Carcinogenesis part III Flashcards
What are the classic examples of tumor suppressor genes?
p53 and retinoblastoma
What does p53 do?
if cell wants to go from G1 to S phase, p53 has to check on the DNA.
if DNA is damaged, p53 may pause things and call in DNA repair enzymes
if the DNA is TOO damaged, p53 calls in BAX to destroy bcl-2. Without bcl-2, the mitochondrial membrane is no longer stable. cytochrome c leaks out and apoptosis occurs
How should I think about p53 mutations and cancer development? Associated cancer syndromes?
both copies must be knocked out for tumor formation
loss is seen in >50% of cancers. usually knocked out somatically, but if the pt inherited a defective p53, he/she has Li-Fraumeni syndrome
What does retinoblastoma do?
regulates G1 to S phase
to go to G1 to S, the cell needs E2F molecule. E2F is normally bound to Rb. to release E2F, you must phosphorylate Rb. CyclinD/CDK4 complex is responsible for phosphorylating retinoblastoma protein. If there is a mutation in Rb, E2F is free, and the cell can easily go from G1 to S phase.
somatic vs. germline retinoblastoma mutations
if somatic, pt gets unilateral retinoblastoma
if germline, pt gets bilateral retinoblastoma and osteosarcoma
What is a final category of genes that can contribute to cancer genesis?
factors taht regulate apoptosis
Bcl2: normal function
mitochondrial membrane, blocking release of cytochrome c. disruption of bcl-2 allows cytochrome c to leak out and causes apoptosis
mutations of Bcl2 in cancer
overexpressed in follicular lymphoma
in follicular lymphoma, you have a 14;18 translocation
Igheavy chain on 14
Bcl-2 on chromosome 18
Bcl-2 is overexpressed. therefore, apoptosis doesn’t occur, even when it should. Apoptosis is particularly important in the follicle, because B cells undergo somatic hypermutation in the follicle. You want them to die if they undergo “bad” mutations in this process, so it is a problem if they don’t apoptose when they should.
What should I know about telomerase and tumor formation?
telomerase is needed for cell immortality. normally, telomeres shorten with serial cell divisions, resulting in senescence. cancers have upregulated telomerase to preserve the telomeres.
What is the role of angiogenesis and what are critical factors in tumor formation?
FGF and VEGF are commonly produced by tumor cells to ensure survival
How do tumor cells avoid the immune system?
they downregulate MHC I to avoid immune surveillance
immunodeficiency also increases the risk of cancer
What are the key steps in metastasis?
- downregulation of E-cadherin
- attachment to laminin within the basement membrane (remember, BM is made of laminin and collagen IV)
- destroy the basement membrane by producing collegenase IV
- go to the ECM and attach to fibronectin
- gain access to blood vessel or lymphatic space
How does downregulation of E-cadherin helpful for metastasis?
cadherins keep cells attached to each other. to spread locally, it must dissociate from its neighbors.
Where do carcinomas spread?
in general, goes to lymph nodes (think of breast cancer) via lymphatics
Where do sarcomas and some other carcinomas spread? Which carcinomas do this?
hematogenous
carcinomas: renal cell carcinoma (renal vein), hepatocellular carcinoma (hepatic vein), follicular carcinoma of the thyroid, choriocarcinoma (these are placental tissue malignancies- esp. trophoblasts)
