Term
| What are the stages of cancer? What are the three things that are looked at? |
|
Definition
Tumor size, Lymph nodes, Metastasis
Stage 1: small, no lymph
Stage 2: moderate, lymph
Stage 3: large, lymph
Stage 4: large, metastasis |
|
|
Term
| How do you can you tell the degree of differentiation of the cancer? (Low grade vs high grade) |
|
Definition
Low grade cancers look similar to the tissue that they are derived from
High grade cancers show a large degree of morphological changes from the tissue of origin |
|
|
Term
| What test can be used to test cancer cell division? |
|
Definition
PCNA can identify cells that have high replication activity.
-Aneuploidy also indicated aggressive tumors |
|
|
Term
| How can antibodies be used to test if cells are cancerous? Give an example of how this is helpful |
|
Definition
Antibodies against growth factors, integrins, and cell adhesion factors can be made.
Example: Metastatic cancers over express alpha v beta 3 integrin
Example: Breast cancers over express her2, growth factor receptor |
|
|
Term
| What antigen can be tested for in the blood of ovarian and prostate cancer? |
|
Definition
Ovarian cancer: CA-125 glycoprotein can be tested for
Prostate caner: PSA- prostate specific antigen -- however there are high false positives and negatives |
|
|
Term
| How can RT-PCR be used to detect cancer? |
|
Definition
| Epithelial cancer cells make cytokeratin intermediate that is not in normal cells, mRNA can be changed to cDNA and amplified |
|
|
Term
| What are the main treatments of cancer? |
|
Definition
| Surgery, radiation, chemotherapy |
|
|
Term
| What do most treatments of cancer aim to do? |
|
Definition
Target the DNA of rapidly dividing cells that have lost proper checkpoints, the cells will enter S phase and will try to replicate, permanently damaging the genome
-normal cells with the damage will not pass the checkpoint and will repair the damage |
|
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Term
| What do Alkylating Reagents do? Examples |
|
Definition
-nitrogen mustard
-cyclophosphamide
-cisplatin
They are electron poor molecules that attack nucleotides (mainly guanosine) and form crosslinks and adducts
-normal cells with this damage will not enter S phase |
|
|
Term
| What are Antimetabolites? |
|
Definition
| Inhibit synthesis of nucleotides that are needed during S phase |
|
|
Term
|
Definition
Antimetabolite
A derivative of folic acid- competatively inhibits the enzyme DHFR that is needed for puridine and pyrimidine synthesis |
|
|
Term
| What is 5-FU? What is Gemcitabine? |
|
Definition
An antimetabolite- inhibitor of the pathway that changes dUMP to dTTP
Gem- similar to 5-FU, only extends life span by one month |
|
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Term
|
Definition
A natural product used to treat cancer from fungi.
-Multi-ringed
-Goes in between bases of DNA to cause partial unwinding
-inhibits topioisomerase
-It has strong effects on cells in S phase |
|
|
Term
| What is Viscristine? What is Taxol? |
|
Definition
It is a plant alkaloid, natural product. Inhibits microtubule polymerization
-Affects cells in G2, no microtubule rearrangement
Taxol- also affects microtubles- stabilizes them and prevents breakdown in G2 |
|
|
Term
| What are some of the side effects of chemotherapy? |
|
Definition
Some cells in the body are naturally rapidly dividing such as hair folicals, epithelial cells, and bone marrow and stem cells.
-hair loss, diaherra/ulcers, anemia |
|
|
Term
| What is hormone therapy and how is it used? What is one issue with it? |
|
Definition
Hormone therapy can be used to interfere with the hormone release of estrogen dependent breast cancer in women and Androgen dependent prostate cancer in men.
--Either use inhibitors of steroid hormones that prevent the signal from the pituitary gland to release hormone
--Drug treatment that blocks receptors
-Toxic to sexual function |
|
|
Term
| What is Taxomifen? How can it be used in hormone therapy? |
|
Definition
4-OHT, it is a drug that outcompetes estrogen for the receptor
-Taxomifen binds to the receptor that binds to DNA and changes the co-activators of transcription so the genes are not turned on |
|
|
Term
| What was the main idea of the Quintana Paper? |
|
Definition
Tumor formation by single human melanoma cells- Tumor stem cell model
-used NOD/SCID IL2 -/- mice
-took cells from 7 patients and looked for tumor in mice, very rare
-no surface markers were able to explain differences in tumorenicity |
|
|
Term
| What is a tumor stem cell? |
|
Definition
Tumor stem cells have tumor forming activity when placed in another host.
