Lecture #20 | Colon Cancer

Multi-step nature of cancer

1. Discrete steps defined clinically

2. Specific molecular events can be identified with different clinical steps

3. Specific sequence of alteration s

4. Consequences for diagnosis and treatment

5. Role of genetic instability

Concept #1: Discrete steps can be defined clinically

Ex: Pap smears from different tissues staining can indicate cancer

• changes in phenotype

Concept #2: Specific molecular events can be identified with different clinical steps

In colorectal carcinoma

Concept #3: Specific sequence of alterations

Different alterations in different cancers, depends on tissue of origin

• sequence can be important

• different sequence in different cancers

Concept #4: Consequences for diagnosis and treatments

• specific molecular changes can be used to distinguish type and stage of tumor more precisely than clinical trials

• Knowledge of specific molecular events can be used to target treatment

Concept #5: Role of genetic instability in cancer progression

Chromosomal abnormality: association with cancer for many decades

• but abnormalities are both and cause and consequence of cancer

• certain changes lead to genomic instability ad that instability causes the subsequent change that are needed to get full blown cancer

Biology of the digestive tract

Stomach→ small intestines → large intestines → rectum

Small intestines biology

Duodenum, jejunum, ileum

• nutrient absorption

Large intenstine = colon

Cencum, asending colon, transverse colon, descending column, sigmoid colon

• water absorption

• colon cancer in humans occurs primarily in the distal portion of the colon = colorectal cancer

Biology of intestines

• villi: hairlike projections that absorb what is needed

• crypts: connective tissue

  • Stem cells in the crypt divide every 11 hrs and differentiate into specific cell types

  • migrate to the tip

  • differentiate into enterocytes (blue) to absorb nutrients

  • keep getting pushed upwards until tip of villus and get shed off

  • 3-5 days from bottom of crypt to being shed at the tp of the villus

    

Colon: no villi

• High turnover rate seeing harmful material→ damaged cells

• Negative consequence = high proliferation rate

Colorectal cancer

1. Very common in US

2. Material is easily accessible

3. Tumor progression can be followed in vivo

4. Specific molecular chances are associated with clinical symptom

5. Several inherited predispositions

Colon cancer is very common in US

50% of Western population develop colorectal tumors by age 70

• 1 in 10 become malignant

• Incidence in young people is increasing while in older is decreasing

• death rate is steadily declining since mid 1980s due to increased monitoring

Material is easily accessible

Colonoscopy can allow for the visualization to find polyps

• identify and removes

Tumor progression can be followed in vivo

Polyps are well defined precursors of colon cancer

• progression of colon cancer is easily followed by histopathology (staining of tissues to see if there are changes

• stalks of benign adenoma leads to invasive carcinoma → liver metastases

Inherited predispositions for colorectal cancers

• 15% of colon cancer is inherited

  • 70% of inherited cancer is Familial Adenomatosis Polyposis

  • Incidence 1 in 8000

  • 100s of polyps (benign) in the 20s and associated with other cancers

APC

Tumor suppressor gene

• mutate in 65% of pts with colon cancer

• only 15% of colorectal tumors have a full length APC

• initiator and promoter of cancer

Wnt pathways

Destruction complex in Wnt pathway:

1. Scaffold: APC

2. Kinase: GSK3b

3. Txn factor: B-catenin

   No Wnt:

   1. Kinase GSK phosphorylayes B-catenin

   2. It gets trapped in Destruction complex and gets degraded

      

If Wnt is available:

1. Wnt binds Frizzled → recruits Axin → GSK is inactivated and B-catenin is stabilized

2. B-catenin activates target gene

What happens when APC is mutated?

No destruction complex

B-catenin mutation?

Targets are involved in cell proliferation and could continue to proliferate

Targets of Tcf-B-catenin

• Cyclin D1, Cyclin e, c-Myc, MMP7, VEGF, UPA

Early development levels

Low APC → High nut. B-catenin → High cyclin D1 → High cell proliferation, Tissue growth

Adult

Normal APC -? Low B-catenin → Low cyclin → low cell proliferation

Expression if APC and B-catenin

Mutations in APC

Often truncated in cancers →Loss of B-catenin binding and down regulation domains

Like frameshift and nonsense mutations

• Majority of frameshift mutations