Molecular Biology of Cancer – Flashcards

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What is cancer?
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term applied to a group of diseases in which cells no longer respond to normal restrains on growth.
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What are the 6 hallmarks of cancer?
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1. sustaining proliferative signaling 2. evading growth suppressors 3. activating invasion and metastasis 4. enabling replicative immortality 5. inducing angiogenesis 6. resisting cell death
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What is tumorigenesis?
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a multistep process reflecting genetic alterations that drive the progressive transformation of normal human cells into highly malignant derivatives. Each genetic change confer one or another type of growth advantage, leading to the progressive conversion of normal human cells into cancer cells. cancer cells have defects in regulatory circuits that govern normal cell proliferation and homeostasis.
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Hallmark of cancer: sustaning proliferative signaling?
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...
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Hallmark of cancer: evading supressors
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avoid deaths.
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Enabling replicative immortality, what does it mean?
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If conditions are provided - machinary, growth factors etc. the cancer can live forever.
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Inducing angiogenesis?
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cancer cell induces the growth of new blood vessels because it experienced hypoxia due to lack of oxygen diffusion from the capillaries. blood vessels development for cancer cells is catotic.
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Actiating invasion and metastasis - hallmark of cancer.
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cancer cell begins to spread to the blood - body begins to recognize cancer as foriegn body and begins to attack atigen. metastasis occurs more often in certain tissues - for instance breast cancer often spreads to the blood but brain cancer often just moves around the brain.
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Where do cancer cells like to grow?
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places that are hospitable to the cancer. i.e.growth factors are present and other factors that help the cancer grow.
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What can cancer free actually mean?
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remission. often the body is not cancer free. a lot of time cancer cells can lie dormant in tissue and wake up years later.
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What are the emerging hallmarks?
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hallmarks of cancer cells recently discovered. 1. degregulating cellular energetics 2. avoiding immune destruction
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What does it mean "deregulation ceulluar energetics?"
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cancer cells use glucose exclusively for ATP production even though Oxygen in the TCA cylce is more efficent. Cancer cells instead use TCA cycle to hyjack by-products like carbon to use as growth factors.
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What are the enabling characteristics?
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characteristics common to cancer cells 1. genome instablity and mutation 2. tumor-promoting inflammation
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How do cancer cells demonstrate avoiding immune destruction?
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often cancer cells can utilize immune response for their own benefit. for instance cancer cells can use inflammation to develope
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How do cancer cells demonstrate genome instability and mutation?
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A certain stress in the environment brings about a mutation in DNA. Once this occurs over and over again pathology develops. Once a cell has one mutation it is easier for it to mutate again and again resulting in cancer. can be a gradual process or in the case of pancreatic cancer very rapid
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Genome instability?
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represents the means that enables evolving populations of premalignant cells to reach the six biological endpoints or hallmarks of the cancer cell phenotype
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Carcinogenesis?
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The process by which the cancer develops.
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What is mutagenesis?
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linked to carcinogenesis. production of changes in the DNA sequence
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What are important contributors to the development of cancer?
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-multiple genetic mutations are needed for the development of a cancer cell phenotype -epigenetic alterations are also important contributors to the development of cancer.
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What is an example of genetic instablitly?
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aneuplodism compared to the normal (euploidy) pathologic karyotypes have many added chromosomes. example chromosome 1 can contain 4 chromosomes or 5. aneuploidism is contributed to cancer.
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Genome instability is often associated with translocation.
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translocation is the movement of certain chromosome parts attaching to other chromosomes
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Genome instability is often attributed with deletions of region. what could cause this?
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platonium radiation
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What is gene amplification?
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an example of genome instablity. oncogene is a gene in over drive. overamplification can be seen when one chromomsome is expressed in thousands and thousands of times rather than just twice in a normal chromosome another example... double minute chromosome.
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What is the Philadelphia chromosome?
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An example of genome instability. It is a change in chromosomal structure. specifically the 22nd chromosome tail transfers to the chromosome 9. All patients with this translocation have leukemia
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What are double minute chromosomes?
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DOUBLE MINUTE CHROMOSOMES derive from chromosomal segments that have broken loose from their original sites and have been replicated repeatedly as extrachromosomal elements; like the chromatids of normal chromosomes, these structures are doubled during the metaphase of mitosis. The double minutes are detected using FISH with a probe reactive against an oncogene, in this case the Myc gene.
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What is gene epigentic silencing?
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Tightly packing genome with histidine so that heturochromatin is expressed. Very difficult to transcribe so gene is silenced. OR Heavy methylation of C nucleotides
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What is genetic gene inactivation?
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A change in hardware of the gene. where a spot in the gene is mutated and then that mutaion is passed on over and over again resulting in silencing.
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Cancer can require as many as 20 genes in one cell to be alltered to drive mutation
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Cancer is the result of repair mechanism failure.
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Proto-oncogenes?
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when normal, produce growth in the cell, like a growth factor receptor. -Dominant "gain-of-function mutation leads to manifestation of oncogene activity with excessive growth promotion -encode growth promoting signaling molecules, cell survival proteins, and transcription factors.
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What is a tumor repressor gene?
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Tumor-suppressor genes. -normally restrain growth. -recessive loss of function mutation leads to excessive proliferation. -encode proteins that put a brake on cell cycle progression, molecules driving anti-growth signals, check piont control proteins.
