Lecture 63 Flashcards Preview

MGM (D) > Lecture 63 > Flashcards

Flashcards in Lecture 63 Deck (46)

A vast majority of cancer is due to what two factors?

1) Genetic predisposition
2) Environmental factors


What occurs in Familial adenomatous polyposis?

1) Predominantly due to Genetic predisposition (Penetrance is 100%)
2) Small benign tumor in colorectal epithelium (adenomas) grow
3) As tumors grow, cells become more disorganized
4) Eventually, a carcinoma forms


How do stomach and colon cancers compare for Japanese individuals living in Japan or the USA?

1) Colon cancer: very low (lifetime risk 0.5% in Japan vs. 5% in USA)
1st gen Japanese in Hawaii, colon cancer up several fold
2nd gen Japanese on U.S. mainland, colon cancer up to 5% (equal to US average)
2) Stomach cancer: common in Japan, rare in USA


What is the relative percentage of sporadic vs. familial cancers?

Sporadic: 90-95%
Familial: 5-10%


What is the age of onset for sporadic vs. familial cancers?

Sporadic: Later
Familial: Earlier


What is the inheritance pattern for sporadic vs. familial cancers?

Sporadic: None
Familial: Single gene dominant (predisposition)


What is the family history for sporadic vs. familial cancers?

Sporadic: Absent
Familial: Present, 1st degree relatives


What is the location of mutation in sporadic vs. familial cancers?

Sporadic: Somatic
Familial: Germline & somatic


What are the number of tumors for sporadic vs. familial cancers?

Sporadic: Single
Familial: Multiple


What are the locations of tumors for sporadic vs. familial cancers?

Sporadic: Unilateral
Familial: Multilateral


What is a relationship between incidence of cancer and age?

Incidence of cancer increases dramatically with age


Why does incidence of cancer increase with age?

1) Accumulation of mutations requires time
2) Perhaps defenses against cancer decline


What does an individual's genetic background determine about cancer?

1) Susceptibility to carcinogens & enzymes needed to metabolize them
2) Susceptibility to DNA damage & efficiency of DNA repair enzymes


What are two types of mutagens that cause errors in DNA replication, repair or recombination and induce cancer?

1) Endogenous mutagens
2) Exogenous mutagens


What do endogenous mutagens result in and what are examples?

1) Spontaneous chemical modification of DNA
2) Result from:
a) Reaction oxygen species via oxidative metabolism
b) Deamination of C, A or G
c) Spontaneous depurination


What are examples of exogenous mutagens?

1) Diet
2) Smoking, sunlight, radon
3) Occupational and non-occupational chemical exposures


What must occur to a cell before cancer can arise?

1) A pre-cancerous cell requires multiple mutations and clonal expansions for cancer to arise
2) Generally 6 steps progress to cancer


What do clonal expansions of pre-cancerous cells with mutations result in?

Somatic mosaicism


What are two enabling characteristics of cancer cells?

1) Genome instability & increased mutagenesis
2) Tumor-promoting inflammation


What are 6 established hallmarks of metastatic cancer cells?

1) Sustaining proliferative signaling
2) Evading growth suppression
3) Enabling replicative immortality
4) Resisting cell death
5) Activating invasion & metastasis
6) Inducing angiogenesis


What are 2 new emerging hallmarks of cancer cells?

1) Avoiding immune destruction
2) Deregulating cellular energetics


What is the nominal mutation rate of each cell?

10^-6 per gene per generation


What is the probability of acquiring cancer?

Probability of 1 in 10^22 of having 6 mutations in one cell


Why does cancer occur if the probability is so low?

Because some mutations:
1) Affect stability of the entire genome, increasing the overall mutation rate ("mutator phenotypes")
2) Enhance proliferation, creating an expanded target population for the next mutation
3) Decrease cell death resulting in retention of cells that would normally die


How does proliferation of cells normally occur?

1) Growth factors (mitogens) are made by specific tissues to signal other tissues to proliferate
2) Growth factors must bind to highly specific growth factors receptors
3) Intracellular signal transducers tell the cell that a growth factor has bound to its receptor by transmitting the signal to a cellular target
4) Transcription factors are induced by DNA binding proteins that affect transcription rates of nuclear genes to alter gene expression


Virtually every cancer contains an error in what?

Cell division (Aberrant stimulation of signal transduction pathways is associated with cancer)


How do integral protein-tyrosine kinases transmit a signal for cell proliferation?

1) Dimerization of a signal molecule binds to an integral protein-tyrosine kinase
2) Phosphorylation occurs to initiate a cascade of signaling events
3) Ras-GDP G-protein is activated to Ras-GTP G-protein
4) Ras-GTP G-protein activates Raf
5) Raf activates cytoplasmic protein kinase cascade
6) Cytoplasmic protein kinase cascade activates transcriptional regulators
7) Transcriptional regulators produce cell proliferation proteins


What are examples of intracellular signal transducers?

