Flashcards in Cancer Deck (18):
What are common viral causes of Cancer?
HPV and Hep B, C
How do cells interact with ECM and neighboring cells differently from normal cells?
Normal cells tend to exhibit contact inhibition - they will divide to fill in space until they contact neighboring cells.
Normal cells will not divide or survive if there is an absence of signals from the ECM.
Cancer cells lose cadherins and detach from other cells and invade neighboring tissue. They do not depend on signals from the ECM and secrete metalloproteases that degrade ECM.
What are two classes of tumor suppressor genes and what are oncogenes? Protooncogene.
And their inheritance?
1. Caretaker genes: are genes that repair and prevent damage to DNA. Loss of their function isn't oncogenic but it promotes mutations accumulating. (MLH, BRCA-1)
2. Gatekeeper genes: they restrain cell division and induce apoptosis. So in this case, a loss of function mutation is oncogenic and allows cell proliferation
Oncogenes: are genes that when expressed cause cancer.
Protooncogenes: are genes which function is to promote cell proliferation. They don't lose their function but they lose control. (ras)
Since tumor suppressor genes tend to be loss of function mutations, they are recessive, you need two losses to get this phenotype.
What two conditions can occur from loss of function mutations in gatekeeper gene Rb.
1. Sporadic retinoblastoma: single tumor of one eye in a family
2. familial retinoblastoma: is inherited and usually multiple family members are affected, tumors are bilateral and sometimes multiple tumors in each eye. As well as younger age of onset.
Describe the mechanism of p53 regulation in regards to cancer? (ARF)
ARF stabilizes p53 so its proapoptotic. ARF is activated by growth factors and will bind to MDM2 (also cell stress)
MDM2 destabilizes p53 and degrades it so no apoptosis occurs.
So destabilization of p53 is likely to happen in cases of cancer.
What is the mTOR pathway.
PIP2 becomes PIP3 (via PI3K) which activates AKT which inibits TSC, inhibitor of mTOR which turns it on leading to protein synthesis and cell growth. '
PI3K - converts PIP2 to PIP3
PTEN - phosphatase that converts PIP3 to PIP2.
AKT phosphorylates and inhibits TSC (protooncogene)
TSC- inhibits mTOR, mutations in this tumor suppressor gene leads to tumors in skin, heart and lung.
mTOR: phosphorylates multiple targets to promote protein synthesis and cell growth.
Describe c-myc activation.
It is a TF that activates 15% of human genes.
In some tumors: INCREASE NUMBER of genes (gene amplification) or translocation increasing the transcription of c-myc. (placing next to a powerful enhancer)
FISH would show a homogenously-stained region or double-minute chromsomes outside of the chromosome.
Describe c-abl activation in CML
A translocation occurs between chromosome 9 and chromosome 22 resulting in a abnormally small Philedelphia chromosome. Both cut sites are in introns and the splice site is preserved. This allows for a functional spliced protein.
c-abl on chromosome 9 is placed next to regulatory region bcr. C-abl expression is enhanced.
The Bcr-Abl protein escapes normal regulation and is constitutively active
1. promotes growth and survival
2. regulates DNA damage repair response
3. gains a domain from BCR that allows it to dimerize so it is no longer folded (its negative regulation) and as a tyrosine kinase, can autophosphorylate itself and is constitutively active.
4. Is constitutively expressed in the cytoplasm.
5. Bcr-Abl drives growth in the neutrophil population.
Describe Ras and Cancer
Tumor supressor gene: NF1 protein - it is a ras-GAP. mutations result in neurofibromatosis
Protooncogenes: SOS aka Ras-GEF.
Ras promotes cell growth, and antiapoptosis,
Most commonly the oncogenic mutation leads to reduced intrinsic GTPase activity.
What is the multiple hit hyopthesis in drug treatment?
What is oncogene addiction.
If mutations in many genes are responsible for intiating cancer, how can one drug prevent cancer progression.
What are the telltale signs of CML?
mild conjunctival pallor - the membrane above and below both eyes is pale, a sign of anemia.
Abnormally high WBC but without signs of infection (stable vitals)
High neutrophil and lymphocyte concentration. From a smear.
Why is splenomegaly associated with white blood cell count?
Alterations in hematopoeitic stem cells leave the bone marrow and take up residence in the spleen.
Now this is because they return to a site where prenatal hematopoeisis occurred which is the spleen.
What do myeloid and lymphoid progenitors give rise to?
Myeloid - basophil, eosinophil, neutrophil, monocyte, erythrocytes
Lymphoid: T and B lymphocytes.
What is the blast crisis and the chronic phase.
Chronic phase is where BCR-ABL stimulates proliferation but the myeloid cells are differentiating properly.
As BCR-ABL prevents proper repair, the cells accumulate more and more mutations.
Blast crisis: the maturation process no longer occurs and you have intermediary blasts taking over (which give rise to neutrophil, monocyte and lymphocytes) These blast cells are genomically unstable and can acquire possibly aggressive mutations leading to blast crisis.
What is the role of TGF-beta pathway?
It is an inhibitor of cell division. SMAD transcription factors lead to the synthesis of CDK inhibitors.
What would increased growth factor signaling do for cancer?
It would be tumor suppressor. Growth factors promotes production of ARF which stabilizes p53, by binding to
MDM2 and promotes apoptosis.
What is typical of polycythemia vera?
Mutation in JAK2 gene.
Ckit is associated with leukemia