EXAM 3 - Session 22: Cancer as a Cellular Disease

Question 1

Define cancer.

Answer 1

Cancer is a multistage pathology driven by progressive acquisition of deleterious mutations leading to uncontrolled replication
* possibly progressing to invasion of local tissue and metastasis.

Question 2

Describe the three cancer stages.

Answer 2

• initiation - contained benign
• promotion - malignant (can be +/- invasion)
• progression - heterogeneity, metastasis

Question 3

Describe initiation - contained benign cancer growth.

Answer 3

FIRST STAGE
small benign overgrowth of cells from mutational event
* initiators = mutagens cause permanent change to genome (2 mutations required)
* contained
* non-cancerous
* initiator examples: UV light, some hydrocarbons, cigarette smoke

Question 4

Describe promotion - malignant (+/- invasion) of cancerous cells.

Answer 4

SECOND STAGE
promoting events/factors –> lead to DNA mutations accumulating
* likely to be prolonged/repetitive - not always permanent
* not always directly mutagenic –> but can increase CC –> more DNA replication errors
* promoters: some environmental toxins, excess growth factors. some viral proteins (HPV protein inactivates p53 function)

Question 5

Describe progression - heterogeneity, metastasis of cancerous cells

Answer 5

Formation of more mutations
* metastatic cells enter the blood stream and can relocate to other areas of the body

Question 6

Explain why sequence and relative timing of 1st versus 2nd stage is important.

Answer 6

The progression of cancer is dependent on when tumor initatiors and promoters are exposed to the cell.

Question 7

Based on this timeline, what is the outcome?

Answer 7

No cancer

Question 8

Based on this timeline, what is the outcome?

Answer 8

Cancer

Question 9

Based on this timeline, what is the outcome?

Answer 9

Cancer
* small time gap between initiator and promotor

Question 10

Based on this timeline, what is the outcome?

Answer 10

Cancer unlikely
* longer time gap between initiator and promoter events
* unlikely because the initiation event/gene must be present during the WHOLe gap and reach the promotion event to result in cancer

Question 11

Based on this timeline, what is the outcome?

Answer 11

Cancer unlikely

Question 12

Based on this timeline, what is the outcome?

Answer 12

Cancer unlikely
* stimulating CC
* not mutagenic - there isn’t a mutagenic gene for the promoter to replicate

Question 13

Based on this timeline, what is the outcome?

Answer 13

+/- cancer

Question 14

Based on this timeline, what is the outcome?

Answer 14

Cancer
* initiating events that proceed the first initiation event will act as promoters
* initiating events are mutagenic

Question 15

Describe the “Hayflick limit”

Answer 15

Normal cells do not divide indefinitely

Replicative senescence - loss of power for growth/replication
* metabolic activity but NO mitotic activity
* permanently out of the cell cycle
* distinct frmo G0 stage

Possible causes:
* end-replication problem (telomere decrease)
* single-stranded DNA breaks (topoisomerase re-ligation failure)

Question 16

Describe the assocation between cancer stem cells and the Hayflick limit.

Answer 16

Cancer cells escape senescence
* initiation and promotion events in multistage carcinogenesis
* MDM2 overexpression preventing cell cycle braking caused by p53

Question 17

List some possible ways to escape senescence.

Answer 17

• inactivation of other tumor supressors like Rb
• ALT - alternative lengthening of telomeres
• expression of activated oncogenes
• dysfunction of CC inhibitors like p21/p27

Question 18

Describe some cancer cell properties.

Answer 18

• replicates despite negative growth control signals (defective CC brakes)
• often leaves site of orgin and invades other tissues
• heritable properties via mutated genome

Question 19

Explain the three typical cancer types.

Answer 19

carcinoma - epithelial cells
* possible reasons: UV and chemical mutagens
* epithelium is highly proliferative - high chance for DNA replication error (mutation)

sarcoma - connective tissue or muscle cells

leukemia/lymphoma - hematopoietic (blood) cells

Question 20

Explain proto-oncogenes.

Answer 20

Normal gene sequence that encodes protein with low level, growth promoting ability
* mutant gene has excessive growth promotion

Question 21

Explain tumor suppressors.

Answer 21

Loss of normal gene leads to excessive replication

.

Question 22

Initial and subsequent mutations: what are possible causes of progressive mutations?

Answer 22

• chemical carcinogens (cause nucleotide changes)
• ionizing radiation (x-rays cause c’some breaks)
• viruses (DNA integration disrupts cell’s genes; p53 degradation)
• genetic plasticity - gene changes due to acquired mutations

Question 23

Describe malignant cell properties on the chromosomal level.

Answer 23

• generalizations from blood cancer studies
• evidence for clonal expansion of cancer stem cells
• analysis of chromosomes and DNA sequence in tumor cells will allow identification of clonal marker and metagenic event that occured

Question 23

Describe malignant cell properties on the chromosomal level.

Answer 23

Generalizations from blood cancer studies:
* evidence for clonal expansion of cancer stem cells
* analysis of chromosomes and DNA sequence in tumor cells will allow identification of clonal marker and metagenic event that occured

Question 24

Describe malignant tumor properties on the tumor level.

Answer 24

Generalizations from colon cancer studies: * progressive accumulation of mutations that confer additional growth advantage

Question 25

Explain the association between HPV and cervical carcinoma.

Answer 25

*Non-mutational* loss of tumor suppressor protein **function** * HPV gets replicated alongside the basal epithelial cells (mitotically active) * HPV progeny cells are released --> shed * HPV genome gets transcribed and tranlated --> inactivate p53 proteins and Rb proteins --> more CC --> increase gene mutations --> cancer/tumor formation * genetic plasticity - accumulation of more mutations

Question 26

What is the effect of the Gardasil-type vaccine on HPV and cervical carcinoma?

Answer 26

The vaccine neutralizes the HPV progeny virus and it can no longer integrate into the cervical epithelial cells

Question 27

Explain the result of cancer mutation progression on the patient level. (example in class of 26-yo male w/ brain cancer)

Answer 27

Progressive mutations --> genetic plasticity --> cancer reoccurance * tumors had taken over the entire body * initial response to new drug: decresed tumors, regained weight, less pain * after time, cancer began to grow within the entire body again - from mutations that allowed drug resistance