Cancer II Flashcards
Distinguish between dominant gain of function oncogenes and recessive loss of function tumor suppressor genes
Overactivity mutation (gain of function):
- Start with a normal cell and in this case a single mutation event can initiate cancer by creating an oncogene. It is a single mutation that gives rise to the activating of an oncogene to promote cell transformation.
- It is easy to prove that overactivity of a gene can produce an effect.
- This is typically dominant only one copy needs to be mutated
Underactivity mutation (loss of function):
- It is harder to look at the loss of something, which is what is done here.
- If we look at a cell and have a mutation event, we inactivate the tumor suppressor gene. The tumor suppressor gene will block the cell proliferation.
- It is recessive Both copies need to be mutated
- If there is only one mutation, the cell is fine!
- So what has to happen is a second mutation event which inactivates the second gene copy and now there are two inactivating mutations that functionally eliminate the tumor suppressor gene, promoting cell transformation.
- To get a cancer phenotype you need both to be inactivating.
- KEY HERE IS INACTIVATION OF A GENE
Driver Mutation
Driver mutations are thought to be the causal factors in the development of the disease. Driver mutations are often seen at a higher frequency and may be present in all cells of a given tumor.
Passenger Mutation
passenger mutations occur in the same cell and may contribute to the cancer phenotype. Passenger mutations are more sporadic, and may not be present in all tumor cells due to tumor heterogeneity.
Know the ways in which genes can be made overactive (Oncogenes) and the mechanisms for generating second hits in tumor suppressor genes
Overactive Oncogene generation:
- The way in which a gene can become over active –> Oncogenes
- There are several different ways that you can activate or create an oncogene
- A deletion or point mutation in a coding sequence can give rise to a hyperactive protein that is made in normal amounts. There is a distinction in a proto-oncogene and an oncogene. The proto-oncogene is the normal copy of the gene. It is the gene, which when mutated, can give rise to an oncogene.
- A regulatory mutation: So something that turns a gene up significantly such as Myc over-expression. In some cases it is due to mutations in the regulatory region
- There are also mutations in gene amplification events: The normal protein can be greatly over produced.
- Chromosome rearrangements: This is where you can fuse nearby regulatory sequences to cause it to be over produced. You don’t change the structure of the gene or protein itself, you are bringing something in that can turn it on at a high level.
Creation of the Second Hit:
-There are some of the mechanisms in how you get loss of one of the genes or loss of heterozygosity.
- Start out with a normal and mutant copy.
- You can lose one chromosome due to nondisjunction and now you only have the bad chromosome
- You can get chromosome loss, then chromosome duplication. This actually does happen. The only way you can get a homozygous chromosome is through this process.
- Can also get LOH through a mitotic recombination event
- Gene conversion
- Deletion of the good copy and retention of the bad copy
- Can get a point mutation in the good copy and now you lost it. These are haploinsufficient
Just know that there are a variety of mechanisms for this to occur
- There are also epigenetic mechanisms in which this can occur
- We say a mutation of the second copy.
- But what if the second copy was there and it is was seemingly fine, how could you get the cancer?
- Through epigenetic silencing of the good gene could result in the cancer without actually involving a mutation
- In some cases you can silence a gene through things like methylation of the DNA or histone modifications
- This then can shutdown one, and through the maintenance methylase it can shutdown both good genes and now you can get the cancer without a mutation at all!
- In another case you can shut off one copy and mutate the other!
- Also, you can mutate one and shut off the other. They can happen in different orders. Can look to see if the mutation existed first
-This just shows that we don’t need to mutate the other copy, it can also be shutdown via epigenetic mechanisms
Loss of Heterozygosity
Usually effects tumor suppressor genes because they are recessive, or need both mutations.
Oncogene vs. Tumor Suppressor Gene Mutations
- When we look at oncogenes, we often see missense mutations occurring and they are often within the same residue! It is a recurrent mutation in a signal amino acid. There are frequent co-occurring mutations in oncogenes
- In tumor suppressor genes typically the majority of mutations are truncating mutations or those that deactivate or get rid of the gene product. These mutations tend to be spread out on the gene.
Describe how the characteristics of a cancer stem cell that gives it a resistance to therapeutics
Cancer Stem Cells Sustain Malignancy, Characteristics overlap with Mesenchymal Metastatic Cells.