These cells rarely divide to give rise to transit amplifying cells |
|
|
Term
| What is a SCID/NOD IL2-/- mouse and why is it used? |
|
Definition
NOD is non-obese diabetic and SCID is severe combined immunodeficient-- does not produce B or T cells
IL2 deficient mice cannot produce Natural Killer cells
These mice will not reject grafts |
|
|
Term
| What is matrigel and how was it used in Quintana paper? |
|
Definition
| A laminin rich basement membrane- increase melanoma tumorigenicity |
|
|
Term
| What is the clonal progression model? |
|
Definition
| One normal cell develops a mutation that gives it a growth advantage. A cell in the group with the advantage develops a further mutation that allows for a bigger more aggressive clone. Process occurs until metastasis occurs |
|
|
Term
| What are the features of the tumor stem cell model? |
|
Definition
Tumor stem cells divide only rarely
They are a small minority of cancer cells
The majority of cells are the aggressive transit amplifying cells
Tumor cells and transit cells have the same genotype but express different genes
Only tumor stem cells can form tumors when transplanted into another animal |
|
|
Term
| What is FACS and how can it be used? |
|
Definition
Flourescence Activated Cell Sorter- cells are treated with different flourescent tagged antibodies against surface markers
- Once separated by surface markers, cells can be grafted to mice to see which markers correspond to tumor growth |
|
|
Term
|
Definition
Acute Myelogenous Leukemia. The tumor cells and can be sorted by minority and majority based on surface makers.
Minority cells could lead to tumor formation in mice- majority could not.
--AML is formed by a small population of self-renewing stem cells that give rise to large populations of more differentiated leukemia cells--these cells lack the ability to divide and produce more tumor cells in animals |
|
|
Term
| How does breast cancer follow the tumor stem cell model? |
|
Definition
Breast cancer cells expressing high High CD44 and low CD24 were able to form tumors in mice.
High CD24 cells were not. |
|
|
Term
| How does brain tumors follow the tumor stem cell model? |
|
Definition
Tumors express CD133 on their surface- this constituted 15% of tumor cells. Acted as tumor stem cells when injected.
CD133 low led to no tumor formation. |
|
|
Term
| What is Docetaxel? How is it used? |
|
Definition
Used in a study of prostate cancer- relative of taxol that disrupts microtubules. The cancer stem cells were resistant to docetaxel.
STEM CELLS- The resistant cells over express Hedgehog and Notch receptors (important for the renewal of tissue).
USE of drugs to inhibit notch and hedgehog led to inability for these cells to form tumors in mice. |
|
|
Term
| What is the main theme of the Weaver paper? |
|
Definition
Looks at the micro-environment of the cancer
Beta4 integrin-dependent formation of a 3d architecture confers resistance to apoptosis for both normal and malignant cells
-lamin-1 is used
-study mammary epithelial cells (HMT-3522)
-Normal was S-1
-Tumor cells T4-2
-Tested with apoptotic agents, chemical and immune |
|
|
Term
| In the Weaver paper, what type of integrin to T4-2 cells express? |
|
Definition
T4-2 express beta-1 integrin all over surface that prevents basal / apical polarity
-Treatment of cells with Beta1 antibody, that blocks beta1- reverts to polarized structure and are resistant to apoptosis |
|
|
Term
| What was used in the Weaver paper to disrupt S-1 cell polarity? |
|
Definition
| Antibody to disrupt E-cadherin- show no basal polarity and are sensitive to apoptosis |
|
|
Term
| What does NFkB do for cells and where is it found? |
|
Definition
| Beta 4 integrin is essential for NFkB activation...NFkB promotes the transcription of anti-apoptotic genes |
|
|
Term
| What are hemidesmosomes and how do they help with cell polarity? |
|
Definition
Hesmidemosomes help establish cell polarity by connecting the basal side of the cell to the basal lamina
