Term
What is carcinoma Initiation?
What is a benign tumor?
What is a malignant tumor? |
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Definition
Carcinoma initation = a mutation is a cell modifying its function = a tumor cell.
Benign = Tumor cell prolifration / mass formation in a localized area
Malignancy = Invasive tumor cells break through the basal lamina and move to new organs / systems. |
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Term
What's an oncogene and how is it formed, where does it come from?
What cell types typically become oncogens? |
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Definition
Oncogene = a gain of function mutation that allows a cell to evade cell death. Cells that should die but don't!
- Usually mutations in the signal pathway that regulates the cell's growth and differentiation = continuous, and avoids cell death.
A proto oncogene is a gene that encodes for a protein that regulates cell cycle, diferentation, apoptosis, etc.
- Examples:
- Growth Factors
- Growth factor Receptors
- signal transduction proteins on cell membranes.
- phosphokinases in cytoplasm
- Transcription factors...
- Ras, Src, Myc... |
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Term
| What is a tumor suppressor gene? |
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Definition
- Tumor suppressor gene =
- A gene that typically suppressess cell growth, differentiation. Controllers that inhibit cell division and apoptosis.
- Loss of function mutation, usually need 2 mutations to effect this loss of cell replication control = cells replicate even if there's DNA damage.
- Example:
Bcl-2 typically reduces cell proliferation and suppresses apoptosis. If it's mutated it losses its function!
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Term
What type of mutation / cell transformation causes Burkett's lymphoma?
2. What molecule would you propose to target with a vaccine to Burkitt's lymphoma? |
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Definition
- Oncogene translocation, placing c-myc gene in a region for the translation of Ig heavy chains = Over expression of c-myc / over express specific Abs, the same Ab.
2. Target: Ab produced by the B cell: these are different for everyone, but the same Ab is mass produced. |
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Term
| How can you detect translocation? |
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Definition
FISH: Flourescence In Situ Hybridization.
= Detects the presence or absence of specific DNA sequences on chromosomes.
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Term
| How does the immune system recognize a tumor cell? |
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Definition
- Tumor resistance is transfered by T cells!
- If you can transfer T cells that recognize tumor cells from the lymph node of one animal into another animal (compatible), then that animal will have resistance against tumors.
- Can keep tumors from growing but can't completely kill tumors off. With CTLs, T cells, etc transfered from one mouse to another.
- confer tumor resistance with recombined tumor Ags. (like attenuated virus / vaccine) |
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Term
| What are some examples of altered gene expression that can contribute to recognition of gene products by the immune system? |
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Definition
1. Modified amino acid sequence
2. Inappropriate expression (usually during development / use of developmental genes)
3. Protein over-expression. |
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Term
| What are 2 ways to induce tumors and how are they different? |
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Definition
1. By chemicals = more heterogeneous tumors, can't predict where the tumor is going to be.
2. Virally induced tumors = more homogenous / target specific organs, tissues, generally more predictable. Virus can infect a specific area of the body / host.
Like HPV inducing cervical cancer. |
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Term
| Can you propose a mechanism by which inflammation can contribute to tumorgenesis? |
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Definition
| Inflammation releases signals (cytokines) for cell proliferation, which will increase tumor mass! |
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Term
| What antigens are normally expressed in early cancer development? |
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Definition
Elevation of alpha-fetoprotein (AFP) and carcinoembryonic antigen (CEA) in a patient's serum with various cancer types.
- These antigens are not common for everyone though! But, a good target for cancer vaccines! |
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Term
| Why are antigens in "cancer testes" sites immunogenic |
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Definition
| Cancer testes sites are immun-privilaged sites, meaning that the Ags, proteins in these sites are sheilded from the body's immune system and can cause an immune response if seen outside of these areas, like the testes. |
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Term
| What method can be used to identify which T cells recognize and respond to tumor Ags? |
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Definition
1. Generate a tumor cell cDNA library.
2. Express tumor cell cDNA in bacterial pools (get more cDNA).
3. Isolate DNA from the pools
4. Introduce the cDNA into cells expressing MHC I.
5. React / Add T cells.
6. Identify positive pools (= T cells that have ID / reacted with tumor Ags).
7. Repeat with bacterial clones = be sure you have the right tumor Ag and MHC I + Tumor Ag expression.
8. Find the DNA sequence of the tumor Ag that the T cell is able to react with! |
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Term
| What is another way tumor antigens can be identified, this time using the humoral system? |
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Definition
Tumor antigens can also be identified by antibody recognition. SEREX = Serological analysis of cDNA expression libraries.
1. Express cDNA library in a gateway yeast vector. (Yeast are used because they are eukaryotes and have glycosylation which is important for the Ag + Ab interaction)
- The cDNA library is an isolation of various tumor cDNA that can be expressed by a plasmid in a yeast cell. (cDNA will translate teh tumor Ag proteins)
2. Add the patient's serum to the yeast expressing the tumor Ags.
3. Find the positives via FACs, as the patient's Ab will be marked with an immunofluorescence / anti-human Ab.
- This method also requires a non-immunogenic tumor cell comparison to be effective. |
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Term
What is another way to see the Ags that tumor cells are express?
