- normal cells work cooperatively, and obey signals and controls on division and growth so the organism can survive
- cancer cells work "selfishly", growing and dividing out of control, nabbing up nutrients and creating blood vessels so they can survive
- know the difference between BENIGN and MALIGNANT (is it invasive)
- several types of cancer by tissue of origin
- carcinoma: from epithelium, most common because epithelium is usually exposed to stresses and dangers (serves as protective barrier, making it vulnerable to damage and mutation)
- sarcoma: from muscle/connective tissue
- leukemia/lymphoma: from white blood cells, lymphocytes, and nerve cells
- cancer cells tend to be all clones of the primary tumor
- patients with CML, a leukemia with the mutation Philadelphia chromosome, show that the chromosome break happens at exactly the same place for all cells in the tumor, but it happens a few hundred basepairs different between patients
- this implies cells of one tumor all derive from one ancestral cancerous cell and are all clones
- cancer results from a genetic mutation, which may be from chemical carcinogens or radiation/UV light
- however, you need more than one mutation in ONE CELL LINE to have cancer
- organisms have a high overall rate of mutation, but that rate is including all the cells of a human (there are several trillion cells in the body, a human has about several trillion mutations over the lifetime, so it's like maybe one mutation per cell per day, and remember that repair machinery usually fixes the mutation)
- cancer usually happens in old age because that's when you've likely built up a lot of mutations and the tumor has had some time to grow into a visible mass
- e.g. leukemia didn't show up until 5 years after the atomic bombs razed Hiroshima, and lung cancer takes 20 years of heavy smoking before surprise!
- rule of thumb: minimum 5 mutations to become cancerous
- creating a mutant cancerous cell takes microevolution
- mutation rate: how fast does this kind of cell get mutations?
- number of reproducing individuals: how many cells in this tissue divide at a time?
- rate of reproduction: how fast can a cell divide and how many times can it divide?
- selective advantage: does the mutation kill the cell or give it a bonus or do nothing?
- you need several rounds of division (epithelial cells divide constantly) with advantageous mutations carrying through each step until you shake loose the body's regulatory systems
- cancer also involves epigenetic mutations
- epigenetics involving histone modification is a way of controlling which genes are active and which are silent
- mutations happen with the enzymes that modify histones, the proteins that interpret the histone code, etc et
- these mutations are also passed on to daughter cells
- because cancer cells proliferate uncontrollably, they are also genetically unstable
- it's usually because the cancers have a mutation in DNA repair/maintenance genes
- the increase in mutation rate plus their rapid division rate makes their evolution rate really fast--cancers with genetic instability speed rapidly towards malignancy
- cancer cells can also accumulate bad mutations that end up killing it, so it is the cancer cell with the right mutations that will persist into tumors and metastases
- the core mutations of cancer cells tend to be in control of cell death, control of cell differentiation, or both (for optimal cancer growth :D )
- any mutation or external condition that promotes cell growth can and will help cancerous cells
- normal tissue growth controlled by apoptosis, especially when apoptosis serves as a control to destroy mutated cells
- cells that don't do apoptosis when they're supposed to keep growing and passing on mutations, potentially forming cancer
- stem cells will produce daughter cells that proliferate for a bit before committing to differentiation
- if the differentiation step is blocked, daughter cells just keep dividing and dividing
- other core mutations are DNA damage response and other stress responses
- the DNA damage response goes hand in hand with the cell cycle checkpoints: mutations in either system won't be able to stop a damaged cell from continuing to divide and pass on the mutations
- being able to survive through these mutations makes them more undefeatable
- the final barrier to cancers is replicative cell senescence, when the telomeres run out, the cell would normally do apoptosis
- cancers can avoid the chkpt when telomeres run out and just keep dividing without telomeres (meaning every round shrinks the chromosome by a bit)
- cancers can also have a mutation that reactivates telomerase or a mutation that creates something similar to telomerase
- new theory suggests tumors are organized with cancer stem cells at the top and limited dividing lower cancerous daughter cells
- if the regular cancer daughter cell is implanted in a mouse, it can't generate a new tumor because it has limited dividing capacity
- only a small percent of cells in a tumor (<1) can propagate indefinitely
- where do cancer stem cells come from?
- (1) from real stem cells and (2) from normal proliferating cells that developed a mutation that makes them propagate indefinitely like a stem cell
- cancer stem cells divide slowly, so treatments that target rapidly dividing cells won't harm them, and then the tumor mass will regrow
- metastasizing cancer is the most dangerous, but it requires cancer cells to overcome some barriers first
- 1st, the tumor cells must invade neighboring normal tissue and keep spreading
- 2nd, the tumor cells must find a blood or lymphatic vessel and get in
- 3rd, the tumor cells must grab onto a new site while floating through the vessel and form a small clump (micrometastases)
- 4th, the clump must develop into a large tumor for stability
- many cells are usually able to get into the vessel, but very few can attach and colonize in a new location
- even forming micrometastases is no guarantee of continued survival
- metastasis usually requires a LOT of mutations in all the right places
- a large tumor also needs a supply of nutrients
- a tumor over 1-2 mm will need to induce angiogenesis: formation of new blood vessel
- normal and tumor cells secrete angiogenic signals in response to hypoxia (lack of nutrients and oxygen)
- these signals activate transcription and secretion of VEGF
- VEGF attract endothelial cells and stimulate growth of a blood vessel
- induced vessels are usually disorganized and go random places with dead ends
- this leaves a lot of area still in hypoxia, which causes natural selection for cells that survive in tough conditions, which makes cancer even tougher to eradicate
- stroma: the surrounding connective tissue, even tumor cells talk with them like normal cells
- stroma contains fibroblasts, white blood cells, etc, for support
- cancer cells send signals to the stroma
- the stroma responds with signals that stimulate growth and secrete proteases to loosen the ECM for invasion
- tumor and stroma evolve together (experiment where a tumor is plucked out and put next to normal fibroblasts showed the tumor can't survive)
- possible source of treatment: inhibit deranged stroma to kill tumors
- sum up of characteristic cancer behaviors:
- survive and proliferate in weird conditions (not attached to substrate, etc, etc)
- insensitive to anti-proliferation signals
- avoid apoptosis
- avoid stress and damage responses
- induce help from stroma
- induce angiogenesis
- invade and proliferate far far away
- genetically unstable
- have stable telomeres
pg. 1205 - 1223
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