Section 6 - Molecular Basis of Cancer

Question 1

Define the properties of cancer cells.

Answer 1

• Divide in the absence of growth factors. do not respond to signals/checkpoints that normally would control cell division
• Immortal: are not sensitive to normal pathways of cellular differentiation or apoptosis
• genetically unstable (aka, they have highly abnormal chromosomes+number)
• malignant cancer cells can escape their normal env and proliferate at foreign sites (metastasize)

Question 2

Indicate how we know cancer is a genetic disease.

Answer 2

Cancer can be traced to a single cell that has undergone an inheritable change that causes it to lose growth control.
Many cancer causing agents damage DNA! (eg, radiation, and chemical mutagens)
thus, susceptibility to cancer can be inherited (eg, skin, colon, breast, etc.)

Question 3

Outline the properties and roles of cancer-causing genes.

Answer 3

1. Oncogenes: genes whose presence in abnormal forms causes cancer. They’ll be abnormal in the localization of the protein product, the activity of the protein, or the overexpression of the protein. (normal gene called proto-oncogene). Gain-of-Function; DOMINANT. –> any little mutation causes cancer. Cancer is a GAINED function (overactivity mutation)
2. Tumour Suppressors: genes whose absence (loss of function/activity, or lack of expression) causes cancer. Involved in DNA repair or the control of cell growth/differentiation (a less-specialized cell becomes a more specialized type), or cell death. Loss of function; RECESSIVE –> need 2 mutations to cause cancer (to inactivate both gene copies); so some people inherit already one copy in chromosome that has a mutation, which increases their chance of getting cancer

Question 4

Describe ways in which biochemistry and molecular biology are leading to new
cures for cancer.

Answer 4

Gleevec as a treatment for Chronic Myeloid Leukemia:
-CML results from abnormal proliferation of hematopoietic stem cells
-CML is caused by the fusion of Bcr gene with Abl gene (translocation) forming Bcr/Abl oncogene
-Abl is a protein kinase that phosphorylates proteins required in cell differentiation, cell division and cell adhesion.
-Fusing Bcr to the Abl kinase alters the substrate specificity of Abl. Abl normally phosphorylates substrate but fusion phosphorylates the wrong things which inhibits apoptosis –> cancer. This activates cell division and inhibits apoptosis of hemopoietic cells
-If you can block activity of bcr-abl you can stop the disease
When the Bcr/Abl protein is over expressed it will phosphorylate substrates leading to the cell having too much of these substrates around, which go on and cause Leukemia.

If we can block the activity of the Bcr/Abl protein, then we can block it from causing cancer. They found a drug called Gleevec which binds the protein causing the protein to no longer be able to phosphorylate substrates=> no Leukemia.
Inhibits the binding of ATP into the active site of the enzyme, no phosphorylation –>no Bcr-Abl complex –>no leukemia
Knowing the structure of Abl allowed an inhibitor to be designed

Question 5

What are some of the Avoidable Causes of Cancer?

Answer 5

Agents that cause DNA damage. (etc. chemical mutagens, radiation)
AND
Tumour Promoters: Agents that cause/let cells to divide – create inflammation
AND
certain viruses
Smoking

Question 6

Why does Cancer increase with age?

Answer 6

A single mutation is not sufficient to cause cancer. Tumour progression involves successive rounds of mutation and selection
At each round the descendent acquires another mutation allowing it to grow faster or in abnormal places
Mutations that allow the cancer to spread pile on each other before cancer is diagnosed
First mutation causes a cell to grow abnormally
Next mutation causes more cells to become abnormal or divide faster
Eventually a mutation causing the cell to go through the basal lamina and metastasize. etc.

Question 7

What are the checkpoints in cell cycle?

Answer 7

G1 -cells gets bigger (increase in cell content)
G1 checkpoint – check for size, nutrient, growth factors, DNA damage
S – DNA replication
G2 – double checks duplicated chromosome to see if good for mitosis
G2 Checkpoint – checks for size, if DNA replication occurred properly. if not, resting state (G0)
Spindle Assembly Checkpoint – during mitosis, checks for chromosome attachment to spindle

Question 8

Functions of cancer causing genes

Answer 8

1. Cancer cells think the growth factor is always present, mutation causing receptor to stay in on position
2. Cancerous cells divide even if the basal lamina isn’t present, and don’t care about space when dividing (cell-cell contact doesn’t inhibit)
3. Cancer cells don’t sense the aging process so they keep going. Cancer cells telomerase is expressed to keep length of telomeres thus avoiding apoptosis
4. Transcription factors

Question 9

Classic Cancer Treatments

Answer 9

Surgery – get it early and out
Radiation – good if it is targeted in a spot. Stops cells from replicating by damaging DNA
Chemo – binds with DNA so DNA Pol can’t go through (eg,cisplatin)
-Or interfere with mitosis machinery
-Reduce dNTPs (replication substrates) available in the cell (eg, methaotrexate)

Question 10

Classic Cancer Treatments

Answer 10

Surgery – get it early and out
Radiation – good if it is targeted in a spot. Stops cells from replicating by damaging DNA
Chemo – binds with DNA so DNA Pol can’t go through (eg,cisplatin)
-Or interfere with mitosis machinery
-Reduce dNTPs (replication substrates) available in the cell (eg, methaotrexate)
BUT these also affect normal cells

Question 11

Difficulties with Cancer Treatment

Answer 11

Different cancers are different diseases because they involve different genes, tissues, locations
Heterogeneity of the tumour: Not all cells within the tumour are identical. The tumour cells are always “evolving”
Drug resistance
Drug can’t get passed BBB to get to tumour