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49 Cards in this Set
- Front
- Back
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Cancer:
Tumors 1) Benign - remains _; problem only if/when they grow too large such that normal tissue is impaired - or if they secrete _ or _ 2) Malignant - invasive -_- the spread of tumor cells and establishment of secondary tumors - most malignant cells acquire metastatic features that overcome the _ _ of the tissue |
localized
toxins, hormones metastasis physical boundaries |
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Many different types of cancer:
1) _- from endoderm or ectoderm, gut epithelium, skin and neural epithelia 2) _- derived from the mesoderm, muscle, blood, connective tissues 3) _- a type of sarcoma, white blood cell cancer - also divided into leukemia, lymphoma, and neuroblastomas |
carcinomas
sarcomas leukemias |
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6 properties of cancerous tumors
1. self-sufficient in _ _ 2. insensitivity to _ signals, so they should avoid activating the fast receptor 3. avoids the process _ 4. have unending _ potential like stem cells 5. capable of _ invasion and _ 6. sustain _- formation of blood vessels fig 25.1 |
growth signals
antigrowth apoptosis replicative tissue invasion, metastasis angiogenesis |
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Metastasis occurs when malignant cells:
1) express surface receptors for _ _ components: - collagens, proteroglycans, glycoaminoglycans 2) secrete _ that digest basal lamina proteins 3) produce and secrete _ _ - protease that cleaves plasminogen - convertinig it into _-a potent protease that destroys the basal lamina - allowing malignant cells to metastasize |
basal lamina
enzymes plasminogen activator plasmin |
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Metastasis occurs when malignant cells:
4) Fewer than 1/10000 malignant cells that escape will actually metastasize - these cells need the right _ _ to interact with cells in other tissues 5) Angiogenesis- growth of blood vessels into tumor masses - tumor or neighboring cells secrete: > _ _ _ _ (_) > _ _ _ _(_) > _ _ _ _ (_) - all necessary for the growth of blood vessels into the tumor - _ and _ block new blood vessel growth > antagonistsof the VEGF receptor also block potential anti-cancer treatments |
surface proteins
basic fibroblast GF (bFGF) transforming growth factor alpha (TGFalpha) vascular endothelial GF (VEGF) angiogenin, endostatin |
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Cancer cells have:
- _ nuclei - _ cell body - _ level of cytoplasm bc of rapid division - enlarged _ which are often used as prognostic indicators fig 25.2 Staining pattern is dif in cancerous and non-cancerous cells. fig 25.2 |
big
small low nucleoli |
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Cancers usually originate in _ _
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proliferating cells
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Properties of the Transformed (Cancer) Cell: fig 25.5
1) changes in cell morphology - normal cells are flat and attached to a _, don't grow on top of each other - _ cells look different 2) changes in membrane properties: - cell-to-cell interactions change - acquire the ability to grow unattached to the _ _ 3) Growth control changes - transformed cells have a _ requirement for GFs or ligands aka _ 4) secretion of plasminogen activator - to digest the _ _ 5) cytoskeletal changes - loss of _ MFs 6) staining patterns are dif - due to hyper-active _ of proteins e.g. _ are enlarged |
substrate
transformed basal lamina reduced mitogens basal lamina actin biosynthesis nucleoli |
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ID of cancer-causing mutations:
- Normal mouse NIH/3T3 cells grow to a monolayer in culture - If genomic DNA from a human bladder carcinoma is added to the 3T3 cells, 1/10^6 3T3 cells will take up the mutation and become "_" - this cell loses its _ _ and grows into a "_" or colony - cells from the focus now show many of the same characteristics of the original human cancer cells - Use _ sequences (only in humans, not mice) to clone out the human cancer-causing oncogene (_) fig 25.6 |
transformed
contact inhibition focus Alu rasD |
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The problem with using cell culture vs. human tissues:
- appears as though one gene (_) - in human tissues, loss of only ras is _ _ for cancer - turns out, the 3T3 cells were defective in _ (cyclin kinase inhibitor) were defective - if transfect normal 3T3's, no _ results - ras mutations are found in many human cancers: > most human _ and _ cancers but these cells have other mutations > cancer is a _-_ phenomenon Note: rasD cannot hydrolyze GTP is encoded by an _ while the normal ras is encoded by _-_. |
rasD
not sufficient p16 transformation colon, bladder multi-hit oncogene proto-oncogene |
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Cell culture VS human tissues:
- _ _: appears as though one mutation leads to cancer-like growth (transformation) - not true for _ cell cultures which undergo a limited number of cell cycles - can also culture cancer cells which are already _ - in human tissues, multiple mutations are required for cancer - turns out, immortalized cells already have one or more mutations - cancer: a multi-hit phenomenon |
immortalized culture
primary transformed |
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The Multi-hit Model:
- several mutations are required to transform normal cells 1) evidence: _-incidence of most human cancers rises exponentially with age - if cancer were a one-hit phenomenon, then the incidence of cancer would be _ of age. fig 25.7 |
epidemiology
independent |
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The Multi-hit Model:
- several mutations are required to transform normal cells 2a) _ effects of multiple oncogenes: - _- transcription factor that is required to activate genes necessary for G1 to S-phase transition and over-expression causes cancer - _- signal transducing G-switch protein fig 25.8 2b) another example of synergy: - cell culture this time - over-expression of _ in cultured cells in the absence of growth factors leads to _ -however, apoptosis does not occur if the cells also over-express _, which is a gene that normally blocks apoptosis. e.g. over-express Bcl-2 bad cells surviv - thus, cells that over-express Myc and Bcl-2 proliferate out of control and are often found in human _ and _ |
synergistic
Myc Ras Myc apoptosis Bcl-2 leukemias and lymphomas |
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Because stem cells divide over the life-span of the organism, oncogenic mutations could accumulate leaving to _.
-_- small secreted proteins that bind to surface receptors on certain cells to initiate cellular differentiation. - In the absence of an essential cytokine, a _ cell undergoes apoptosis. |
cancer
cytokines progenitor |
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The Multi-hit Model:
- several mutations are required to transform normal cells: Hematopoietic Pathway in Bone Marrow: - Cytokines secreted by _ cells of the marrow - progenitor cells > _- stem cell that produces granulocytes, monocytes, platelets, erthrocytes, eosinophils > _- stem cell that produces T and B cells of the immune system. fig 21.15 |
stromal
myeloid and lymphoid |
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The Multi-hit Model:
- several mutations are required to transform normal cells 3) Somatic Mutations - colon cancer is well documented in its progression - ras is the 2nd mutation aka _-_ - DCC is the 3rd mutation aka _ _ - p53 is the 4th mutation aka _ _ - All 4 genes usually mutated in human colon cancers so cancer is _-_ phenomenon |
ras
DCC p53 multi-hit |
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The Multi-hit Model:
- several mutations are required to transform normal cells 4) Inherited mutations that increase the risk of cancer - people who inherit a defective _ gene have a single normal gene in their germ line. - If this single normal APC gene were to mutate in somatic colon cells: > incidence of forming polyps rises sharply at an earlier age > the incidence of multiple primary tumors also rises - genetic pre-dispositions to cancer usually involve mutations in _ _ _ _ > both copies have to be defective > the inherited defective allele is not sufficient to cause cancer |
APC
recessive tumor suppressor genes |
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The Multi-hit Model:
- several mutations are required to transform normal cells 5) Intracellular Transducers are products of Proto-oncogenes A) Ras oncogenes - remember Ras- _ _ _, activated by SOS, activates phosphorylation cascade - first _-_ oncogene discovered - substitiution of _ by any AA reduces Ras intrinsic GTPase activity - found in cancers of the bladder, colon, breast, skin, lung. In neuroblastomas and leukemias - Ras has a farnesyl group that anchors it to the inner leaflet of the _ _ - even oncogenic versions of ras need to be anchored - so why not KO the farnesyl transferase with inhibitors |
G switch protein
non-viral Gly12 PM |
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Very important concept in cancer biology:
- _ _ continue to proliferate over the life-span of an organism > can accumulate mutations over time, hence are the type of cell that often gives rise to cancer NOTE: stem cells are undifferentiated, - a given type can differentiate into a given cell type or set of cell types either _ or _ - only embryonic stem cells are _ - cancer requires _ _ that proliferate cells, for survival, etc fig 25.4 |
stem cells
pluripotent unipotent totipotent multiple mutations |
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There are 7 types of proteins that participate in controling cell growth and proliferation: mutations in these contribute to cancer development.
