Cancer Flashcards
Cancer
Not a single disease, but a group-of diseases classified by the tissue that is affected
What is cancer?
- Unregulated cell division
- Cells that lose the ability to regulate their mitotic or meiotic division grow uncontrollably, which produces tumors in the affected tissues
All cancers are Genetic - Karyotype of Malignant
- All cancers are result of genetic mutation, but not all of those genetic mutation are the result of inheritance
- Malignant cancers tend to accumulate various genetic mutations until the genome becomes unrecognizable
Mutation in the DNA of somatic and germ cells
Somatic mutation -> mutant cell -> mitosis -> population of mutant cells
Germ mutation -> mutant cell -> sexual reproduction -> all cells carry mutation ; no cells carry mutation
Inherited Cancer Mutations -Retinoblastoma
- Recessive mutation inherited from parent
Alfred Knudson’s Two-hit Hypothesis: - Two mutations withins single cell are necessary for cancer development (1971) - Lasker Award
-Retinoblastoma model
Inherited cancers
- 10-15% of all cancers are inherited from parent
- cancers with familial links breast, colon, prostate, ovarian (these cancers can also arise due to environmental exposures
- Cancer is a multigenic disease - not a simple asnwer
Recessive acting mutation
- One “functional” copy of the gene is enough to keep the cell divisional normal
- Two mutated copied of the gene results in unregulated cell division -cancer
Dominant acting mutation
One mutated copy of the gene is enough to cause unregulated cell division - cancer
Inherited mutation recessive acting
Retinoblastoma is an example of a recessive acting gene mutation
Four cell pathways of cancer
- Cell cycle control genes (direct or indirect role)
- Signaling pathway genes for cell cycle control
- Cell cycle arrest genes
- DNA repair genes
Proto-oncogenes
- Genes whose normal function is to drive cell division
- Mutations in these gens make the “oncogenes”
Mutations resulting in cancer are usually “dominant- acting” gain of function mutations
Tumor suppressor genes
- Genes who’s normal function is to inhibit cell division
- Mutations resulting in cancer are usually “recessive -acting” loss of function mutations
Cell cycle control genes
Mitosis - ~1 hour (metaphase, anaphase, telophase)
Gap 1 (Pre-DNA synthesis) -~10 hours
Synthesis -~9 hours
Gap 2 (post-DNA) synthesis-~4 hours
Control of the cell cycle
- Two types of proteins drive cell division
Cyclin-depended kinases (CDKs)
Inactive until bound to cyclin
Phosphorylates cell division machinery
Allows cell to overcome cell cycle checkpoints
Cyclins
Accumulate in the cell if the cell is healthy
Activate the cyclin-dependent kinases
Are quickly degraded after the cell overcomes the cell cycle checkpoint
Different pairs of CDKs and cyclins for each checkpoint
Cyclins during cell cycle
G1- D- Cdk4, D-Cdk6
When synthesis is initiated E- Cdk2
S - A-Cdk2
G2- B- Cdc2
Cyclin -CDK complexes (G1 to S)
- In order for cell to move from Gq to S phase, the cell must inactivate the tumor suppressor. Retinoblastoma (Rb) and must activate replication licensing machinery CDC6
Function of Rb protein?
Inhibits transcription of cell cycle gee by sequestering E2F
Function of Cyclin D-CDK and E-CDK
- Phosphorylates Rb
- Releases E2F
Function of E2F?
Transcription factor of S phase genes
Rb Inactivation via Growth Factor Stimulation (pt 2)
- E2F once released from aRb binds to the DNA and induces transcription of genes that allow cell to start cell division process
- Also makes cyclins E an A which will start to accumulate and eventually help the cell move into S, and then G2 phase
G2 to M transition (9c-MYS GEne Mutation)
- MYC is a transition factor that stimulates production of cell cycle progression genes (cyclins)
-Fusion protein c-MYC results in over-expression; thus constitutive expression of cell cycle progression genes.
