Cancer II Flashcards
what are tumor suppressor genes and how do they do their duty?
- TSGs generally encode proteins that inhibit cell proliferation
- they encode proteins that restrict cell growth and proliferation AND/OR proteins that maintain integrity of the genome
what are some examples of proteins that normally restrict cell growth and proliferation?
proteins that inhibit progression through G1/S in cell cycle (eg. Rb, CKI)
receptors or components of a signaling pathway that inhibit cell proliferation
proteins that promote apoptosis (caspases)
what are some examples of proteins that maintain integrity of the genome
- check point control proteins (ATM, ATR - detect DNA damage - stops cell cycle)
- ATAXIA TELANGIECTASIA **
- DNA repair enzymes or pathways
What are some stats on Retinoblastoma?
- its a TSG; prevents over-proliferation of cells by inhibiting cell division
- inherited eye cancer in children
- rare childhood tumor: 1/20,000
- occurs before age 2
- 95% of cases diagnosed before age 5
- loss of BOTH Rb genes leads to cell and tumor proliferation in retina
How many forms of retinoblastoma are there and what are they? how would you detect them?
there are two forms: hereditary and sporadic
- 40% is familial in which bot eyes are affected (tumors)
- 60% of retinoblastoma is sporadic (no family history) - single tumor, one eye
hereditary form Rb
loss of function or deletion of one copy of Rb in every cell- because defect is INHERITED
these cells are predisposed to be cancerous, but still have one good Rb gene copy
somatic event occurs - eliminates the one good copy and tumor forms
this is called LOH - loss of heterozygosity
Sporadic form Rb
- non-hereditary – start off with all normal cells
- cancerous cells have both copies of Rb mutated
- *Two- hit hypothesis – first Rb gene obtains mutation then need second mutation Rb
- Rb protein is a regulator of cell cycle
how does Rb protein work?
- remember that E2F binds to PROMOTORS of G1/S cyclin and S cyclin genes, which drives cell to divide
- E2F is inhibited by interaction with Rb protein (Rb inhibits cell division this way.)
- Rb protein can be inactivated by phosphorylation
- loss of Rb means no control over cell proliferation
explain how Rb pathway includes proto-oncogenes and tumor suppressor genes
- Cdk or cyclin overproduced = oncogene
- overproduction of cyclin or Cdk genes could overcome amount of CKI’s; phosphorylate Rb so cannot stop E2F, which leads to uncontrolled growth (cancer)
- CKI or Rb = TSG
- CKI or Rb could be lost, leading to cancer. No CKI = no control of Cdk-cyclins; no Rb = no suppression of E2F; both mean entry into cell division at cancerous rates
what is p53?
its a huge tumor suppressor gene. its involved in (1) cell cycle arrest; (2) DNA repair; (3) apoptosis; (4) block of angiogenesis;
over 50% of cancers have mutation in p53
what happens if you lose p53?
you lose several functions
- loss of checkpoint control in cell cycle
- loss of cell cylce arrest in response to DNA damage
- loss of DNA repair activity
- loss of apoptosis in response to DNA damage
what else does p53 do?
(1) stimulates transcription of gene encoding CKI called p21 (p21 binds to G1/S-Cdk and S-Cdk, stopping cell cycle)
(2) p53 also activates expression of pro-apoptotic proteins BH123 (proteins that aggregate on mito surface, inducing cytochrome c release) and BH-3 only (protein that blocks Bcl2 activity, inducing apoptosis)
what are a few things that activate p53? what does it lead to?
hyperproliferative signals, DNA damage, telomere shortening, hypoxia
cell cycle arrest, senescence, apoptosis
what is one virus that causes cancer?
papilloma virus - causes warts and cervical cancer
how?
typically the viral DNA exists as extrachromosomal material (plasmid-like); but if the viral DNA integrates with host DNA - it may interfere with control of cell division in basal cells - malignant tumor develops
what are the viral proteins of papilloma virus?