This one is a little simpler |
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Definition
1. Use an acid to elute the peptides from the surface of a tumor cell.
2. Purify the peptides via HPLC (High preformance liquid chromoatography)
3. Sequence the peptides.
- Need to compare with a non-immunogenic tumor cell.
- Does nto tell you if these tumor Ags are inducing any kind of immune response. |
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Term
| What are some formats for boosting the immune system's reactivity to tumor antigens? |
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Definition
1. Make adjunats for tumor vaccines...
2. Proteins, like HLA-2: But this would be specific to the patient with that HLA-2 peptide in their MHC
3. RNA.
4. DNA: the vaccine would be long lasting and reproduce for a long time but how would it be stopped? |
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Term
| What location would you introduce an anti-tumor vaccine? |
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Definition
Into circulation or at the site of the tumor? Depends on the nature of the vaccine and the cancer...
- Anywhere intramuscular. Like the deltoid.
- Or into the skin so the APCs pick up the tumor Ag from the vaccine. |
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Term
What are some typical componenets of anti-tumor vaccines?
1. Active immunization
2. Passive immunization |
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Definition
1. Tumor Ags.
- Cytokines
- Co-stimulatory molecules (enhance T cell avidity (binding) and activate CTLs via B7 increased expression)
- Chaperones
- Antigen presenting cells
= All envoke an immune response via the adaptive IS and create memory.
2. Antibodies
- T cells
= Transfer of Abs from one source to another. Like mother to baby, or made in a horse and injected into a human (Anti-toxin) |
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Term
| Would you want to use immature or mature DCs in anti-tumor vaccines and why? |
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Definition
Mature DCs: they focus more on Ag expression via MHC II than phagocytosis as immature DCs do.
- Mature DCs also secrete more immune recruitment cytokines for a larger anti-tumor response. (CTL activation, etc...)
= Pulse DCs with tumor lysate and re-inject into the patient. |
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Term
How can cytokines be used as a component of tumor vaccines, what can they do?
- Such as IL-2 or TNF... |
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Definition
Cytokines can recruit other immune cells to respond to the tumor.
- TNF can find and specifically kill tumor cells as they are expressing the TRAIL receptor to activate TNF / Fas ligand killing.
- Can also increase the expression of Effector T cells (CTLs) via IL-2 but be careful that Tregs aren't over expressed to as they will suppress the immune reaction agains the tumor cells!
Normal cells are spared as they are not expressing the TRAIL receptor for TNF. |
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Term
- How are tumor specific Abs created?
Name an advantage and a disadvantage to using antibodies over T cells in anti-tumor therapy. |
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Definition
- Tumor specific Abs are created as hybridomas in a mouse that recognize your specific tumor, and then are injected into you. = Anti-idiotype hybridomas for passive immunization.
- An advantage to using Abs = can select cells and activate an effector cell response.
- Abs can be specific to Ags on the outside of tumor cells
- T cells can be selective against infected / tumor cells that have problems inside the cell. |
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Term
How do tumor cells escape the immune system?
- 7 ways! |
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Definition
1. Loss of MHC I expression. Low MHC I expression can escape and continue to proliferate.
2. Loss of tumor Ag expression.
3. Tumor Ag variation.
4. Defects in tumor antigen presentation (TAP)
5. Tumor can release cytokines affecting T cell's Ag recognition and function (Like decreasing inflammation via IL-10, 2, 3)
6. Tumor cell protects itself from apoptosis by upregulating the expression of immunoprotective molecules (Bcl-2... stops expression fo the Fas receptor = FasR is on the target cell!)
7. Recruit Tregs, Via IL-2
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Term
What is tumor immunolgy based / built on?
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Definition
| The opportunity to target transformed cells with a modified antigenic repertoire. |
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Term
| Where can tumor antigens come from? Their origin? |
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Definition
1. Virus
2. Mutant gene products
3. Overexpressed genes
4. Deviantly expressed developmental genes. |
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Term
| An effective anti-tumor response is mediated by? |
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Definition
| T cells (at least in mice) |
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Term
| Growing tumor cells that are not spontaneously erradicated can be targeted by? |
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Definition
1. Preventative vaccines
- Prevent infection using natural / wild pathogen
2. Therapeutic vaccines
- Prevent infection of cancer causing viruses.
3. Passive immunity vaccines
- Transfer of Ab, T cells
4. Actie immunity vaccines
- activation of the adaptive IS against tumor Ags. |
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Term
| Besides tumor targeting Ags, what else can tumor vaccines include? To aid in an anti-tumor IS response... |
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Definition
- Co stimulatory molecules (B7)
- Cytokines (TNF, IL-2) |
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Term
| What are the 2 forms of immunity tumor vaccines can target tumors? |
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Definition
1. Humoral = Abs
2. Cell mediated Immunity (CMI) = Immune cell recruitment of NKs, macrophages, etc, just not T or B cells. |
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