Cancer Flashcards
How does a primary tumor differ from a secondary tumor?
Primary: benign, restricted to site of origin, often treatable by surgery, requires blood supply.
Secondary: metastatic, able to degrade ECM, invasive.
Define: oncogene.
What are the two categories of oncogenes?
A gene containing a gain of function mutation or a mutation that acts in a dominant manner to contribute towards tumor formation.
- c-onc (mutated chromosome)
- v-onc (virally encoded)
Definition: tumor suppressor gene
A gene whose loss of function contributes to tumor formation - often acts recessively or in a haploinsufficient manner.
List the 10 hallmarks of cancer
- Self-sufficiency in growth signals
- Insensitivity to anti-growth signals
- Evading programmed cell death
- Immortality
- Sustained angiogenesis
- Tissue invasion and metastasis
- Deregulated metabolism
- Evading the immune system
[9. Genome instability - Inflammation]
What is the clonal expansion theory of tumor development?
If cell N gets a mutation, it will divide to give T1 cells that can divide more frequently than N. If T1 then gets another mutation, the resulting T2 cells will divide more frequently than T1. As this goes on, more cells gain mutations and have growth advantages over all other cells.
What are the requirements for mammalian cell proliferation?
- Nutrients e.g., amino acids
- Macromolecular nutrients e.g., insulin
- Attachment molecules (sometimes) e.g., fibronectin
- Serum i.e., PDGF, EGF
What are the markers of cell cycle entry?
- S6 phosphorylation of the ribosome
- expression of TFs
- Cyclin D expression
- DNA synthesis
What is the Warburg effect, and how does it help to explain metabolic changes observed in cancer cells?
The Warburg effect is the reliance of cancer cells on aerobic glycolysis to generate energy, rather than oxidative phosphorylation. This increases glucose metabolism.
Perhaps this is because aerobic glycolysis generates an excess of metabolic intermediates that can be diverted into other pathways to make other molecules needed for growth.
How does angiogenesis relate to cancer cells? What can tumors do to increase this?
Angiogenesis is the process by which new blood vessels are formed from existing vessels.
In cancer, angiogenesis is a necessary step for tumor growth beyond a certain size, as tumors require a blood supply to obtain oxygen and nutrients necessary for their survival and proliferation. Tumors can secrete pro-angiogenic factors, such as vascular endothelial growth factor (VEGF), which stimulate the growth of new blood vessels. These new blood vessels can also provide an avenue for tumor cells to spread to other parts of the body through the bloodstream.
How can chronic inflammation cause cancer?
Chronic inflammation can lead to DNA damage, genomic instability, and alterations in cell signaling pathways, all of which can contribute to the development of cancer. Inflammatory cells can secrete cytokines and growth factors that can promote cell proliferation and survival, stimulate angiogenesis, and promote tissue remodeling, all of which can contribute to tumor growth and metastasis.
What is the epithelial-mesenchymal transition? What causes it? How does it relate to cancer?
EMT is the process by which epithelial cells acquire mesenchymal properties, such as the ability to migrate and invade surrounding tissues. This can be triggered by increases in TGFb which results in the repression of epithelial markers and activates mesenchymal markers.
EMT is heavily associated with tumor invasion and formation of secondary tumors. It can also contribute to resistance to chemotherapy.
Why are growth factors hard to purify?
They’re present in very low concentrations within the body. Tumors are rich sources of them, although they may be mutated versions.
What are the differences between the INK4 and Kip families of CDK inhibitors? How are they inhibited?
INK4 prevents cyclin binding
Kip inhibits the complex
Mitogens inhibit the actions of p21 and p27 by AKT/PKB phosphorylating them to promote cell-cycle progression.
List 4 mutation types by which an oncogenes can be activated. Give an example for each.
- Point mutation e.g., Ras
- Gene amplification/overexpression e.g., estrogen R
- Chromosomal translocation e.g., bcr-abl
- Association with viruses e.g., SV40 T antigen
What are the 2 classes of tumor-forming retroviruses? What are their differences? How do they give rise to cancer? Give an example of each.
Class I:
- Rapid formation of tumors
- Tumors arise from multiple founder cells
- Rare
Encode constitutively active versions of proteins involved in GF signaling.
e.g., Avian leukosis virus (ALV) which captured the tyrosine-kinase Src
Class II:
- Slow formation of tumors
- Not all infected get tumors
- Tumors arise from a single founder cell
- Common
Integration of gene next to a cellular gene that’s transcriptionally active.
e.g., MHC leukemia virus
How might avian leukosis virus have picked up the Src gene?
ALV undergoes reverse transcription and integrates somewhere into the genome. This may be random or via hot spots, and at one time integrated into the scr gene. A fusion RNA was then transcribed that contained v-src and was packaged into the viral capsid. Viral capsids can’t tolerate change in length of information (they will lose some of the viral genome to replace it with src).
The particle will then infect another cell, but will now carry the v-src protein and have high levels of expression (strong promoters and enhancers) resulting in overexpression of the protein. These also mutate very rapidly and so the src will start to pick up mutations that lead to activation of the protein. These mutations will be selected for so that invasion of the next cell will result in overexpression of an activated src protein, resulting in a progressively more aggressive cancerous phenotype.
List the ways that oncogenes can be identified.
- Class I retroviruses: assay for the ability of the virus to transform cells in culture and look at the genome sequence.
- Class II retroviruses: identify site of viral insertion and clone sites either side.
- Isolation from tumor-derived DNA.
- Identify commonly occurring rearrangements and breakpoints in chromosomes.
- Identify regions of genome amplification.
List 3 ways in which a chromosomal rearrangement can give rise to cancer.
- Movement of gene to be under a strong promoter.
- Changing of 3’UTR structure so that miRNA cannot bind to degrade it.
- Creation of a novel fusion protein.