E6 and E7; they being to 2 tumor suppressor genes: p53 + Rb
- this leads to cells replicating in an uncontrolled manner
first explain how normal cell proliferation is blocked via Rb and p53
- Rb bound to E2F protein (gene regulatory protein) to inactivate transcription of cyclins. This means no production of G1/S-Cdk and S-Cdk
- p53 induces expression of p21 (a CKI) to prevent activity of Cdk’s in cell cycle
cell proliferation is blocked both ways.
now explain how activation of proliferation by DNA tumor viruses occur
- viral protein E7 binds to Rb and so E2F can cause over expression of G1/S-Cdk and S-Cdk. cell grows and divides uncontrollably
- viral protein E6 binds to p53 and inactivates it and so CKI is not produced and Cdk’s can act uncontrollably
this is how cell proliferation is activated by DNA virus
oncogenes vs tumor suppressor genes
(1) overactivity mutations: gain of function - oncogenes - involves single mutation event and activation of gene causing proliferation (dominant) - “the gas pedal”
(2) under activity mutations: loss of function - tumor suppressor genes - involve genes that inhibit growth. mutation event: one gene = no effect; second mutation causes problems (recessive) - “the brakes”
explain oncogene collaboration
example of Myc Tg x Ras Tg mouse - where offspring expresses both Myc and Ras oncogenes - develops tumor earlier AND at a higher rate
what is one way the body stops cancer spread?
barriers to metastasis
first step is to escape from parent tissue (which is difficult to do); then travel through circulation (easy); then colonize a remote site (difficult)
Stopping cancer: colorectal cancer
- one of the most preventable cancers via colonoscopy
- takes 10 years for tumor progression
- start at age 50
explain colorectal cancer
- arises in the epithelial lining of large intestine
- gut is renewed at a rapid rate; this renewal is from stem cells
- mutations that disrupt organization signals begin tumor progression for colorectal cancer
- cancer: 600K deaths/year; 10% of those are colorectal cancer (age: >55%)
what can a colonoscopy detect? explain what it is.
it can detect a polyp, which is an adenoma. a small protruding benign tumor.
polyps are precursors of colorectal cancer; its a slow disease progression: 10 years.
you cut off the polyp - cure. if its left alone, malignant tumor develops from adenoma (polyp)
what mutations are common in colorectal cancer, and at what percentages?
- loss of Apc - >80%
- point mutation (activation) of K-Ras - 40%
- loss of p53 - 60%
what is hereditary colorectal cancer?
it’s a familial adenomatous polyposis coli (FAP)
hundreds of polyps
at least one polyp will become malignant
it is caused by inactivation of tumor suppressor gene APC
patients with FAP have inactivating mutations of one copy of Apc - then there is LOH, so no Apc gene is transcribed
most colorectal cancers are not hereditary but more than 80% of these cancers show inactivation of both copies of the Apc gene - acquired through lifetime
what is HPNCC
hereditary non-polyposis colorectal cancer
these cancer cells are unusual; normal HPNCC cells have normal number of chromosomes, but the cancer cells usually have multiple copies of chromosomes
the colorectal cancer usually has a chromosomal mess with abnormalities such as translocations, deletions and abnormal number of certain chromosomes
HNPCC - defects in DNA mismatch repair
whats another cancer treatment?
chemotherapy - drugs that treat cancer; it stops cell division - impact on rapidly dividing cells:
follicle cells produce hair = hair loss
stomach lining cells = nausea
blood-producing cells = anemia and immune dysfunction
whats the strategy with chemo?
give as strong a dose as possible to kill tumor and almost kill patient
what causes CML?
Philadephia chromosome
there is a Bcr-Abl fusion protein that results from the chromosome translocation
what is Bcr-Abl result in?
Abl is a tyrosine kinase for cell signaling
N-terminus Bcr makes it hyperactive
coding sequence of Bcr is fused to Abl when chromosomal translocation occurs; this makes highly active tyrosine kinase, and it is highly expressed
leads to cell proliferation = CML
whats a treatment for CML?
Gleevec therapy
it inhibits tyrosine kinase activity
gleevec causes disappearance of philadelphia chromosomes in >80% patients
gleevec binds to ATP site on Bcr-Abl protein which induces cell proliferation and survival, this binding means no signal. it is also thought to induce apoptosis via BH3-only protein
**Gleevec takes place of ATP on Brc-Abl; the substrate is NOT changed
what is combination therapy?
strategy: treat patients with drugs simultaneously, its an advantage for cancer therapy (CMH)
whats next for therapy?
personalized medicine
gene expression profile of a cancer can be analyzed by microarray to identify dysregulated cancer-critical genes
custom-driven treatments can be selected to target specific dysregulated cancer-critical proteins
what therapy did Folkman come up with?
anti-angiogenesis therapy
the idea that cancer tumors require formation of new blood vessels lead to the idea that if you starve the tumors, you prevent cancer.
used endostatin in cycles til cancer stopped coming back in lewis lung carcinoma
