III. Signal transduction & cell cycle | 52. Molecular background of tumor generation

Question 1

What is Tumorigenesis?

Answer 1

Tumorigenesis is the formation of a cancer, where normal cells are transformed into cancer cells.

Question 2

I. Stages of tumor formation
1. What are the stages of tumor formation?

Answer 2

• We will first have a normal tissue with a
  constant number of cells
• Sometimes a cell in the basal layer keeps proliferating faster (e.g. due to carcinogens)
  -> a colony of a cell will form = benign tumor
• Benign tumor does invade nearby tissue or spread to other parts of the body
• But if the proliferation of benign tumor increases, the risks for further mutations
  will also increase -> malignant tumor
• Malignant tumors are cancerous as they can invade nearby tissues
• They can grow quickly and spread to other parts of the body, via lymph system or bloodstream, in a process called metastasis

Question 3

II. Tumor formation
2. The genes that are important for normal controlled proliferation can be divided into 2 classes which are?

Answer 3

1) Proto-oncogenes
2) Tumor suppressors

Question 4

II. Tumor formation
3. What are the features of Proto-oncogenes?

Answer 4

Proto-oncogenes:normalgeneswhich, when altered by mutation, become oncogenes that can contribute to cancer
- GFs and their signaling
- Inhibitors of apoptosis (the ones that keep the cell alive)
- Activators of cell cycle

Question 5

II. Tumor formation
4. What are the features of tumor suppressors?

Answer 5

• Differentiation factors and their signaling
• Activators of apoptosis (the proteins that kill the cell)
• Inhibitors of cell cycle (the ones that prevent the cell from proliferation)

Question 6

II. Tumor formation
5. What happen if there is a genetic alteration in the cell?

Answer 6

When there is a genetic alteration in the cell, that affects proto-oncogenes and tumor suppressors, then they can increase the tendency of tumor formation

Question 7

II. Tumor formation
6. How can proto-oncogenes lead to tumor formation?

Answer 7

Proto-oncogenes: when they are modified so that they are hyperactive and overproduce, then they will lead to tumor formation
- If a cell secretes a large amount of GFs, it can induce tumor
- If we stimulate inhibition of apoptosis, the cell will not commit suicide even if there is a severe damage -> cell will proliferate with the genetic defects

Question 8

II. Tumor formation
7. How can tumor suppressors lead to tumor formation?

Answer 8

Tumor suppressors will cause problem when they are missing or inhibited

Question 9

III. Role of p53 and Rb tumor suppressor proteins
1. What does benign tumor cause?

Answer 9

Tumor formation (benign) includes the inhibition of the p53 and Rb tumor
suppressor proteins = would allow the cell to proliferate beyond the requirement

Question 10

III. Role of p53 and Rb tumor suppressor proteins
2. What is the effect of DNA viruses on tumor suppressor proteins?

Answer 10

DNA viruses can inhibit the tumor suppressor proteins (ex: papilloma virus [DNA], adenovirus)

Question 11

III. Role of p53 and Rb tumor suppressor proteins
3. What is p53?

Answer 11

p53 is the #1 tumor suppressor protein, due to its activation by a wide variety of stresses

Question 12

III. Role of p53 and Rb tumor suppressor proteins
4. What is Rb (retinoblastoma protein)?

Answer 12

Rb (retinoblastoma protein) is also a tumor suppressor protein – it prevents excessive cell growth by inhibiting the cell-cycle progression (at restriction point) until a cell is ready to divide

Question 13

III. Role of p53 and Rb tumor suppressor proteins
5. What happen if there is a severe problem in the cell (e.g. oxidative stress, activation of oncogenes, telomere shortening, DNA lesion)

Answer 13

If there is a severe problem in the cell (e.g. oxidative stress, activation of oncogenes, telomere shortening, DNA lesion), different proteins will alarm the tumor suppressors

Question 14

III. Role of p53 and Rb tumor suppressor proteins
6. Name the proteins that will inhibit Rb?

Answer 14

INK proteins will inhibit the Rb protein

Question 15

III. Role of p53 and Rb tumor suppressor proteins
7. What is the role of ARF proteins?

Answer 15

• ARF proteins will inhibit the ubiquitination of p53, thereby activating it -> p53 induces p21

Question 16

III. Role of p53 and Rb tumor suppressor proteins
8. What happen if p53 is activated?

Answer 16

When p53 is activated, it has several effects on the cell:
- Pro-survival mechanisms: (1) cellular senescence = cell-cycle arrest (2) activate DNA reparation
- Activate apoptosis

Question 17

IV. Malignant transformation of immortalized cells
1. Describe Malignant transformation of immortalized cells

Answer 17

• Cells of benign tumors (with defect/inhibition of tumor suppressors) can transform into cells of malignant tumors via (1) obtaining viral oncogenes or (2) there is a formation of oncogenes within the cell
• Retroviruses bring oncogenes (mutant src gene) into the cell
• The oncogenes brought into the cell by retroviruses are all mutant versions of the oncogenes found in the cell
  => Retroviruses do not transform the cell, but cause mutation in the (already
  present) oncogenes of the cell

Question 18

IV. Malignant transformation of immortalized cells
2. What can Cells of benign tumors do?

Answer 18

Cells of benign tumors (with defect/inhibition of tumor suppressors) can transform into cells of malignant tumors via
(1) obtaining viral oncogenes
or (2) there is a formation of oncogenes within the cell

Question 19

IV. Malignant transformation of immortalized cells
3. What do Retroviruses do in malignant transformation of immortalized cells?

Answer 19

• Retroviruses bring oncogenes (mutant src gene) into the cell
• The oncogenes brought into the cell by retroviruses are all mutant versions of the oncogenes found in the cell
  => Retroviruses do not transform the cell, but cause mutation in the (already present) oncogenes of the cell

Question 20

V. Proto-oncogenes
1. What are the features of Proto-oncogenes?

Answer 20

Proto-oncogenes are GFs, active regulators of cell cycles and inhibitors of apoptosis
- Our own proto-oncogenes, present in all our cells, can get mutated into oncogenes
- When the proto-oncogenes are hyperactive, they produce more proteins = endogenous oncogenes

Question 21

V. Proto-oncogenes
2. Give an example of proto-oncogenes

Answer 21

Example: oncogenic mutation of Ras small GTP-binding protein
- Small GTPase Ras gets activated when GTP is bound, but inactive when GDP is bound
- A missense mutation (single nucleotide exchange) is able to change an amino acid in the sequence
- The missense mutation can eliminate the GTPase activity of Ras: mutant Ras activated
-> binds GTP and gets activated
-> stimulates cell growth, proliferation and survival
-> BUT: will never turn off, because it cannot break down GTP due to the mutation