Deegan colorectal ca Flashcards
Describe 2 anti-cancer mechanisms of p53
Response to DNA damage
- When DNA is damaged, P53 becomes activated and responds by activating P21
-P21 can then inhibit cyclin-CDK complexes thereby preventing progression of that cell through the cell cycle.
-This allows for P53 to promote expression of DNA repair genes.
Promotes apoptosis
- If DNA damage is irreversible P53 can induce pro-apoptotic gene expression.
- These pro-apoptotic mediators such as BAX can then release cytochrome C from the cell mitochondria which results in downstream cascade leading to cellular apoptosis.
Explain how APC and KRAS genes normally function in mediating cellular proliferation
APC
- Tumour suppressor gene
-APC normally functions to bind and degrade β-catenin, which is a key transcriptional activator of genes that drive cellular proliferation, such as MYC and Cyclin D1.
-Mutations in the APC gene lead to loss of β-catenin degradation, causing its accumulation in the cytoplasm and eventual translocation to the nucleus, where it upregulates Wnt target genes involved in uncontrolled cell growth.
-E-cadherin proteins require regulated β-catenin levels to maintain epithelial integrity.
–> E-cadherin and β-catenin bind at adherens junctions, contributing to strong cell-cell adhesion in epithelial tissues.
–> Dysregulated β-catenin levels reduce the availability of β-catenin at these junctions, leading to weakened intercellular adhesion.
–> This disrupts tissue architecture and promotes tumor progression by allowing cells to become discohesive, facilitating invasion and metastasis.
KRAS
- Oncogene
- KRAS gene encodes for a GTP-binding protein that binds to GTP forming an active conformation which increases the activity of the MAPK pathway which drives cellular proliferation
- KRAS mutation causes hyperactive GTP-binding protein which causes excessive activation of MAPK pathway.
Outline how microsatellite instability plays a role in colorectal tumor-genesis
Microsatellites are regions in the genome of short, repeated DNA sequences. During DNA replication, these regions may experience errors in their sequence which are typically repaired through expression of DNA mismatch repair genes.
DNA mismatch repair gene mutation can result in accumulation of errors in these microsatellites which can become shorter or longer than usual thereby affecting normal protein function. This is called microsatellite instability.
2 examples of genes affected by MSI are:
(i) TGF-B II gene–> Normally functions to inhibit cellular proliferation of colonic epithelial cells. Therefore in mutation TGF-B genes, this function is lost.
(ii) BAX gene –> Normally promotes apoptosis by facilitating cytochrome C release from mitochondria, which activates caspase-mediated cell death. Therefore mutation in BAX gene results in loss of apoptosis.
Describe the 3 histological patterns of adenomatous polyps
(1) Tubular adenomas
-Most common type
-These are typically small (<1cm), pedunculated polyps with > 75% of the architecture being branched tubular gland pattern.
-Lined by dysplastic columnar epithelium
-Low risk (<5% transform to cancer) unless >1 cm or with high-grade dysplasia.
(2) Villous adenomas
-1% of adenomas
-These are sessile growths with frond-like projections and lined with dysplastic glandular epithelium
-They contain >50% villous architecture.
-High risk of malignancy (>50% if >2cm)
(3) Tubulovillous adenomas
-10% of adenomas
-Combination of tubular and villous architecture
-Intermediate size (1-3 cm), can be pedunculated or sessile.
-intermediate risk of malignancy; risk increases if higher proportion of villous architecture.
Name 3 features of polyps that determine likelihood of malignant change
(1) Size (most important feature)
(2) Histological architecture –> higher risk if sessile villous
(3) Degree of dysplasia –> usually found in villous areas
Name 4 types of colonic polyps and the histological feature of each
(1) Hyperplastic
-Most common type of polyp that occurs sporadically.
-Non-neoplastic with no malignant potential
-Decreased epithelial turn over with accumulation of mature epithelial cells.
-Typically small (<5mm) and found on the surface of mucosal folds.
(2) Hamartomatous
-Rare and sporadically occuring
-Disorganised proliferation of hyperplastic mucosal epithelium and arborizing smooth muscle pattern
-Low risk of malignancy unless associated with genetic syndromes
(3) Adenomatous
-Neoplastic polyp
-Dysplastic glandular epithelium associated with a tubular, villous or tubulovillous architecture.
-Demonstrates usual dysplastic features e.g. nuclear hyperchromasia
-Malignant potential depends on the type, size and severity of dysplasia.
(4) Inflammatory
-Associated with conditions such as inflammatory bowel disease.