1) G-proteins
2) Non-receptor protein tyrosine kinases
3) Serine-threonine protein kinases


Compare mitogen dependence in normal vs. cancer cells

1) Normal cells are dependent on mitogens for cell division
2) Cancer cells are independent of mitogens for cell division


Compare anchorage dependence in normal vs. cancer cells

1) Normal cells require a matrix to attach to in order to carry out mitosis
2) Cancer cells do not require a matrix to attach to in order to carry out mitosis


Compare contact inhibition in normal vs. cancer cells

1) Normal cells stop dividing when they are in contact with other cells surrounding them
2) Cancer cells continue to divide even when they are in contact with surrounding cells


Compare mitotic index in normal vs. cancer cells

1) The number of normal cells that are currently dividing is low
2) The number of cancer cells that are currently dividing is high


Compare genetic instability in normal vs. cancer cells

1) Normal cells have very stable genes
2) Cancer cells have very unstable genes


Compare lifespan in normal vs. cancer cells

1) Normal cells are mortal
2) Cancer cells are immortal


Compare dissemination in normal vs. cancer cells

1) Normal cells cannot spread from one organ to another
2) Cancer cells can undergo metastasis in which they are spread from one organ to another


Compare differentiation in normal vs. cancer cells

1) Normal cells are very differentiated
2) Cancer cells are more stem-cell like and are very pluripotent


How is the cell cycle controlled?

Cell-cycle progression is controlled by orderly expression of heterodimeric protein kinases & kinase inhibitors:
1) Cyclins - regulatory subunits whose levels vary through the cell cycle and are specific to activating certain cyclin-dependent kinases (CDKs)
2) Cyclin-dependent kinases (CDKs) are catalytic subunits that have activity only when associated with a cyclin
3) Cyclin-dependent kinase inhibitors (CDKIs) bind to the Cyclin-cyclin-dependent kinase complex
Alterations in one of these groups is found in nearly every cancer examined


What is retinoblastoma (Rb) protein?

1) Rb is a critical inhibitor of cell cycle progression
2) Rb protein binds and inacivates E2F, a transcription factor, when no proliferation is needed


What is the p53 protein?

1) p53 is a key inhibitor of cell cycle progression
2) It is also required for DNA repair, apoptosis, & cellular senescence
3) When p53 activity levels are high in a cell, CDKI levels are also high to prevent mitosis


How is retinoblastoma (Rb) protein inactivated?

1) When an S-cyclin binds to a CDK, the cell is ready to enter S-phase and trigger DNA replication machinery
2) This causes the inactivation of Rb protein


What are four cell cycle control checkpoints?

1) Improper spindle formation (M Arrest): Is the mitotic spindle correctly assembled? If no, arrest mitosis until corrected
2) DNA Damage (G1 Arrest): Is DNA damaged? If yes, arrest cell division until repair is completed (G1-arrest)
3) Unreplicated DNA (S Arrest): Is S phase complete before mitosis begins? If no, cells arrest until DNA replication is finished (S-arrest)
4) DNA Damage (G2 Arrest): Is DNA damaged? If yes, arrest cell division until repair is completed (G2-arrest)


What is apoptosis and what are examples in which apoptosis is required?

1) Apoptosis is programmed cell death
2) Formation of embryonic cavities or limb buds (prevents webbed hands or feet)
3) Removal of nerve cells that fail to make the correct connections
4) Destruction of damaged cells
5) Turnover of antibody-producing cells that are no longer needed


Describe the process of apoptosis

1) Shrinkage, blebbing (budding), & broken mitochondria
2) Chromatin condensation
3) Cell fragments
4) Formation of apoptotic bodies
5) Uptake by scavenger cells (Phagocytic cells)


What are key proteins in apoptosis?

1) Caspases: Proteases that cleave many target proteins, including other caspases (Caspases have cysteine in their active sites & cleave target proteins at aspartates)
(Caspases are expressed as proproteins and activation requires proteolytic cleavages of the "pro" domain)
2) Bcl-2 (B cell lymphoma protein 2) family members regulate caspases (Bcl-2 family members can be anti-apoptotic (Bcl-2) or pro-apoptotic (Bax)


Both the intrinsic and extrinsic pathways for apoptosis ultimately converge at what point?

Caspase 3


Describe the intrinsic pathway of apoptosis

1) When apoptosis is signaled, a protein activates Bad protein
2) Bad protein has a high affinity for Bcl protein (mitochondrial membrane protein)
3) Bcl protein is normally bound to Bax protein (mitochondrial membrane protein), to prevent it from functioning
4) When Bad protein binds to Bcl protein, Bax protein is released, allowing it to form a pore or channel in the mitochondrial membrane
5) Cytochrome C, which is normally inside the mitochondria can now travel through the Bax protein channel to activate Apaf 1 in the cytosol
6) Apaf 1 activates Caspase 9
7) Caspase 9 activates caspase 3
8) Caspase 3 causes cellular cleavage and cell death