Neoplasia Flashcards
Neoplasia
Growth comprised of transformed cells
The cells are genetically altered (mutated)
They no longer behave normally
Clinical significance varies form none to fatal
Neoplasia:
Pathogenesis
- Mutation and transformation into a neoplastic cell can occur from a wide variety of insults
- Causes include:
- Inherited - many
- Chemical exposure - after birth
- Infectious agent - after birth
- Physical agents - after birth
- In all cases, these inherited or acquired insults result in cells with an abnormal genome
- Genetically altered cells must replicate in order for neoplasia to occur
- Apoptosis is the normla outcome for cells with unrepaired DNA damage
Neoplasia:
Causes:
Inherited
Germline DNA abnormalities are passed from generation to generation
Heritable familial neoplasia and predispostition ot neoplasia occur
Neoplasia:
Causes:
Chemical exposure
Many endogenous and exogenous chemicals act as mutagens and or carcinogens
Neoplasia:
Causes:
Infectious agents
Viruses are notable causes of neoplasia
They can directly incorporate oncogenes into a cell
They can activate endogenous oncogenes
They can suppress host responses against neoplastic cells
Neoplasia:
Causes:
Physical Agents
Radiation with short wavelengths induce DNA damage.
UV radiation, x-rays, gamma rays
Cell Cycle: Review
The cell cycle is the process by which a cell replicates into two identical cells
Cell Cycle: Checkpoints
Cell cycle checkpoints assure that all events happen correctly before a cell progresses to the next stage of the cycle.
- Abnormalities detected at a checkpoint result in cell cycle arrest
- Upon correction of the abnormality, the cell cycle continues
- If the abnormality persists, apoptosis is activated
- There are many differen types of checkpoints,
- DNA damage checkpoints
- Located at G1/S, S, and G2.M
- Arrests cell cycle when DNA damage is present
- DNA replication checkpoints
- Located at G2/M
- Arrests cell cycle until DNA replication is complete
- DNA damage checkpoints
- There are many different types of checkpoints
- Spindle Checkpoint
- Located at M stage
- Arrest cell cycle until all chromosomes are aligned
- Morphogenesis checkpoint
- Located at G2/M
- Arrests cell cycle when cytoskeletal abnormalities are present
- Spindle Checkpoint
Cell cycle
Each checkpoint involves multiple proteins and pathways
If any of the checkpoint proteins or pathways are impaired, genetically abnormal cells may inappropriately pass the checkpoint and replicate
Neoplasia: Pathogenesis:
Alterations in certain groups of Genes
- Most commonly associated with cell transformation
- Genes that promote cell growth and division
- protooncogenes
- Genes that inhibit cell growth and division
- Tumor suppressor genes
- Genes taht regulate DNA repair
- Genes taht regulate apoptosis
- Genes that promote cell growth and division
Pathogenesis:
Protooncogenes
are normal genes that code for proteins that stimulate cell growth and differentiation
Growth factos and their receptors (hst and erb genes)
Signal transducers and mediators of intracellular pathways (ras genes)
Stimulatory regulators of the cell cycle (myc gene, cyclines and cyclin-dependnet kinases)
Pathogenesis: Protooncogenes
Genetic injury to a protooncogene forms an oncogene: the products of which can promote cell transformation
Damage may occur in the protooncogene coding sequence resulting in an abnormal protein (oncoprotein)
Damage may occur oustide the coding region resulting in dysregulation of expression (Normal protein, but inappropriately produced)
Pathogenesis: Protooncogenes:
Oncoproteins
Have similar function to the normal protooncogene product, but without regulatory controls
They do not obey external signals such as growth facots or cytokines
Internal regulatory controls are disobeyed
Oncoproteins promote progression of the cell cycle, even when this is inapproptiate.
Pathogenesis: Protooncogenes:
Mutations in RAS
- Mutations can lead to permanent activation of the pathway even in the absence of external activity
- Persistent activity causes increased incidence of neoplasia
*
Pathogenesis:
Tumor Suppressor Genes
Code for proteins that inhibit cell growth and differentiation
- Inhibitory cytokines and their receptors
- Transforming Growth Factor - B receports
- Signal transducers and mediators of intracellular pathways
- Nf-1 and APC genes
- Inhibitory regulators of the cell cyce
- RB and p53 genes
The products of these genes tend to counteract the stimulatory effects of protooncognes proteins
- Tumor suppressor proteins slow down or stop the cell cycle to inhibit cell division
Pathogenesis:
Tumor suppressor genes:
RB
- Mutation causing hyperphosphorylation of RB results in it’s inactivation, and allows cell progression through G1/S phase check point.
Pathogenesis:
DNA repair genes:
BRCA1
BRCA1 combines with other DNA sensors and tumor suppressor genes and RNA polymerase 2 to influence DNA repair and transcription regulation
Repairs double stranded breaks in DNA
Pathogenesis:
Apoptosis Genes:
p53
- DNA-binding protein that regulates transcription of many genes involved in cell cycle arrest and apoptosis
- P21 - cell cycle arrest
- GADD45 - DNA repair
- DNA damage is unrepaired, persistent high levels of p53 activate pro-apoptotic events to initiate apoptosis
Pathogenesis:
Apoptosis genes:
Mitochondria
An important location of p53-inducible events that modify the apoptotic stimulus
bax, bad, bcl-xS
bcl-2, bcl-xl
Cytochrome C release
