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Week 5
Cancer cells
55
Biology
Graduate
09/08/2008

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Term
Define hyperplasia, dysplasia, neoplasia.
Definition
Increased proliferation, morphologic abnormalities and loss of architecture without invasion, new tissue growth either benign or malignant
Term
Which of these 3 are reversible and which is a point of no return mutation: hyperplasia, dysplasia, neoplasia?
Definition
Hyper/dysplasia reversible, neoplasia no return
Term
Distinction between benign and malignant neoplasms?
Definition
Malignant are invasive and metastatic
Term
Define invasion.
Definition
Tumor that grows and LOCALLY invades through basement membrane or through other tissue barriers
Term
Define metastasis.
Definition
Cells detach from primary tumor and travel via lymphatic or venous system, multiplying at distant sites.
Term
Why is it important to understand the molecular basis of invasion and metastasis?
Definition
Determines diagnoses/therapy/prognosis; tumor cell heterogeneity necessitates multiple therapies, invasion and metastasis are the features responsible for the lethality of cancer
Term
Since metastatic cells are a result of tumor progression in a stepwise fashion, why can those small percentage of cells (<.01%) move?
Definition
Because they have a selective advantage for metastasis among tumor cells.
Term
What is chemotaxis?
Definition
Cellular movement based on chemical concentrations/affinities in their environment
Term
What are the first four steps required for both invasion and metastasis?
Definition
Detachment of tumor cells from one another, adhesion to the basement membrane, protelytic dissolution of the basement membrane, locomotion of cells across the extracellular matrix
Term
After the first 4 steps required for invasion and metastasis, what are the last 8 steps needed for successful metastasis?
Definition
Intravasation (enter blood vessel/lymp), detach endothelium, attach at distant endothelium, extravasation, attach ECM distant site, distant site growth, angiogenesis, evasion of immune response
Term
What are the 3 clinical approaches to cancer therapy?
Definition
Surgery removes primary tumor, radiation kills micrometastases, chemo kills metastases but limited by bioavailability and vascular access
Term
True or False: The types of targets drugs will attack for controlling metastasis are anti-adhesion molecules, protease inhibitors, anti-growth factors, anti-angiogenic factors.
Definition
True
Term
Why is it important to always use combinatorial approaches in cancer therapy?
Definition
Tumor cell heterogeneity and high mutation rate
Term
What is a mitogen?
Definition
Agents that induce a cell in a G-0 state to G1 and progress through the cycle
Term
During what phases of a cells cycle does the DNA content double and half?
Definition
S-phase, M-phase
Term
True or False: a flow microflourimeter is used to determine cancer metastasis.
Definition
False, determines DNA content of individual cells
Term
Why is there a great increase in G2-M histone kinase activity at the end of G2 cell cycle?
Definition
Because when histones are created in S phase, they are then subject to post-translation phosphorylation in preparation for M phase.
Term
At the cell cycle restriction point G1/S, which transcription factor repressor must become phosphorylated to activate transcription factors to get past this point?
Definition
Restriction boundary protein, it must be dephosphorylated to before the restriction point in the next cell cycle
Term
If you want to synchronize cells at the G1/S point what can you add to a group of cells?
Definition
DNA synthesis inhibitor
Term
What does cell fusion data using heterokaryons indicate about transitions between cell phases?
Definition
That there are distinct controls and regulator activities that mediate the cell in different stages.
Term
The most famous protein kinase regulating cell cycles is cdc2 kinase, what type of kinase is it and what regulates it?
Definition
It is a cyclin-dependent protein kinase, and it is regulated by cyclin and phosphorylation at 2 sites.
Term
Since CDK can phosphorylated twice, what does each one do to the CDK/Cyclin complex?
Definition
One activates its enzymatic activity, and the other inactivates it.
Term
True or false: Cyclins are are absent in G1, synthesized in S-phase, accumulate in G2, destroyed in mitosis.
Definition
True.
Term
How are cyclin proteins destroyed and how are proteins repaired?
Definition
A ubiquitination mechanism that marks the cyclins or proteins with a protein called ubiquitin to be degraded or corrected in a proteosome.
Term
A distinct CDK is required for a cell to pass which cell cycle check points?
Definition
G1/S to phosphorylate restriction boundary protein, DNA synthesis at S-phase, and G2/M
Term
True or False: The cdc2/cyclin B complex is a poor histone kinase.
Definition
False, it is a potent kinase for histones.
Term
In regards to the cell cycle, what 3 states do cells exist?
Definition
Postmitotic, cycling, non-dividing but able to respond to mitogenic signals
Term
Briefly, what happens to G-0 cells following mitogenic stimulation to go past the G1/S restriction boundary?
Definition
Mitogen stims a Cdk complex which phosphors a restriction boundary protein which is on a transcription factor, this releases Rb and allows the trans factor to create genes needed for the G1/S transition.