Leads to Burkitt’s lymphoma ( B cell cancer)
Signaling pathway proteins trigger the cell cycle
- Cells are constantly receiving signals from their surrounding
- if tissue needs to grow or repair, cells secrete soluble proteins that stimulate neighbors to enter the cell cycle
- Growth factors stimulate cell division by increasing production of cyclins
Growth factors attach to membrane receptors
-Activation of Ras a G protein
Results in activation of cell cycle by increasing cyclin production downstream
Activated Ras stimulates signa cascade
- Function of Ras proto-oncogene
- Increase in transcription of cyclins
Ex. Mutation of signal protein leads to chronic myelogenous Leukemia (CML)
- Fusion protein - gain of function -active protein
-ABL is a cell division stimulant, attachment of BCR makes it constitutively active
-Cell division is constitutively stimulated
BCR potentially involved in signaling cascade
ABL- kinase, activated by CDKs
Targeted cancer therapies (drugs interfere with known molecular targets )
- Gleeves - CML chronic mylogenous leukemia
Chemotherapy (BAD side effects)
Induces apoptosis in cancer cells - Herceptin -specific cancers involving the human epidermal growth factor receptor
Blocks growth factor signaling in HER2 receptor - Tamoxifen - chemical that blocks binding of estrogen growth factor hormone to receptor in breast cancer.
Cell cycle arrest and apoptosis
- At each checkpoint the cell pauses to check for abnormalities
Cell size too small to support division
Not enough cytosol
Not enough nutrients (nucleotides)
DNA damage and mismatches - If abnormalities are detected and the cell cannot recover, then the cell will enter programmed cell death-apoptosis
These checkpoint pathways are collective referred to as “arrest and apoptosis”
Many arrest and apoptosis pathways
Major players:
- Master tumor suppressor [protein p53
- Tumor suppressor 21
- Other tumor suppressors ( 14-3-3a, GADD -45)
Activation of p 53
- Several cell cycle arrest and apoptosis pathways converge in activation of p53
-p53 is constitutively made in the cell, but does not become active until it is released from Mdm2
-must be phosphorylated and acetylated to be released from Mdm2
Once active, p53 activated downstream signaling proteins which ultimately arrest the cell cycle.
If arrest lasts long enough, the cell will enter apoptosis pathway.
Activation of p53 pt 2
- Function of Mdm2 is to move p53 to the cytoplasm for degradation
- When Mdm2 is active, p 53 is degraded
- Phosphorylation and acetylation allow Mdm2 to release p53
- When p53 is activated due to DNA damage, Mdm2 cannot degrade it.
Arrest and repair pathway
- Action of p53 depends on cell cycle stage
- p53 increase transcription of genes for p21, GADD45 and 14-3-3a
- p53 decreases transcription of the gene for cyclin B
G1- p21 inhibits G1 cyclin -CDKs and blocks G1/S transition by blocking transcription for DNA synthesis and activation of replication complexes
S- GADD45 -PCNA reduces processivity of DNA polymerase, thus slowing or blocking DNA synthesis.
G2/M - 14-3-3 blocks activation of cyclin B-Cdc2 by preventing Cdc25C mediated dephosphotylation of Cdc2;
Apoptosis pathway triggered by p53, balance of BAX and Bcl2
- Increased Bax due to p53 activation results in Bax homodimers and induction of apoptosis
- Increased levels of activated Bc12, brought about through, for example oncogene activation blocks apoptosis
- Bax and Bcl2 balance are normal cells
Dna repair genes
- If cells sences that DNA is damaged, the cell cycle will be arrested through p53
- The cell has a brief opportunity t fix the broken DNA
- If cell cannot fix the DNA, it will eventually undergo apoptosis
BRCA1 and BRCA2 - DNA repair genes
- Normal function of BRCA1 and 2 genes is repair of DNA breakage (tumor suppressors)
- Mutant proteins lose function, cannot repair breakage
- One type of inherited mutation that predisposes individual to developing cancer.
Cyclin D
Impact: Over-expression
Type of cancer: Esophageal carcinoma, breast
Ras
Impact: Overexpression
Types of cancer:brain tumors
Mdm2
Impact: Overexpression
Types of cancer: Adipose tumors
p53
Impact: Loss of function
Types of cancer: colon, melanoma, lung, bladder, prostate
p21
Impact: Loss of function
Types of cancer: prostate
Rb
Impact: Loss of function
Types of cancer: retinoblastoma, lung carcinoma
Uncontrolled gene proliferation
- Impact of oncogene mutations
Usually gain of function mutation (or loss of regulation)
Usually dominant-acting mutation
-Impact of tumor supressor gene mutations
Usually loss of funtion mutation
Usually recessive- acting mutation - Inherited versus non-inherited cancers
can result in “loss of heterozygosity” of tumor suppressor activity