, NFkB activation for anti-apoptotic genes Disruption hinders polarity |
|
|
Term
| How can T4-2 cells regain polarity? |
|
Definition
| In 3D acini formation, blocking the B1 integrin with an antibody against it allows for normal B4 expression leading to hemidesosome directed polarity, activation of NFkB |
|
|
Term
| What is epithelial to mesenchymal transition? |
|
Definition
| Damaged tissues must be repaired- surrounding epithelia of wound must undergo reversible EMT |
|
|
Term
| hat are Mesenchymal cells? |
|
Definition
| They are motile, non-polarized, resemble fibroblasts |
|
|
Term
| What is released during wound healing? |
|
Definition
| Fibrin proteins clot, matrix metalloprotease release, activation of TGF-beta, release of PDGF |
|
|
Term
| What is vimentin and what does staining show? |
|
Definition
| Vimentin is an intermediate filament expressed my cells undergoing EMC as they move to fill a wound. Vimeten is no longer expressed when the wound is healed. |
|
|
Term
| What type of cadherins do EMT cells produce? What does this loss do? |
|
Definition
Stop producing E-cad and start producing N-cadherin
Loss of E-cadherin means that Beta-cat can enter the nucleus and transcribe cell division factors (mimics loss of APC) |
|
|
Term
| How to cancer cells resemble EMT? |
|
Definition
| They have lost polarization, alter cadherin expression, migrate, attract different stromal cells |
|
|
Term
| What is the mammary gland made up of? Where does it start? |
|
Definition
The mammary gland is made of specialized ductile epithelium that grows by invading into the fatty breast stromal connective tissue.
They start at the nipple
-Epitherlial cells that line the mammary duct system form a single layer of tubules
-These are surrounded by myoepithelial cells
-Then basement membrane |
|
|
Term
| What is signaled in the mammary epithelial ducts to avoid branches running into each other? |
|
Definition
|
|
Term
| Where does breast cancer occur? |
|
Definition
In the epithelial cells surrounding the ducts
-Tamoxifen can help if the tumor is estrogen sensative |
|
|
Term
| What do myoepithelial cells secrete that promote polarization of epithelial cells in mammary ducts? |
|
Definition
| Lamin-1 is secreted to promote polarization |
|
|
Term
| What did Bissel find that T4-2 tumor cells overexpressed? |
|
Definition
Beta-1 integrins, involved in besolateral surface binding as well as increased EGF receptors
--If blocked, normal growth could occur |
|
|
Term
| What is the role of the Extracellular matrix (ECM)? |
|
Definition
Provides
-signals (cell proliferation/differentiation)
-support (cell morphology)
-strength (cell adhesion)
-organization
-many different forms
-migration |
|
|
Term
| What is the ECM's role in cancer? |
|
Definition
Cancer cells must change their interaction with the ECM
-Must activate enzymes to allow them to chew through the matrix |
|
|
Term
|
Definition
-Basal lamina= basement membrane
-Loose connective tisuse
-Hard Connective tissue |
|
|
Term
|
Definition
| Carbohydrates, fibrous proteins, adhesive glycoproteins |
|
|
Term
|
Definition
Glycosaminoglycans that are the carbohydrates of the ECM
-form loose hydrated gels |
|
|
Term
| What are the fibrous proteins of the ECM? |
|
Definition
| Collagen, Laminin- (basal lamina) |
|
|
Term
| What do the adhesive glycoproteins of the ECM do? |
|
Definition
Glycoproteins link cells to the ECM
EXAMPLE: fibronectin |
|
|
Term
|
Definition
Integrins are transmembrane heterodimers that consist of a beta and alpha unit that link the cytoskeleton the ECM for movement, adhesion and morphology!
-Different alpha and beta combos specify different binding attachment factors |
|
|
Term
| What do the cytoplasmic domains of integrins do? |
|
Definition
| Cytoplasmic domains interact with microfilaments or intermediate filaments |
|
|
Term
| What is FAK? How does it relate to integrins? |
|
Definition
FAK is focal adhesion kinase, it is a tyrosine kinase that can be activated by certain integrins.
