Cancer Intro Flashcards
Cancer
A disease of uncontrolled cell division
Development and progression of Cancer is usually linked to…
Changes in the activities of cell cycle regulators
–> A loss of cell cycle control
Main molecular causes of Cancer (4):
1) Growth Factor Abnormalities
2) Signaling Machinery Defects
3) Improper Replication
4) Failure of Apoptosis
Growth Factor Abnormalities (Cancer) (2)
1) Make their own growth factors
2) Growth factor pathways are always ON
Genes for growth factors in normal cells are usually _______ and only _________ ____ when needed
–> How is this changed in cancer cells?
1) OFF
2) TURNED ON
–>These genes are usually selectively activated
–> In Cancer cells, mutations in these genes cause them to ALWAYS be ON = production of growth factors even when not needed
–> Don’t need the appropriate signal to activate the production of growth facotrs
Cancer cells don’t need a signal to activate the production of growth factors
Cancer cells may have abnormal signaling pathways that are…
ALWAYS ON (Constitutively active)
OR
that fail to convey growth factor signals (specifically STOP signals from a lack of the growth factor)
Some Cancer cells have been observed “tricking”…
neighboring cells into producing their own growth factors
Signaling Machinery Defects in Cancer cells
Have defects in cdks or other singaling machinery that ensures DNA replication and mitosis occur only under FAVORABLE conditions
–> Usually defects in machinery that STOPS cell division
What is the result of signaling machinery defects in Cancer cells?
Cells with continue to divide even under UNFAVORABLE conditions
–> They can’t stop themselves
Improper replication/division in Cancer Cells
IF and when Cancer cells do STOP dividing, they usually do so at random points (not at the regular checkpoints)
What is the result of improper replication/division in Cancer Cells?
Creates abnormal cells that have stopped dividing at random points in the cell cycle
–> Usually produces cells with severe deformities such as wrong # chromosomes
–> These cells will continue on to divide, proliferating the damage and abnormalities
Proliferation of damaged cells
Failure of apoptosis in Cancer Cells
Cancer cells typically fail to undergo apoptosis even under conditions in which normal cells would (ie. DNA damage)
Apoptosis in Normal vs Cancer Cells
Normal Cells –>
Unfixable DNA Damage = APOPTOSIS
Cancer Cells –>
Unfixable DNA Damage = Cells continue dividing
Main families of genes causing Cancer:
1) Oncogenes
2) Tumor Suppressors
Oncogenes
Genes that normally promote cell division (when not mutated)
What do oncogenes encode for?
1) Growth Factors
2) Growth Factor Receptors
3) Regulatory proteins of signaling pathways involved in cell division
Oncogene vs Proto-Oncogene
Oncogene = The over-active (Cancer promoting) form of these genes
Proto-Oncogene = The not-yet-mutated (normal) form
First identified human oncogene
RAS
RAS (gene)
A family of genes that encode for the G-Protein (GTPase), Ras
Ras (protein)
A G-Protein (GTPase)
–> Relays a signal from a growth factor receptor (TK) to a cascade of protein kinases
GTPase
A G-Protein that is active when bound to GTP
Ras signaling pathway causes…
Upregulation of Cyclin D levels
Cyclin D
Required for transition from G1 to S phase (G1 checkpoint)
Ras Pathway Steps
1) Growth factor binds to a Tyrosine Kinase Receptor
2) The TK receptor auto-phosphorylates
–> 2.1) Ras-GDP (inactive form) gets activated to Ras-GTP
3) Active Ras initiates the phosphorylation cascade involving various protein kinases
4) Cascade leads into the nucleus where a transcription factor is activated
5) Leads to transcription of the gene encoding for Cyclin D production
6) Cyclin D is produced
7) Cell cycle is stimulated (pushed through G1 checkpoint)
In Cancer, Ras protein is…
HYPERACTIVE
–> It’s always “ON” = Always in the GTP bound (active) form
Due to Ras being hyperactive…
There is continuous transcription of the Cyclin D gene === overproduction of Cyclin D
*** Means Ras is ON without a growth factor “turning it on”
–> Doesn’t need the growth factor signal to induce Cyclin D production, it simply does it all the time
Normal vs Cancerous Ras Pathway
NORMAL
Ras-GDP <—-> Ras-GTP = Controlled Proliferation
CANCER
Ras GDP ——> Ras-GTP = Uncontrolled Proliferation
Problems with inhibiting Ras as a treatment?
Ras is an essential component of the normal cell response to growth factors
–> Inhibiting Ras would also affect healthy/normal cell division
What percent of Cancers have a Ras mutation?
20% of all human cancers
Tumor Suppressors
Genes that normal SUPPRESS cell division (when not mutated)
What do tumor suppressors encode for?
Encode proteins that HALT cell cycle progression
p53 (protein)
The best characterized tumor suppressor protein
–> A transcription factor that binds and activates specific genes that encode for proteins that arrest the cell cycle, promote DNA repair, and promote apoptosis
What does p53 do?
Acts at the G1 checkpoint to HALT the cell cycle in response to DNA damage
In response to DNA damage, p53…
1) Stops cell cycle progression
2) Initiates DNA repair pathway
3) Promotes apoptosis (if needed)
What is p53 known as? Why?
“The Guardian of the Genome”
–> Prevents the proliferation of damaged cells, specifically those with abnormal genetic content
p53 Pathway
1) DNA Damage in cell –> p53 is bound to DNA
2) p53 activates 2 genes:
2.1) Activates gene that transcribes p21
2.2) Activates gene that transcribes DNA repair enzymes
3) The genes transcribe their respective encoded proteins
4) p21 = cyclin inhibitor = inhibitor of the active cdk-cyclin complex
5) G1 checkpoint arrests (prevents DNA replication)
6) DNA repair enzyme attempts to repair DNA
6.1) If DNA is repaired = Cell cycle continues
6.2) If DNA is NOT repaired = apoptosis
p21
Cyclin Inhibitor –> Gets created (transcribed) thanks to p53 activating the gene that encodes for p21
p53 in Cancers
Usually non-functional, missing, or under-active
== No arresting of cell cycle and/or repair of DNA
Main mutation affecting p53
Causes the p53 protein unable to bind to DNA
p53 and Ras as the most frequently mutated gene in human cancers:
~1/2 of all tumors contain a mutation in p53 or Ras
