polyp shape?
Pedunculated:
- Stalk, slender, fibromuscular
- Prominent blood vessels from submucosa
- Lower risk to becoming cancerous
Sessile:
- Flat but slightly raised
- Broad and firmly attached to membrane
- No stalk
- Slightly higher risk of becoming cancerous
What are the different classification of adenomas?
Tubular: small, pedunculated polyps. Composed of small, rounded, or tubular glands
Villous: larger, sessile, covered by slender villi
Tubulovillous: some tubular, some villous, non-cancerous polyp, precancerous growth > adenocarcinoma.
What are the histological appearance of colonic adenomas?
Tubular adenoma: Long thin tube shaped glands, enlarged hyperchromatic nuclei
Villous adenoma: cells connect to each other to form long villi. Enlarged, hyperchromatic nuclei
What is the process of the defecation reflex?
Peristalsis moves stool towards rectum by mass movement and haustral contraction
Stool collects in the rectum and activates stretch receptors > urge to defecate begins
Intrinsic pathway activates the myenteric plexus and imitates local peristalsis
Extrinsic pathway activates parasympathetic input further stimulates peristalsis and causes internal and external anal sphincter relaxation
If defecation is not desired, voluntary contraction of external sphincter can delay it
If defecation is appropriate, series of reflexes:
- relaxation of external sphincter
- contraction of abdominal wall muscles
- relaxation of pelvis wall muscles
What is the difference between internal and external anal sphincter?
Internal anal sphincter:
- smooth muscle
- Parasympathetic control
- relax involuntarily
External anal sphincter:
- Skeletal muscle
- Somatic nerve supply (voluntary)
- Innervated by pedundal nerve
How can a patient reduce risk of CRC?
- Increase fruit and veg intake: increase fibre and folic acid
- Stop smoking
- Reduce alcohol
- Healthy weight
- Be physically active
- Participate in bowel cancer screening
What are the non-modifiable risk factors for CRC?
Family history: HNPCC (MLH1 gene), FAP (APC gene)
Condition: IBD or other chronic GI conditions increases risk over time
Age: 9 in 10 cases are 60+, accumulation of mutations over time
What are the modifiable risk factors for CRC?
Weight: estimated 20% cases are caused by obesity. Adipokines and hormones released from adipocytes involved in pathogenesis of CRC
Diet: Lots of alcohol, red/processed meat
Exercise: insulin levels affect pathway in pathogenesis of CRC
Alcohol and smoking: increases damage to DNA, accumulation of mutations
