Cancer (Block 1)

Question 1

Cancer Cell Types

Answer 1

Carcinoma (80-90%)

• in situ/invasive
• epithelial cells (squamous cells and adenocarcinomas from secretory cells)

Sarcomas (1%)
- solid tumors of connective tissues

Leukemia/Lymphoma (7%)

• Leukemia - circulating cells
• lymphoma - solid mass

Neuroectodermal (1.3%)
- gliomas, blastomas, schwannomas

Question 2

Tumor Suppressors

Answer 2

TP53 (p53) - inhibits G1 to S phase of cell cycle; promotes repair or apoptosis. Causes proliferation of damaged cells if mutated.

Rb - hyperphosphorylation inhibitis G1 to S phase of cell cycle. Can cause oncogenesis if mutated

Note: Both are phosphoproteins

Question 3

Abnormal Cell Functions in Cancerous Cells

Answer 3

• Monoclonal tumor growth
• Genetic Instability
• Anchorage Independence
• Avoid Replicative Senescence
• Loss of Contact Inhibition
• Disregard signals for cell cycle control
• Avoid suicide by apoptosis
• Angiogenesis (Note VEGF role in this)
• Invasive
• Metastasis

Question 4

Cancer Inheritance

Answer 4

Direct: Inherited mutation in oncogene or suppressor gene = increased susceptibility to certain type of cancer

EX: Breast Cancer (BRCA1 and 2)

Indirect: Defect DNA repair mechanism = increased susceptibility to cancer

EX: Xeroderma Pigmentosum

Question 5

Three stage model of Chemical Carcinogenesis

Answer 5

1. Initiation: change in DNA
2. Promotion (of clonal expansion)
3. Progression: changes cause/lead to metastasis

Question 6

Direct vs. Indirect Carcinogens

Answer 6

Direct: Electrophilic compounds that react with DNA

Indirect: Metabolized before reacting with DNA
- Ex: Benzo-a-pyrene (tobacco smoke/coal tar): forms DNA adducts

Question 7

Transforming Viruses cause Cancer

Answer 7

Viruses (10-20%)

Burkitt’s Lymphoma/EBV

Retroviruses (Viral Sarcoma)
- HIV indirectly causes Kaposi’s Sarcoma and Lymphoma

DNA Viruses
- HPV linked to cervical cancer

Question 8

Bacterial Infections cause Cancer

Answer 8

Heliobacter pylori (Gram -, infects stomach and duodenum)

Question 9

Oncogenesis Mechanism

Answer 9

Proto-oncogene activation/mutation

• Gain of function mutation
• Only 1 mutation needed

Tumor suppressor gene (caretaker) mutation

• Loss of Function
• 2 mutations needed on same chromosome

Activation of anti-apoptotic genes/loss of proapoptotic gene expression

Question 10

Oncogene Activation Types

Answer 10

Deletion or Point mutation in coding sequence/Gene Sequence Mutation
- Hyperactive protein expressed/Constitutive Activation

Regulatory Sequence Mutation
- Increased Protein expression

Gene Amplification
- Increased protein expression

Chromosome Translocation

• Chimeric Gene product
• over-expression

Question 11

Oncogenic Activation by chromosome Translocation

Answer 11

Translocation event leads to over-expression of proto-oncogene
- Burkitt Lymphoma = t(8;14)

• Follicular Lymphoma = t(14;18)

Translocation event creates fusion/chimeric gene
- Chronic Myeloid Leukemia (CML) = t(9;22) aka Philadelphia Chromosome

• Acute Promyelocytic Leukemia (APL) = t(15;17)
• Ewing Sarcoma = t(11;22)

Question 12

Tumor Suppressor Genes

Answer 12

Gatekeepers (p53, Rb, Nf1)

• Cell Cycle control
• growth inhibition (contact inhibition)
• Pro-apoptotic factors
• Mutation = uncontrolled cell growth

Caretakers (BRCA1 and 2, Mismatch Repair Genes)

• DNA repair
• Genome Integrity
• Mutation = mutation accumulation

Question 13

Knudson’s 2 Hit Hypothesis (Tumor suppressor genes)

Answer 13

If 2 mutated suppressor genes exist in a cell, tumor will begin

Somatic cells in a normal individual will be fine, while some rare cells will have one mutation.

