Book Notes: Cancer Part 1

• 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:
1. survive and proliferate in weird conditions (not attached to substrate, etc, etc)
2. insensitive to anti-proliferation signals
3. avoid apoptosis
4. avoid stress and damage responses
5. induce help from stroma
6. induce angiogenesis
7. invade and proliferate far far away
8. genetically unstable
9. have stable telomeres

pg. 1205 - 1223