Topic 10: Cancer Flashcards
What causes cancer?
90% of all cancers are epithelial in origin (occur at the interface of the body and the environment), called carcinomas
uncontrolled cell division results in a mass of cells called a tumor
cancer cells divide more rapidly and retain the capacity to divide more than normal cells
How do mutation occur in cancer cells?
can be naturally occurring or induced from the environment
when DNA is replicated sometimes there are errors
UV light induces a type of mutation called thymidine dimers
advanced cancer cells have accumulated a large number of mutations including gross chromosomal abnormalities
many different mutations are required for full blown cancer
What physiological changes must cells undergo before developing into a tumor?
detachment (anchorage dependence contact inhibition)
mitotic dysregulation
immortalization
failed DNA damage response
What is the loss of anchorage dependent growth in cancer cells?
do not require a solid surface (ie basal membrane) to grow and divide
normal cells are inhibited from growth and division if not attached to a substrate by triggering apoptosis from signaling of the integrins
cancer cells must be able to detach from rest of cells
normal cells are prevented from dividing if they are nor anchored to ECM (integrins signal the cell not to divide), if signal is lost cells undergo apoptosis
cancer cells have mutations that allow them to somehow ignore anchorage-depending
What is the loss of contact inhibition in cancer cells?
normal cells only grow a monolayer in culture
cells stop dividing when monolayer is complete (contact inhibition)
contact between cells stimulate signaling cascade that blocks cell division (coadherins play a role)
cancer cells acquire mutations that allow it to escape contact inhibition (eg loss of intracellular domain of coadherin)
What is immortalization in cancer cells?
normal cells have a finite number of cell divisions (~300) they can undergo before entering a senescent phase
normal cells undergo senescence because of the problem of telomere shortening
cancer cells need a way to increase the buffer areas called telomeres that allow for immortality
telomeres are end of eukaryotic chromosomes that shorten with every cell division, eventually the DNA that is lost in this process is important (senescence)
Hayflick limit must be ignored to develop tumors
cancer cells acquire a mutation in telomerase (enzyme that normally extends ends of chromosomes)
treatment for cancer could be inhibition of telomerase
How do cancer cells divide indefinitely?
ignore signals to stop division or have mutations that constantly promote cell division
avoid apoptosis
What are tumor suppressor genes?
are genes that normally prevent passage through the cell cycle, if mutant (non-functional) they can allow for uncontrolled cell division
How does Retinoblastoma act as a tumor suppressor gene?
normally inhibits E2F transcription of G1 checkpoint genes
if missing, the G1/S checkpoint proceeds without control
Rb is a hereditary cancer, two-hit hypothesis
Rb is inherited in a autosomal recessive manner (requires mutations in both copies)
inactivation of Rb drives cell cycle forward
What are oncogenes?
gene whose presence can trigger the development of cancer
most oncogenes have a normal function in promoting the cell cycle in a regulated way, we call the proto-oncogenes in this state
in the event of a mutation, where they lose the ability to respond to regulation, they become oncogenic
it is the mutant form of a proto-oncogene that promotes cell cycle in a unregulated way (gain of function)
What is a proto-oncogene?
normally functioning copy of a gene that promotes cell cycle
What is angiogenesis in cancer cells?
tumors cannot grow beyond a few millimeters in diameter without blood vessels to supply nutrients and remove wastes
a major step in cancer progression and the ability to metastasize is stimulation of angiogenesis (development of a blood supply for the tumor)
requires more spontaneous and random mutations
in order to grow into cancer, tumor must overcome hypoxia (lack of oxygen)
What is HIF-1 in the angiogenesis in cancer cells?
HIF-1 (hypoxia inducible factor) is normally upregulated in response to hypoxic conditions and is a transcription factor that controls many genes that ensure a constant supply of oxygen to the tissue
HIF-1 regulated genes allow survival in hypoxia and trigger blood supply
HIF-1 normally upregulates VEGF (vascular endothelial growth factor)
in tumors: VHL is a TSG that normally blocks HIF-1 (mutations in VHL are oncogenic)
therapeutic targets include VEGF and HIF-1
How does the immune system react to cancer cells?
most pre-cancerous cells are naturally killed by the immune system (branch of immune system that kills diseased or damaged self-cells)
cancer immunotherapy: trigger a heightened immune response to increase attack on cancer cells
What is evidence of the immune system fighting cancer?
SCID mice: lack immune system, have a huge increase in cancer rates
AIDS: multiple cancers that co-occur
stress: increases risks of cancer