2 out of cell 2 after signaling/in cytoplasm 3 in nucleus 1 after growth and division fig 25.11 |
signal receptor and molecule
intracelluar transducers intracellular receptors transcription factors cell-cycle control proteins DNA-repair proteins apoptotic proteins |
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Proto-oncogenes and Tumor Suppressor Genes:
Proto-oncogenes - promote cell _ - anti-_ proteins, components of signaling and _ _ pathway - mutations are genetically _ Tumor-Suppressor genes - inhibit cell _ - _-promoting proteins, inhibit cell cycle progression - mutations are genetically _ - _ _ are similar to tumor-suppressor genes but involved in DNA repair |
proliferation
apoptotic, signal transduction dominant proliferation apoptosis recessive caretaker genes |
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Oncogenes:
- First discovered in cancer-causing _ - first was called _ _ _ (_)- a retrovirus that infects chickens > genome is simple-only 4 genes > _-_ is the oncogene - RSV transforms bc v-src is over-expressed and is constitutively active by a _ _ _ - v-Src is dominant to c-Src so it is a _-_-_ |
Retroviruses
Rous Sarcoma Virus (RSV) v-Src protein tyrosine kinase gain-of-function |
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Oncogenes:
Some retroviruses do not carry oncogenes, but cause cancer over long latency periods - their provirus integrates near cellular _-_ - _ into promoters and enchancer - for example c-myc gene which gets over-expressed - reason for long latency > provirus insertions are _ > insertion events are random > additional mutations are necessary for cancer to develop (Bcl-2) Some DNA viruses are also associated with tumors: - SV40- usually kills the cell, some transformed cells survive - _-genital warts |
proto-oncogenes
insertions rare papillomaviruses |
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Delayed cancer caused by retroviruses: Pro-virus insertion near c-myc gene:
as an _ or _ insertions |
promoter
enhancer |
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Tumor suppressor genes: protein products inhibit cell cycle progression:
1) cell cycle regulators/nhibitors- _-_ _ (p16) 2) receptors and signal transduction pathways for some specific hormones >_-_ Growth Factor _ (_) which functions to inhibit cell proliferation 3) Cell cycle check pt control proteins (_) 4) Proteins that promote apoptosis (_) and Bax is a proto-oncogen bc it prevent apoptosis. 5) DNA repair enzymes (_ _) 6) (_) also a cell cycle inhibitor/regulator in 1 but very important - Mutations in Tumor Suppressor genes are _ > both alleles need to be mutated to promote tumor formation > considered to be loss-of-function - no protein product made - or protein with no function made |
cyclin-kinase inhibitors
tumor-derived GF beta (TGFbeta) p53 Bcl-2 caretaker genes Rb recessive |
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Tumor suppressor genes: protein products inhibit cell cycle progression:
_ (_) was first characterized - hereditary genes for it causes retinal tumors early in life usually in both eyes > inherit one copy of RB gene then are more likely to develop cancer at young age > a second _ _ in the one normal RB gene is required for tumor development - therefore, RB mutations are recessive, - but the predisposition for retinal tumors in children is inherited as an _ _ _ _ _ - both Rb alleles were inherited as normal wild type genes - but over time, both alleles have been mutated in retinal cells - occurs later in life - usually affects one eye |
Retinoblastoma (Rb)
somatic mutation autosomal dominant trait sporadic retinoblastoma |
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Tumor suppressor genes: protein products inhibit cell cycle progression:
(_) behaves somewhat like RB - it is a tumor suppressor gene - same hereditary predisposition for _ _ - women who inherit a defective copy have 60% chance of contracting breast cancer _ and colon cancer already discussed is also tumor suppressor |
BRCA1
APC |