-It interacts with src tyrosine kinase to transduct events that are important for cell survival and division |
|
|
Term
| What integrins are found on the basal side of normal epithelial cells? What is different in cancer cell? |
|
Definition
Normal have a3B1 and a6B1- allows interaction
Cancer cells have integrins all over taking away polarity- any side can interact with basal lamina |
|
|
Term
|
Definition
| It is an integrin that is expressed a low levels in normals cells and high levels in cancer cells --It has a very broad specificity allowing it to bidn to any of the glyoproteins, allowing cancer cells to migrate It can also bind to metalloproteases to digest the ECM |
|
|
Term
| What happens to E-cadherin and N-CAM expression in cancer cells? What does that lead to? |
|
Definition
E-cad and N-CAM provide cell-cell contact
-In cancer they are lost and promote metastasis |
|
|
Term
| What is the main idea of the O'Reily paper? |
|
Definition
Endostatin is an endogenous inhibitor of angiogensis and tumor growth
-Used EOMA cell line
-First thought angiostatin was the inhibitory molecule
-Used HPLC high performance liquid chromatography to isolate inhibitory molecule
-Found C-terminal fragment of Collagen XVII to be the inhibitor
-Regression of tumors in mice after infected with recombinant Ecoli vector with endostatin |
|
|
Term
|
Definition
Formation of new blood vessels to supply cells with nutrients and oxygen
- cells must be within 0.2mm of a capillary or they will become hypoxic |
|
|
Term
| What does endostatin do to inhibit endothelial growth ? |
|
Definition
Endostatin binds to integrins to alter cell and ECM interactions
-Blocks VEGF receptor 2
-Alters wnt signaling
-Blocks cell cycle in G1 |
|
|
Term
| How can the regression of tumors after endostatin treatment be explained? |
|
Definition
| Recently formed endothelial cells express Fas death receptors that mature endothelial cells do not-- leaving them more sensitive to endostatin treatment |
|
|
Term
| What signals are used to initiate angiogenesis? |
|
Definition
|
|
Term
| What happens to hypoxia inducile factors in response cells in normal oxygen conditions? |
|
Definition
HIF-1a and HIF-1b- under normal conditions proline hydroxylase uses O2 to convert two prolines on HIF-1alpha to hydroxyprolines
-pVHL recognizes the hydroxyprolines and targets it for degradation |
|
|
Term
| What happens to HIFs under hypoxic conditions? |
|
Definition
| Proline hydroxylase cannot work and HIF-1a is stabilized. HIF-1a binds to HIF-1b and they turn of genes that signal VEGF |
|
|
Term
|
Definition
| Induce cell division as well as matrix protease and integrins and adhesion for capillary formation |
|
|
Term
| What is the difference between capillaries in tumors and normal tissues? |
|
Definition
| Capillaries in tumors are leaky, poorly organized, and have loose associations with pericytes |
|
|
Term
| What is thrombospondin? (TSP) |
|
Definition
It is an anti-angiogenic protein. Usually bound to the surface of endothelial cells to a receptor CD36
-causes the release of Fas Ligand that binds to Fas receptor on newly formed cells |
|
|
Term
| What is a Avastin and what does it do to VEGF? |
|
Definition
| A monoclonal antibody that binds to VEGF and blocks its function. |
|
|
Term
| What are metalloproteases? What is an exampe of one? |
|
Definition
| They require Zn2+ or Ca2 for their activity. MMP1- collagenase, MMP3 stromelysin |
|
|
Term
|
Definition
Plasminogen activator that is secreted by stromal cells and tumor cells.
