Lecture 14 - Tumorigenesis Flashcards
Why is tumorigenesis a complex multistep process?
Because cancers, in most cases, require more than just a single mutation to be successful. They require multiple mutations that can only accumulate over time.
Also, not all the mutations are desirable. It can take a while for the right combination to finally happen. The total number of mutations in a cancer cell’s genome is far greater than necessary for tumorigenesis.
Cancer development can take decades.
What can speed up the rate of tumorigenesis?
Mutagens, carcinogens
Promoters and initators etc…
Exposure to materials such as tobacco, asbestos, etc…
Why are colon and epithelial tissues awesome places for tumors to form?
What are the four stages of tumor progression?
Colon and epithelial tissues are great places for tumors to form since there is an extremely high turnover rate in cell life, and mutations can accumulate more rapidly.
Four stages of tumor progression: 1- Hyperplastic 2 - Dyoplastic 3 - Polyps and Adenomas 4 - Carcinomas
Adenomas turning into carcinomas is a truly complex multistep mechansim (requires the right mutation combination).
What is the 5 step tumor progression process of tumorigenesis?
Which is more consistent: the loss of tumor suppressor genes or the activation of oncogenes?
1 - Normal epithelium 2- Hyperplastic epithelium 3 - Early/Intermediate/Late Adenomas 4 - Carcinoma 5 - Invasion & Metastasis
The loss of tumor suppressor genes is more consistent than the activation of oncogenes.
Why are alternative genetic pathways and how are they related to cancer progression?
Why is APC interesting in relation to this notion?
Depending on the individual and the cancer cells’ environmental conditions, tumorigenesis can follow various mutation pathways in order to succeed.
However, pathways or proteins that are responsible for many tasks and functions (used more than once) are more likely to be mutated through some form or another.
An example of this is APC, a protein that is mutated in 80% of all colon cancers. Similar to Ras which is almost always eventually knocked out.
How can Darwinian evolution partially explain cancer progression?
What are some of the complications related to the Darwinian model?
Darwinian evolution: the cell that mutates more easily is more likely to get the right mutation combination and will therefore proliferate and take over the ecosystem.
Complications: not all cells arising from tumors are identical. The generation of new alleles may move faster than actual selection. Therefore… even if a cell has the best suited alleles, it may not get the chance to dominate as new competitors are being introduced so quickly.
Basically, certain cells sharing some common traits that make them succeed and proliferate in an environment will grow together, even if they aren’t completely the same.
What are some further difficulties to the Darwinian model of cancer progression?
1 - Many mutations beyond those necessary to succeed
“Passenger” Vs. “Driver” mutations
2- Difficult to account for gene silencing (methylation) which is a normal developmental process
3 - It is hard to determine the development kinetics since you can’t really distinguish the rate limiting steps
“Oncogenic Collaborative Transformation”: define and give an example.
Many DNA tumor viruses carry the ability to alter more than just one single protein or pathway (multiple mutations).
An example is the collaboration of myc and ras mutations:
Myc - cytoplasmic signalling pathways
Ras - nuclear signalling pathways
Why is it so much more difficult to immortalize human cells? Give three reasons.
1 - Serial passages automatically result in senescence
2 - co-transfections have little effect
3 - Required multiple pathway deregulation is difficult to induce properly
What is so interesting about the relationship between non-mutagenic agents and tumorigenesis? Give and describe an experiment
Non-mutagenic agents can alter the environment to allow a typically normal substance to have a oncogenic effect.
There are usually two types, an initiator (he who alters the DNA) and the promoter (increases proliferative signal).
An example would be DMBA, which when administered in weekly treatements eventually developed into a papilloma which eventually developed into a carcinoma
Experiment: Initiator only - No effect Promoter only - No effect Initiator + Promoter - Papilloma Initiator + Promoter in diff spot - No effect
Further testing:
Initiator + Promoter (then stop Promoter) - No effect
[eventually the body recovers]
Initiator + Promoter (painting papilloma with promoter) = Papilloma
[persistent papilloma]
Initiator + Promoter (painting papilloma with initiator) = Carcinoma
[Worst possible scenario]
Give an example of a tumor promoter. Explain why it is effective.
An example of a tumor promoter is TPA. It is effective as it mimics DAG and stimulates proliferation.
How does Chronic Inflammation promote tumor progression?
What is Inflammation Dependent Tumor Progression?
—–tomorrow