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Tumor suppressor genes: protein products inhibit cell cycle progression:
Loss of Heterozygosity (LOH) can occur during _-_ or _ _ - allows cells to proliferate better but can fix itself in cell population - rare to get mutation in 2nd copy but very likely to be fixed later on |
mis-segregation
mitotic recombination |
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Cell circuitry that is affected by cancer-causing mutations:
fig 25.15 - signal transduction pathways for proliferation get _ - pathways that prevent cell proliferations get _ - pathways that promote apoptosis get _ - pathways that repair DNA get _ - Ras in transduction pathways bc it promotes cell proliferation through the _ _ pathway which activates early-response genes like _ - Rb, tumor suppressor found activated in cancer bc it inhibits entry into _-_ so it inhibts the E2F transcription factor - p53, most important protein for cell proliferation, involved in _-_ response pathways that causes cell cycle arrest for cyclin-dependent kinase and can lead to apoptosis - Like with RAS we have the RTK involved in _, _, and _ - Bax promotes cell _ - Bcl 2 promotes cell _ |
activated
deactivated inactivated inactivated MAP kinase MEK S-phase DNA-damage JUN, Fos, and Myc survival death |
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Oncogenic Mutations Affecting Cell Proliferation:
1) Ligands- only one example known in which a ligand is the _ _- the sis gene encodes a type of (_) 2) receptor tyrosine kinases and cytokine receptors/JAK tyr-kinases are often invovled a) _ is the normal ligand to signal the differentiation of erythroid progenitor cells - gp55 produced from spleen focus-forming virus > causes Epo receptors to _ > mimics ligand binding and acts as an _ fig 25.18 - Point mutations or deletions could also cause RTKs to act constitutively in the absence of ligand. > _ normally binds EGF-like ligands but point mutation in its transmembrane domain causes the receptor to dimerize in the _ or ligand > deleted version of EGF receptor dimerized in absence of ligand fig 25.16 |
oncogene product
PDGF erythropoeitin dimerize agonist Her2 absence |
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Oncogenic Mutations Affecting Cell Proliferation:
chromosomal translocation combines two genes to produce a fusion protein - parts of 2 chromosomes exchange with each other giving you 2 _ _ - coiled coil portion of _ now dimerizes the Trk kinase domains > mimics ligand binding > fusion resides in the _ > phosphorylates the wrong _ fig 25.17 |
mutant chromosomes
tropomyosin cytoplasm proteins |
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Oncogenic Mutations Affecting Cell Proliferation:
3) Intracellular Transducers are products of Proto-oncogenes: A) Ras oncogenes - Ras, switch protein, activated by _, activates phosphorylation cascade - first _-_ oncogene discovered - substitution for _ by an AA reduces Ras intrinsic GTPase activity - Ras has a farnesyl group that anchors it to the _ leaflet of the PM B) GAPs (GTP-activating protein): proteins that accelerate the hydrolysis of _ by Ras to inactive RAS - must have mutated copy of both alleles to have mutation effects - _ gene encodes a GAP - Mutations in NF1 cause Ras to remain active in sheath cells that surround _ _ - leads to neurofibromatosis benign tumors of the sheath cells - mutations are _ like the Rb mutations - but the propensity is inherited as an _ _ like RB |
SOS
non-viral Gly12 inner GTP NF1 nerve cells recessive autosomal dominant |
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Oncogenic Mutations Affecting Cell Proliferation:
3) Intracellular Transducers are products of Proto-oncogenes: c) c-Src is another protein of Tyr kinase, but with _ and _ domains (adapter proteins) - Tyr527 is phosphorylated to _ Src, so SH2 domain binds it which inhibits kinase function - Removal of phosphate from Tyr527 activates Src - In oncogenic Src proteins, Tyr527 is usually _ - v-Src was the first oncogene discovered; missing the last 18 AAs; therefore is was constitutively _ = no phosphorylation of Tyr so it can't inhibit itself. fig 25.19b D) The Philadelphia chromosome and chronic myelogenous leukemia - Translocation results in a fusion of the _ gene with the _-_ gene (kinase) -Imatinib = Gleevec was the first cancer drug targeting signal tranduction protein of tumor cells fig 25.20 - N terminus of bcr protein forms _ _ - c-Abl is a protein Tyr kinase that normally resides in the _ - Bcr-Abl fusion protein forms tetramers that reside in the cytoplasm > erroneously phosphorylates cytoplasmic proteins- _ and _ - all in the absence of GFs - translocation and production of Bcr-Abl fusion is not enough: second mutation (_) is necessary for acute leukemia - Gleevac/Imatinib inhibits _ _ to target a signal transduction protein unique to tumor cells |
SH2, SH3
inactivate missing active bcr c-abl coiled coils cytosol JAK2, STAT5 p53 Abl kinase |
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Oncogenic Mutations Affecting Cell Proliferation:
4) Transcription Factors encoded by oncogenes: - Myc, Fos, and Jun are encoded by _ _ genes - both are transcription factors needed to activate delayed response genes then encode: > _ _, _#/#, and other growth-related products - normal c-Fos and c-Jun sometimes associate to form a heterodimeric transcription factor called _-#, a major transcriptional activator protein fig 25.22 Stimulation of c-Fos and c-Myc proteins by PDGF we see c-Fos drop quickly and c-Myc drops more slowly so it is needed for _-_ transition |
early response
D Cyclins Cdks4/6 AP-1 G1-S |
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Oncogenic Mutations Affecting Cell Proliferation:
4) Transcription Factors encoded by oncogenes: - Both c-Fos and c-Myc proteins and their mRNAs are _ so you lose these two rapidly - prolonged presence of active proteins would be _ - tumor promotion by over-expression of wild-type proteins, or expression of unregulated mutant versions. e.g. _ _- myc gene is translocated and activated by antibody gene enhancer (_ _) |
unstable
oncogenic Burkitt's lymphoma B cells |
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Oncogenic Mutations in Cell-Cycle Control Genes
1)D-type cyclins are the first cyclins produced in mammalian G1 after mitogen stimulation: - D-type cyclins associate with _ and _ - form a catalytically active kinase that phosphorylates _ protein (_) - positive feedback loop at _ _ so cant get past it - 3 D-type cyclins D1, D2, D3 - Cyclin D1 is encoded by a _-_: >over-expression due to a translocation in antibody-producing B cells, or amplification of D1 gene: e.g. breast cancer - if mitogens are removed before positive feedback loop kicks in, Cdk inhibitors block cyclin D/Cdk4 or 6 - inhibitors are _ and _ (tumor suppressor genes) - deletion of p16 mimics over-expression of cyclin D > leads to hyper-phosphorylation of Rb thus tumor progression |
Cdk4, Cdk6
retinoblastoma (Rb) restriction point proto-oncogene p27 p16 |
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Oncogenic Mutations in Cell-Cycle Control Genes
2)Retinoblastoma (Rb) - binds a small family of transcription factors to inhibit them (_) - Rb-E2F at first is a transcription _ - when Rb is phosphorylated by G1 cyclin-dependent kinase at the restriction pt, it releases E2F which then activates genes for _-_ - loss of Rb leads to many types of cancers - loss of Rb can occur by interaction with viral proteins > E7 of papillomavirus > Large T antigen of SV40 |
E2F
repressor S-phase |
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Oncogenic Mutations in Cell-Cycle Control Genes
2)Retinoblastoma (Rb) - either over-expression of D-cyclins (_ _ -_-_) promotes cell proliferation or elimation of p16 or RB (_ _-_-_) aka tumor suppressors can lead to cancer fig 22.25 |
dominant gain-of-function
recessive loss-of-function |
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Tumor-derived growth factor beta (TGFbeta): inhibits cell proliferation:
- secreted by most body cells - inhibit growth of many cells - loss of TGFbeta could result in _ _ - Types I and II TGFbeta receptors which are kinases that phosphorylate... - _ and _ are activated/phosphorylized and made into dimers that go into nucleus and function as transcription factors - activate genes for _ _ _ (_)- breaks down extracellular matrix and p15 that inhibit cell cycle fig 25.24 |
tumor formation
smad 3 and smad 4 plasminogen activator inhibitor (PAI) |
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Tumor-derived growth factor beta (TGFbeta): inhibits cell proliferation:
p15, G1 cyclin-kinase inhibitor - when expressed, it displaces p27 on _-_ _ - p27, now freed, binds to Cdk2-Cyclin E to block entry into _-_ and cell cycle arrested in G1 |
Cdk4-cyclin D
s-phase |
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Genome Stability and Cancer
- many cancer cells lack DNA repair mechanisms; therefore, mutations _ - one repair mechanism involves p53 which functions as a _ _ _ for damaged DNA - In normal cells, p53 is very _ (Ub)- thus found in low amts - p53 is activated (stabilized) by stressful conditions like gamma irradiation, heat, and low oxygen which all cause DNA damage which activates _ _ which phosphorylates p53 so it cannot function with mdm2 and functions as a _ _ to activate cyclin kinase inhibitor genes |
accumulate
G1 check pt unstable ATM kinase transcription factor |
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p53 has several functions:
- transcription factor for _ gene which binds to and inhibits Cdk-cyclin complexes - cells with damaged DNA arrest in _ and without p53 this damaged DNA could be replicated - once damaged DNA is repaired, _ is phosphorylated and _ levels fall and cell resumes cycle by entering S-phase |
p21
G1 p53 and p21 |
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If p53 is activated for a long period of time and you have accumulation, this promotes _
- DNA damage is too severe to repair - best if cell dies - programmed cell death involves regulated (_) that releases caspase activators by the _ - caspases are _ _ that kill the cell |
apoptosis
Bcl-2 mitochondria cytosolic proteases |
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p53 also functions at the G2 to M-phase transition
- again using p21 to block _ _/_-_ complexes p53 works as a tetremer, transcription factor - if one of both alleles are mutated, the tetramer complex is likely not to work > contains at least one non-functional subunit - defective allele is functioning as a "_ _" |
cyclin A/B-Cdk1
dominant negative |
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MDM2 binds to N terminus of p53
- blocks p53's transcriptional activation of _ - and makes p53 _ - _ kinase phosphorylation stabilizes p53 by displacing MDM2 in the presence of DNA damage |
p21
unstable ATM |
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Carcinogens: Cancer-causing chemicals:
- benzo(a)pyrene- in cigarette smoke is converted into a: > powerful _ > causes G to T transversions in codons of p53 gene - aflatoxin, found in molds- G to T in codon |
mutagen
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Carcinogens: Cancer-causing chemicals and other DNA Repair genes:
Xeroderma pigmentosum- XP DNA repair genes: - _ _ disease - senesitive to UV light - high incidence of skin cancer - can't repair DNA damage caused by UV > _ _ mechanism is defective > seven different human genes involved (XPgenes) Hereditary non-polyposis colorectal cancer - inherited predisposition to cancer - loss of function mutation in human so they are tumor suppressor - loss of heterozygosity= loss of _ _ _mechanism so there is an accumulation of mutationsin oncogenes |
autosomal recessive
excision repair mismatch DNA repair |
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Cancer cells express telomerase which most _ _ do not
- If they are shortened greatly, then you go through _-_-_ cycle fig 25.30/25.31 |
somatic cells
breakage-fusion-bridge |
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Promoter DNA methylation inhibits _ _ and can play a role in cancer
- p16 gene is found hyper-methylated or turned off in lung cancers |
gene expression
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