Binds to uPAR on cancer cells- cleaves other inactive proteases to activate them for degradation of the ECM |
|
|
Term
| What are capillaries made of? What are they surrounded by? |
|
Definition
| They are made of endothelial cells that are surrounded by basal lamina and pericytes |
|
|
Term
| What are the three phases of angiogenesis? |
|
Definition
1. Hypoxic cells produce growth factors that cause a sprout of nearby cells and blood vessels
2. Endothelial precursor cells are recruited
3. Growing spouts of endothelial cells digest their way through ECM, reform basal lamina
4. Multiple sprouts occuring in the region fuse to form a capillary bed |
|
|
Term
| What is the main theme of the Bodnar paper? |
|
Definition
Extension of life span of cells by the introduction of temlomerase
hTRT- catalytic subunit
hTR is the RNA component used to recognize the complementary 3' end
-Telomerase only found in germline cells
-Used RPE-340 reitnal pingment epithelial cells
-BJ-Foreskin Fibroblast cells |
|
|
Term
| What are the main ideas of the Tabin paper? |
|
Definition
Tabin- trying to find the mechanims of activation of the human oncogene
-cloned EJ from human bladder cell
-pEC does not have transforming activity
-Ha-Ras protein and mRNA levels were the approx the same in each
-Used a cut and swap method for plasmids to isolate gene
-Found a single mutation at Gly 12- leading to constitutively active Ras because GTP cannot be changed to GDP |
|
|
Term
| What are the main ideas of the Donehower paper? |
|
Definition
Mice that re deficient of p53 develope normally but are susceptible to spontaneous tumors
-over expression of p53 leads to G1 arrest
-mice lacking p53 develop normally but have extremely high rates of malignant tumor formation |
|
|
Term
|
Definition
It plays a role in the check point system of the cell cycle
- arrests cell cycle and blocks proliferation if DNA damage occurs
-Promotion of apoptosis
-inhibition of oncogenes |
|
|
Term
|
Definition
p53 is usually degraded by mdm2 through ubiquitnation
-DNA damage leads to activation of a kinase that phosphorylates p53 and causes it to separate from mdm2
-active p53 enters nucleus and promotes transcription of proteins such as p21- a G1/S cyclin-cdk inhibitor |
|
|
Term
| What is a tumor supressor? |
|
Definition
| Loss of function leads to tumor formation |
|
|
Term
| What are the stages of the cell cycle and what are they dependent on? |
|
Definition
| Go, G1, S, G2 and M-- they are dependent on cyclin dependent kinases to move them to the next step |
|
|
Term
| What is the Restriction site in G1? |
|
Definition
| Step at which the decision to enter the cell cycle is made |
|
|
Term
| What is the checkpoint at the G1 phase? |
|
Definition
| At the G1 before entering S phase the cell must see that there is no DNA damage- it must be repaired before it can go to the next phase |
|
|
Term
| What is the checkpoint as the cell leaves the S phase? |
|
Definition
| It must see that DNA has been completely replicated |
|
|
Term
| What is the checkpoint in mitosis? |
|
Definition
| All mitotic spindles must be in place for anaphase to occur |
|
|
Term
| What are CIPs and INK4s? What do they do in relation to the cell cycle? |
|
Definition
CIPs are cyclin inhibitory proteins that are activated after DNA damage to shut down the cell cycle
ex: p21, p27, p57- bind to cyclin CDK complexes
INK4s are inhibitors of kinase (p15, p16,p18, p19) They inhibit CDK4 and CDK 6-- that interact with cyclin D-- binds to the CDK receptor adnd lowers affinity for cyclin D to halt the cell cycle |
|
|
Term
| What is the role of the Rb protein in the cell cycle? |
|
Definition
It plays a role in the decision making to move past the restriction point
-phosphorylation of Rb changes during different times of the cell cycle |
|
|
Term
| What are the different stages of phosphorylation of Rb? |
|
Definition
G1- hypophosphorylated with a single phosphate in G1
---repressing E2F that promotes cyclin E and A synthesis
Late G1--R point- hyperphosphorylated
---Rb releases E2F
End of mitosis- rapdily dephosphorylated |
|
|
Term
| What does Mdm2 do in regard to p53? |
|
Definition
Mdm2 represses p53 activity to keep the cell cycle going.
-it marks p53 for degradation |
|
|
Term
|
Definition
| It is stabilized by phosphorylation after DNA damage that activates ATM kinase |
|
|
Term
| How does the assembly of p53 effect the way one bad copy acts as dominant? |
|
Definition
| p53 assembles as a tetramer. All four parts must be functional in order to bind to DNA correctly- 15/16 will not work properly and the majority of function is disrupted |
|
|
Term
| How does p53 activated apoptitic pathways and what is apotosis? |
|
Definition
Extended activation of p53 leads to activation of the apoptitic pathway.