-Often called pseudopolyps
-Caused by regenerating mucosa bulging into colonic lumen
Describe 4 differences between first intention and second intention wound healing
(1) Wound edges
-Closely opposed in first intention
-Farther apart in second intention
(2) Degree of inflammation
-2nd intention healing has more severe inflammation due to more extensive tissue destruction –> +++ macrophages and neutrophils required to clear debris
(3) Granulation tissue
- More granulation tissue/ fibroblast proliferation seen in 2nd intention in order to fill the defect
(4) Wound contraction
- more extensive contraction in 2nd intention to try heal the wound (+++ myofibroblasts)
(5) Epitheliazation
-Faster in first intention
(6) Scar formation
-More extensive fibrosis in scar formed during 2nd intention healing
Describe the 4 phases of wound healing
(1) Hemostasis (sec-min)
-Platelet activation, aggregation and clotting factor release to form a fibrin clot at site.
(2) Inflammatory (0-3days)
-Inflammatory response with vasodilation, vascular permeability etc
-Neutrophils initially enter the site and release proteolytic enzymes to help degrade damaged tissue components and debris
-Macrophages then enter the phagocytose the debris.
(3) Proliferation (3 days to weeks)
-Granulation tissue is set down
-Fibroblasts are activated and deposit type III collagen
-VEGF release increases angiogenesis
-Epithelial cells begin to proliferate to regenerate the epidermis.
-Myofibroblasts begin wound contraction
(4) Remodelling
-Type III collagen is replaced by stronger type I
-Collagen cross linking increases wound tensile strength
-Capillaries regress as wound matures.
-Scar formation
Describe the morphological characteristics of i) right-sided and ii) left-sided colorectal carcinoma and give two correspondent clinical consequences for tumours on each side.
Right sided
-Exophytic, polypoid or fungating that grows along the bowel wall and can protrude into the lumen
-mucinous/ colloid pattern
-Consequences: iron deficiency anemia, melena, vague symptoms e.g. fatigue, weakness.
Left sided
-Annular (ring like) and encircling with heaped up edges
-More ulceration and stenotic formation
-Usually more tubular/villous architecture
-Consequences: constipation, obstruction (LLQ pain), occult bleeding
Describe the MOA of 5-FU
(1) Inhibits Thymidylate Synthase (TS)
-TS catalyzes the conversion of dUMP to dTMP, which is required for DNA synthesis.
-5-FU is converted to 5-fluoro-2′-deoxyuridine monophosphate (FdUMP), which forms a stable complex with TS and folate cofactors, irreversibly inhibiting TS.
-This leads to thymidine depletion, disrupting DNA replication and causing thymineless cell death.
(2) Disrupts RNA Processing
-5-FU is converted to fluorouridine triphosphate (FUTP), which gets incorporated into RNA instead of UTP.
-This disrupts normal RNA function and processing, leading to defective protein synthesis and ultimately apoptosis.
Explain the rationale behind the addition of Leucovorin to the 5-FU treatment regimen.
Leucovorin is folinic acid and acts as a co-factor in the interaction between 5-FU and Thymidylate synthase, stabalaising the FdUMP-TS complex.
This increases the duration and potency of thymidylate synthase inhibition leading to greater DNA synthesis blockade and stronger tumour cell death
Explain the rationale behind a hemicolectomy during surgical intervention for CRC.
When surgically removing a colorectal cancer, the bowel segment supplied by the same arterial branch as the tumor is typically resected (e.g., hemicolectomy). This is because lymphatic drainage follows the arterial supply, and removing the entire arterial territory ensures complete oncologic resection, including potential lymphatic metastases.
Name 4 early and 4 late complications of CRC surgery
Early
(1) Anastomotic leak
(2) Thromboembolism
(3) Bleeding/hemorrhage
(4) Ileus
(5) Would dehiscence.
Late
(1) Anatomotic stricture
(2) Erectile dysfunction
(3) Chronic pelvic pain
(4) Bowel or bladder incontinence
Describe the innervation of the internal and external anal sphincters to maintain continence
(1) Internal anal sphincters
-Under autonomic control: sympathetic innervation via the inferior hypogastric plexus causes contraction, parasympathetic innervation via the pelvic nerves causes relaxation by inhibiting contraction.
(2) External anal sphincters
-Under somatic control via the pudendal nerves (s2,3,4), contracting along with levator ani muscles to postpone defecation
What are the dermatomes to which pain from the foregut, midgut and hindgut is referred?
foregut: T5-9 (epigastrium)
Midgut: T5-12 (umbilical)
Hindgut: T12-L2 (suprapubic)
All visceral afferents travel via the thoracic splanchnic nerves, first entering the sympathetic trunk, and synapsing in the cord with 2nd order somatic neurons at that level
