Oncogenes / sustained proliferation Flashcards
Definition of an oncogene
An oncogene can transform a normal cell into a tumor cell and will promote or allow the uncontrolled growth of cancer
What is the most central characteristic of a cancer cell?
To maintain constant proliferation/growth factor independence
What are the properties of transformed (cancer) cells?
§ Altered morphology (rounded shape) § Loss of contact inhibition § Anchorage independence § Immortalization § Reduced requirements for mitogenic growth factors § High saturation density § Inability to halt proliferation in response to growth factor deprivation § Increased transport of glucose § Tumorigenicity
How were oncogenes identified (the discovery that v-src is actually a kidnapped cellular gene)?
SRC virus normally doesn’t have the src oncogene, so many times it can infect cells but nothing happens.
But randomly it can infect a cell and integrate its viral genome next to a proto-oncogene of the host’s genome (c-src) and get the proliferative properties, that’s when it becomes v-src
What could possibly turn a proto-oncogene into a oncogene?
A mutation or any other genetic aberration
What are the 4 different classes of oncogenes?
- Overproduction of growth factors
- Receptors no longer require growth factor binding
- No stimulation needed for cell division
- Transcription factors always bind to their target gene promotor
What receptor do most growth factors bind to?
Most growth factors binds to Receptor Tyrosine Kinases (RTKs), needs abundant tyrosine kinase to activate the signaling pathway
What are the 3 steps for a receptor tyrosine kinase to get activated?
- Growth factor binding
- Two receptor tyrosine kinase form a dimer
- Phosphorylation of the tyrosine kinase
What are the two most important mitogens growth stimuli (factors for cell cycle)?
Cyclin and Cdk
What are the 3 common types of DNA changes that create oncogenes?
- Deletion or point mutation in coding sequence (hyperactive protein made in normal amounts)
- Gene amplification (normal protein greatly overproduced)
- Chromosome rearrangement (nearby regulatory DNA sequence causes normal protein to be overproduced)
What are the 2 main disadvantages of classical chemotherapy and irradiation?
It induces massive DNA damage/cell death and is targeting normal cells as well as tumor cells
What is the main advantage of targeted therapy compared to classical chemotherapy and irradiation?
Targeted therapy is direct against a specific target aberrantly present in tumor cells (but it requires a genetic test before start of treatment)
What are the X types of targeted therapies and how do they act?
- Blocking antibodies (prevents receptors dimer formation)
- Small molecules inhibitors (for example inhibition of BARF in melanoma)
- CDK4/6 kinase inhibitors (targeting the core cell cycle machinery)
Once a targeted therapy works, are we off the hook?
No, because cancer cells can develop a resistance to the therapy and the patient relapses
Why is it useful/needed to do combinatory targeted therapy?
Because cancer cells can develop a resistance to the therapy and inhibiting one molecule may not be enough to stop proliferation (some molecules can be compensated by others)