1) Telomerase expression is high in stem cells, results in immortality (self-renewal). Typically, in order for a cancer to develop and continue, you need upregulation of telomerase
2) ABC transporters high in stem cells, giving them a drug resistance.
3) Proliferation rates are low in stem cells, giving them resistance to drugs that selectively act on cells progressing through the cell cycle.
4) Cancer stem cells can arise from non-stem cancer cells through mutational and epigenetic changes
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5) Cancer stem cells require TGFB and Wnt (extracellular) signaling proteins from either self (autocrine) or from their microenvironment (paracrine).
6) TGFB and Wnt signaling induce pluripotency transition-factors that generate stem cell phenotype.
Just know that there are cytoskeletal and membrane changes
Describe how the role of the tumor microenvironment in support of the cancer stem cell phenotype and the role of the TGFB and Wnt signaling pathway
The TGFB and Wnt induce the EMT shift. This is also assisted via the cancer cell’s microenvironment because they communicate with the cells around them. Other cells in the microenvironment can release the TGFB and the Wnt or the tumor cell itself can release them
Explain the epithelial to mesenchymal transition (EMT) and its function in cancer
This allows the cells to become more stem-cell like so that they can metastasize. It de-differentiates the cells
Define cell plasticity in the metastatic cell and the purpose of MET reversion in metastasis
The cell plasticity is the ability of the metastatic cell to adapt and change. The purpose of the MET reversion is so that the tumor cell can now lock in and express these factors to get the cells to lock in and form a new tumor in the new environment
Understand the process of developing cancer cell heterogeneity
It is the process of the tumor cells mutating differently from one another and allowing these cells with an advantageous mutation to survive and divide.
- When we talk about the process of becoming cancerous we said there are multiple driver mutations.
- Each of those driver mutations as they occur can take maybe one population of cancer cells and through environmental constrains, single cells within that population can evade those restrictions and you get a second hit. Not all cells will continue to survive but those that do can get a third hit. And then a 4th, etc.
- Cells acquire more and more mutations as they go from a normal state to a metastatic state
Understand the role of transit amplifying cells
Just know that the transit amplifying cells contribute to the growth of the tumor and they can become cancer stem cells themselves
Stem cells divide to form transit amplifying cells and mutations in the transit amplifying cells can revert them back to stem cells themselves.
Explain the role of epigenetic gatekeepers in preventing early tumor progression
- We start out with a stem cell which gives rise to these precursor cells but normally there are these mechanisms in the body that prevent cancers from forming –> these are called epigenetic gatekeepers or things that either keep genes on or off
- So if you lose these epigenetic gatekeepers, or things that keep genes on, now you turn genes off. If you turn off important genes this can cause the loss of these gatekeepers and now you have a cell which cannot turn off these gatekeepers for growth and proliferation.
- If you turn off the epigenetic gatekeepers which would normally inhibit this continued proliferation, now you can get a second mutation in one of these genetic gatekeepers such as the APC tumor suppressor which now gives rise to cancer.
- You can lose gatekeepers at different points in the process
- If you lose factors that are important to block cell division or but limits on cell growth or cell cycle, then this can start the process. Can lose the epigenetic gatekeeper and now then cell can acquire different properties.
- This could be a driver mutation.
Epigenetic silencing of genes such as p16 in stem and precursor cells may serve to abnormally lock these cells into stem cell-like states that foster abnormal clonal expansion. These genes are termed ‘epigenetic gatekeepers’ because their normal epigenetic pattern of expression should allow them to be activated during stem/precursor cell differentiation as needed to properly control adult cell renewal.
Explain the concept of common genetic mutations leading to stages in the progression to the malignant form of a cancer
The common pathway is the mutation and loss of the Apc, then the activation of K-Ras, then the loss of Smod4, then loss of p53 which then leads to other mutations. The point is that there are specific driver mutations associated with cancers. As the tumor progresses and becomes more severe, you are likely to see more mutations, especially in the drivers.
Genetic instability is not an accidental by-product of malignant behavior, but a contributory cause. Explain how cancer cells can acquire this instability in multiple ways
This because as the tumor progresses, it is continuing to mutate genes that are involved in the checking of the cell cycle, replication, division, etc. And if these genes or proteins are no longer present or they are overactive, then you can get genetic instability!