A patient with an inherited susceptibility to cancer will have many/all somatic cells with one mutation; a second mutation will generate a tumor.

Question 14

Sporadic vs. Inherited cancer (Knudson’s 2 hit model)

Answer 14

Inherited case: all cells carry one mutation, 2nd mutation from any of those cells will cause tumor

Sporadic case: all cells are normal, one cell must generate two mutations in order to cause tumor.

Question 15

Mechanisms for “2nd Hit” (Knudson 2 hit model)

Answer 15

(Recheck/watch slide 99)

Genetic:
- gene inactivation due to accidental change of nuc sequence in DNA leads to many cells with inactivated gene

Epigenetic

• accident causes either packaging of DNA into heterochromatin or methylation of C nucleotides, which leads to many cells with inactivated gene
• accident can reduce chromatin condensation and activate genes that promote proliferation

Question 16

miRNA in cancer

Answer 16

RNA-mediated inhibitition of target genes
- binds to a protein complex after being degraded, and will bind to any target mRNA with complementary sequence, preventing expression of that gene

Note: 100x expression of miR21 in glioblastoma

Question 17

p53, Rb1, Nf1

Answer 17

p53

• DNA binding protein (TF)
• stop cell cycle and repair damage, or induce apoptosis

Rb1
- If Hypophosphorylated, cell cycle comes to a stop.

NF1 (RasGAP)
- Inactivates Ras proto-oncogene by increasing GTPase activity of Ras

Question 18

Wnt signalling pathway (Effect on Beta Catenin)

Answer 18

• Wnt binds to Frizzled and activates Dishevelled
• Dishevelled inhibits gSK-3B/Axin/APC Complex (typically active except for in bottom of Colon Crypts)
• Beta Catenin nonphosphorylated, so not degraded (typically degraded because it is a proliferation promoting protein)
• Beta Catenin will then enter nucleus and bind to Tcf/Lef proteins, which in turn transcribe MYC and cyclin D genes

Question 19

Telomeres

Answer 19

Specialized repetitive DNA sequences at ends of chromosomes: (TTAGGG)n

• protect ends of chromosomes and permit completion of chromosomal DNA replication (end replication problem solution)
• regulate integrity of chromosome during cell division as well as determine/enforce cell life span
• maintained by Telomerases (they renew the telomeres in germline, and cause immortalisation in cancer cells)
• grow shorter through life; if too short, cell death triggered

Question 20

T-loop

Answer 20

Capping structure that protects the ends of chromosomes
- without T loop, p53 would observe ends of chromosomes as “breaks”, and would begin attempting repair or degradation of the chromosome.

Question 21

Telomerase

Answer 21

Protein-mRNA complex that maintains telomeres.
- TERC: TElomerase RNA Component (mRNA template)

• TERT: TElomerase Reverse Transcriptase (protein)
  (synthesizes telomere DNA from TERC)

Mechanism of Renewal

• Telomerase extends the existing parental telomere from its 3’ end (5’ to 3’)
• DNA polymerase elongates lagging strand (3’ to 5’)

Reactivation in Cancer (90%)
- Upregulates MYC (which upregulates telomerase)

Question 22

Shortened/Lack of Telomeres

Answer 22

Shortening of Telomeres triggers cellular senescence (chromosomes become unstable if divided with too short telomeres); typically activates p53 cell-cycle arrest (which is usually followed by apoptosis)
- acts as a tumor suppressor mechanism

Lack of Telomeres
- end-capping structures absent leads to instability of chromosomes, which usually results in cell death but can also result in fusion events between chromosomes, which can also generate tumors.