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What are DNA maintenance or caretaker genes?
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-normally protect genome integrity and their effect is more indirect -if they are inactivated or mutated, cells acquire additional mutaitons at an increased rate - Encode proteins involved in DNA repair.
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Haplo-sufficiency?
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usually one copy of a tumor suppressor gene is sufficient to produce the amount of protein needed to maintain normal cell fuction. Some exceptions...
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Haplo-insufficiency?
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with some tumor suppressor genes, however, half the amount of product is not sufficient for normal cellular function; in this case the loss of just one of the 2 genes can lead to caner. this is the exception to haplo-sufficiency.
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Cancer cells have the ability to grow on their own without the input of other cell's growth factor. Why?
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reduced dependence on exogenous growth stimulation through different strategies. -alteration of extracellular growth signals -alteration of cell surface receptors that transduce extracellular signals -alteration of intracellular circuits translating the extracellular signals. -oncogenes can produce their own growth factors
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oncogenes have autocrine stimulation
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the cancer cell can synthesize its own growth factors. It has autocrine abilities on its membrane to know when it needs to produce more growth. Example - cancer cells do better in a nutrient depleted agar plate then they would in a new plate with lots of nutrients because the old plate contains the cancer's GF's.
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Cancer cells can alter how their receptors respond to extracellular signals. What are 2 mechanisms?
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1. cell becomes hyper-responsive to extracellular levels of growth factors that otherwise would not trigger proliferation. 2. ligand-independent signaling. a structural alteration of the receptor that transduces a signal without ligand binding.
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Mitogen?
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increases cell division
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How do growth factors work?
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a factor that will favor the increase in cell ass by up-regulating biosynthesis of macromolecules, membranes and organelles.
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What is a specific growth factors?
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insulin
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What is a simple way of coordinating cell growth and divison?
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critical cell size thresholds
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Mitogens, generally cause cells to divide they have been found to have other roles depending on the tissue niche. What are those other roles?
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Cell growth Cell survival Cell differentiation Cell migration Growth factors can have other roles too. its not all in the name. its about the tissue where it functions.
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What are anti-mitogens?
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They oppose cell division. They interupt some section of the cell cycle. Can be used as a way of ridding the tissue of a cell you don't want.
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The fate of a cell is controlled by a cell cycle clock that integrates signals from outside and inside. What part of the cell cycle would a cell enter if growth factors and nutrients are not avaliable?
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Go - an reversible stage where the cell can re-enter the cell cycle if its need are met = quiescent state.
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senescence?
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the cell enter Go. IRREVERSIBLE. the cell is dying. However, he mentioned in class that research is currently finding ways to induce post-mitotic cells back into the cell cycle.
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What part of the cell cycle are most liver cells exist in?
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Go. unless damage occurs. then cells will re-enter the cell cycle.
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What stimulates the cell cycle divison?
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-Double the amount of RNA and protein content -Double the amount of chromosomes -Distribution of daughter cells into new cells
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When does the cell decide to replicate genetic material and complete cell cycle? what factors help make this descion?
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end of G1 Nutrients, mitogens, growth factors, cyotstatic factos, extracellular matrix Once cells commit to the cell cycle it is irreversible. regardless of mitogenic factors
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What do cyclin-dependent kinases do?
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- Regulator of the cell cycle! - Abundance does not fluctuate much druing the cell cycle - They never act on their own. - Activity depends on associated regulatory subunits, the cyclin proteins, which fluctuate during the cell cycle. Each part of the cell cycle posses a different form of cyclin - ex. cyclin a, or b, or c ... act by regulating target proteins.
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cyclin: CDK:
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regulatory subunit. (because it cycles) catalytic subunit. (always present in the same concentration)
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When cyclins are associated with CDK's what happens with the cell cycle?
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the catalytic activity of CDK partners.
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When cyclin and CDK are bound how much does enzymatic activity increase?
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400,000 times
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What does D-type cyclins do?
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transduces information from the mircroenvironment via mitogens.
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Besides cyclins. what else regulates cyclin-CDK complexes?
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INK4 proteins. - inhibitors of G1 cycle -very early Cip/Kip CDK inhibitors - are activated throughout the cell cycle. general and promiscus These inhibitors are just another checkpoint used to ensure safe reproduction.
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Remember that when cyclin and CDKs meet up they allow ATP to fit into a pocket created between the two complexes. The inhibitors (INK4 and Cip/Kip CDK inhibitors) are the opposite. So what do they do?
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They don't allow ATP to bind to the complex and therefore slow down the cell cycle tremendously.
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How can cancer drugs use cyclin-CDK inhibitors?
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drugs can cause the over expression of P27 thereby decreasing the ability of ATP to attach to the cyclin-CDK complex. Really works best in the nucleus! unability to do anything in the cytoplasm. So cancer can be the drug by moving the complex to the cytoplasm.
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what do E2Fs do? and what binds them and makes them unavailable for their job?
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E2Fs are synthesize DNA, expressed in late G1. E2Fs are bound by Rbs and are in their inactive state. E2Fs must be free inorder to act. In some breast cancers E2Fs are always freeed and have therefore beat one of the checkpoints in DNA synthesis.
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