Term
What is a dominant oncogene?
Definition
Oncogenes that gain an autonomous function and can drive the cell into division
Term
What is a tumor suppressor gene?
Definition
Gene who’s loss of function enables the expression of cancer phenotype.
Term
What is a proto-oncogene and why is it relevant to RNA tumor retroviruses?
Definition
A normal gene that is captured and mutation by virus, this leads to the insertion of the modified oncogene back into the human genome where it causes cancer.
Term
Give a basic overview of how the cellular Ras signal molecule affects gene expression and mitotic division.
Definition
Ligand binds receptor, receptor phosphors, Grb2/GNEF binds receptor, binds Ras and activates with GTP, active Ras bind protein kinase cascade (Raf/MAPK), MAPK phosphors transcription factors
Term
What is the difference between a normal cellular Ras signal molecule and a mutated one that causes cancer?
Definition
Ras needs to be inactivated by GTPase Activating Proteins(GAP), mutated one can’t bind to GAP so it is always on.
Term
True or False: The mutated Ras oncogene is a dominant oncogene, therefore it cannot caused by a single point mutation in its gene.
Definition
False, single point mutations can cause changes in the Ras protein giving it inability to deactivate.
Term
What are the three ways dominant oncogenes are activated?
Definition
Point mutations, chrome translocations (either unregulated DNA expression or fusion proteins with transforming properties), gene amplification
Term
What is a tumor suppressor gene?
Definition
Genes who’s loss of function allows cell to express cancer phenotype
Term
What is the most commonly mutated human cancer gene and what does it do?
Definition
P53 prevents cells with damaged DNA to continue to replicate instructing the cells to fix DNA or apoptosis; it is a trans factor that expresses a Cdk inhibitor
Term
True or False: Genes involved in cell control - Cyclin D, Rb gene, Cdk Inhibitors - are all altered in different human cancers.
Definition
True.
Term
What is a better predictor of cancer patient survival, gene profiling of cancer cells or traditional clinical data?
Definition
Gene profiling
Term
True or False: Cancer rates are relatively linear as you age.
Definition
False, they increase exponentially around 40-50 yrs old.
Term
True or False: Cancer is a multigenic, multistage process.
Definition
True, it requires mutations in multiple oncogenes to intiate, promote, and progress cancer.
Term
What is the role of PET scans in cancer treatment?
Definition
PET scans analyze whether the imaging molecule FDG is being changed by Hexokinase activity which indicates cancer activity and therefore the size and spread of cancer.
Term
What is the role of PTEN phospholipids phosphotase in tumor progression?
Definition
If PTEN is missing then the AKT/PKB kinase has greater activity on TOR (targets of Rapamycin) substrates increasing cell proliferation, promoting migration, preventing apoptosis.
Term
What drug can bind to TOR, targets of Rapamycin, to limit kinase activity when the PTEN regulator protein is missing?
Definition
Rapamycin.
Term
True or False: Only 20-30% of cancers have an environmental causation.
Definition
False, 80-90%.
Term
In cancer development, which one of these is genotoxic: initiators or promoters?
Definition
Initiators, promoters are non-genotoxic
Term
What is an iniator carcinogen?
Definition
It is a carcinogen that is genotoxic that usually require metabolic activation by phase 1 enzymes (CYP450) making it electrophilic and able to mutate DNA, ie - PAH, benzopyrene, alflatoxin B1
Term
What is the ultimate carcinogen?
Definition
Benzopyrene, BPDE, it attaches to guanine residues in DNA to pair with A instead of C, it has long half life, resistant to metabolism. aflatoxin B1 is also very potent iniator.
Term
True or False: All carcinogenic initiators require metabolism before they become active.
Definition
False, some are directly acting alkylating agents.
Term
Define a carcinogenic promoter.
Definition
An non-mutagenic agent that binds to cellular receptors preferentially stimulating the growth of intiated cells
Term
Briefly, how do the promoters TPA and Dioxin function?
Definition
TPA mimics DAG and activates PKC and is therefore a mitogen with a long half-life, Dioxin binds to Ah receptor and stimulates growth and also has a long half-life
Term
What are the targets of genotoxic carcinogens?
Definition
Protooncogenes, tumor suppressor genes, and DNA repair genes
Term
How is it that diet can protect against cancer?
Definition
Certain foods(broccoli, resveratrol) modulate metabolism of carcinogens, for example either inhibiting the amount of phase 1 CYP metabolites formed or stimulating phase 2 enzymes to quickly remove metabolites
Term
For reference what are the normal levels of hematocrit for women, men, and what is the critical value?
Definition
34-42%, 37-47%, <20%
Term
Elaborate on the complete cell cycle without the details of mitosis.
Definition
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