Cancer Genetics II (Sept. 18 - Schultz)

Question 1

Cancer stem cells are similar to these two other types of cells and share common characteristics with them…

Answer 1

Stem cells & Mesenchymal cells

Question 2

List the 5 characteristics of cancer stem cells which promote/allow their pluripotency

Answer 2

1. High telomerase expression (results in immortality)
2. ABC transporters -> drug resistance
3. Proliferation rates low -> allow resistance to drugs which selectively act on cell cycle
4. Cancer stem cells can arise through mutation and epigenetic changes
5. Regulated by TGF-3 and Wnt signaling proteins
   through autocrine or paracrine pathway.

Question 3

What two factors play a role in the EMT/MET pathway?

Answer 3

TGF-beta & Wnt pathway

Question 4

What happens into the epithelial to mesenchyme transition?

Answer 4

1. Cells lose E-cadherin
2. Cells lose cell-cell and ECm contacts
3. Activation of PI3K/AKT and classical RAS/MAPK pathways
4. Increased protease secretions (UPR/Type IV collegenase)

Question 5

What are the genetic instabilities that lead to cancer

Answer 5

1. malfunction of DNA repair pathways
2. inability to go through anaphase checkpoint leading mitotic catastrophe
3. loss of P53
4. Deficiency in telomerase
5. massive environmental damage (carcinogens)
6. regain of telomerase activity
7. survival and proliferation

Question 6

Describe the incidence of function with age and exposure to carcinogens

Answer 6

A single mutation is not sufficient to cause a cancer.

1. accumulation of mutations
2. length of exposure to carcinogen

Question 7

Describe the heterogeneic phenotypes of cell within a tumor

Answer 7

1. Tumors are derived from a single abnormal cell (mosaicism and X-inactivation)
2. Cells within a tumor are heterogeneic and exhibit multiple phenotypes (genetic/epigenetic differences)

Question 8

Carcinogenesis requires two features/events to occur. They are:

Answer 8

• An exposure to an initiator (mutagenic)

- A tumor promoter

Question 9

Which of the following combinations lead to tumors:
(A) initiator followed closely by 6 promoters
(B) initiator followed distantly by 6 promoters
(C) 6 promoters followed by an initiator
(D) initiator followed by 6 promoters evenly and distributed distantly from the initiator
(E) repeated segments of initiator mutations

Answer 9

(A), (B), and (E)

Question 10

What is the function of SMAD2/3 in the TGF pathway

Answer 10

Normal cells will respond to TGF-Beta in a canonical manner. The receptor for TGF will phosphorylate SMAD causing inhibition of cell division and migration

Question 11

Describe the development from normal epithelial to metastatic cancer and the pathways that go wrong. (4 of them)

Answer 11

1. Loss of APC (polyps and early adenomas)
2. Activation of K-RAS (Intermediate adenoma)
3. Loss of SMAD 4 and TSG (Advanced)
4. Loss of p53 (carcinoma)

Question 12

In what pathway does APC work to inhibit carcinogenesis

Answer 12

APC works in the Wnt pathway preventing the expression of Beta-Catenin.
Beta-Catenin destroys E-cadherins and upregulates Myc

Question 13

What are the types of methods that are being explored to treat cancer?

Answer 13

1. Microdissection followed by proteomic analysis
2. SELDI-TOF protein MS analysis

Aimed at

• diagnosis
• staging
• specific molecular-targeted therapy