Apoptosis is programmed cell death- better than necrosis because it could activate an immune response leading to inflammation
-cytochrome C and Smac/DIABLO are released |
|
|
Term
|
Definition
| They are activated during apoptosis, when they leave their procaspase form by cleavage of proteases |
|
|
Term
| What is the Lin paper central theme? |
|
Definition
MicroRNA polycriston as a pontential human oncogene
-mir-17-92 pri-miRNA targets tumor suppressors for degradation |
|
|
Term
| What is the myc oncogene? |
|
Definition
| A transcription factor that is activated by mitogenic signaling-- it activated transcription of protein that promote entry into the cell cycle |
|
|
Term
| What are microsatellites? |
|
Definition
| Tandmm repeats of nucleotides that DNA polymerase struggles to correctly replicate |
|
|
Term
| What is Direct Reversal Repair? |
|
Definition
| Special enzymes recognize the base and directly repair the modification |
|
|
Term
| What is Base excision repair? |
|
Definition
| Minimal helix distorting effects- cleavage of base and repair by DNA polymerase |
|
|
Term
|
Definition
Repair of small insertions or deletions
Msh6 and Msh2 bind to the new strand with mismatch--recruit pms1 and m1h1 |
|
|
Term
|
Definition
| Inability to do mismatch repair do to a mutation of either msh2 or msh1 |
|
|
Term
| How can microsatelitle instability cause truncation of the TGF-beta receptor? |
|
Definition
| There is sequence within the receptor that has repeating adenosines |
|
|
Term
| What is the main idea of the Fishel paper? (HNPCC) |
|
Definition
Homolog MSH2 mutation and it's association with hereditary nonpolyposis colon cancer
-it is autosomal dominant
-M2H2 is lost- it is part of the mistmatch repair pathway- cannot bind MlH1
-DNA polymerase has trouble replicating microsatellites so mismatch repair must fix it
-Found a T to C mutation at MSH2
-No experiments looking at splicing of mRNA or mRNA levels of MSH2 proteins in tumors |
|
|
Term
| What proteins are created in the human adenovirus? |
|
Definition
| E1A binds to Rb to inhibit function and E1B binds to p53 to inhibit function |
|
|
Term
| What proteins are created in HPV to promote cancer? |
|
Definition
E6 and E7, E7 binds and inactivated Rb, E6 binds to p53
E2-- function is lost and cannot repress E7 and E6 |
|
|
Term
| What is the central idea of the Bodnar? |
|
Definition
Extension of Life Span introduction f telomerase into normal human cells
-T-loops for stability
-lagging end loses bases where RNA primer is
-hRT- RNA template
-hTRT- catalytic subunit with telomerase activity
-telomerase in the germ line cells
-RPE-340
-BJ Foreskin fibroblast
-TRAP assay |
|
|
Term
| What is Multi-drug resistance? |
|
Definition
Cancer cells express P-glycoprotein, an ATPase pump that uses ATP hydrolyis energy to drive it
-It can drive small molecules out of th cell bind nonspecific binding
-lowers levels of drug in the cytoplasm |
|
|
Term
| How can cancer cell avoid drugs? What can they over express to do so? |
|
Definition
Point mutations so the drug cannot bind
or
The can increase the expression of DNA repair enzymes to make cells resistant to DNA damage by crosslinkers |
|
|
Term
| What is oncogene addiction? |
|
Definition
| Some cancers require the oncogene for initial formation and continued growth of the tumor |
|
|
Term
| What is Gleevec and what is it commonly used to treat? |
|
Definition
Gleevec is used for the Bcr-abl oncogene that is caused by a chromosomal translocation that leads to a bcr-abl fusion protein
-this protein has hyperactive kinase activity
-common in CML
-Gleevec binds to the ATP domain of abl to inhibit it |
|
|
Term
| What is is Tarceva used to inhibit? |
|
Definition
Tarceva was used to inhibit a tyrosine kinase, the EGF receptor
-taking the drug leads to inhibition of oncogene activity but the cancer is not gone. The person must remain taking the drug to stop cells from dividing |
|
|
Term
| What is AMN107 and how does it relate to Gleevec? |
|
Definition
AmN107 is a tyrosine kinase inhibitor that binds even more tightly to the ATP domain of the BCR-ABL protein to inhibit function
-It is used for patients that have developed a point mutation that makes the oncogene resistant to Gleevec |
|
|
Term
| What are BaF3 cells and how are they used to anticipate drug resistance? |
|
Definition
BaF3 cells are Pre-B lymphocytes to which a BCR-ABL Ecoli plasmid with a high mutation rate is transfected into to create a cell addicted to the oncogene for division
-Retroviruses infect the cells containing BCR-ABL
-the cells are treated with Gleevec and the cells that survive are mutant
-The mutations can be mapped and new drugs can be created |
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|
