4.28.2010

1. Mutations2. Oncoprotein

a. Trki. Increase in activity leads to increase in cell mitosis

b. Muscle topomyosin protein, the gene that controls that is inadvertently c. Trk usually dimerizes and autophosphorylates, but in this case doesn’t

depend on growth factorsd. Each tropomysoin protein is linked with a Trk receptor peptidee. PDGF receptor and PDGF ligand – platelet derived growth factor

i. We have a coding region for a transcription factor that forms a helix shape

1. Tel and PDGF recepts bind and a. Dimerized transcription factor and due to helix shape,

keeps i. Tel acts as an oncogene and drives cell mitosis

1. Causes to be always on3. RB mutations

a. Rb in unPi state will ind to E2F and restrict gene transcription required for S phase

b. When Pi, ras signaling is turned on, leading to activation of G1 cyclini. Cdk Pi Rb

1. E2F regulates gene transcription and translation for enzymes and other S phase proteins

c. Seen in childreni. Tumors in retinas

d. If inheritedi. Will be a single mutation in those gene cells

ii. If there is another hit on the healthy allele that produces Rb, there will be hereditary retinoblastoma

e. If not inheritedi. At some point, environmental stress can lead to mutaion on RB gene and

take a second hit after that to lead to an RB oncogenic transformation4. Methods to help restrict cell growth

a. P53 pi, turns on two mechanisms for regulating cells that have mutationsi. Upregulated CKI – p21

ii. Activate PUMA – inhibit Bcl2, driving apoptosisb. P53 is the guardian of the gene

5. Cell Stress that can be recognized by p53a. Treatment induced

i. Chemicals used to try to eliminate tumorsb. Intraceullular stress

i. Can lead to cell death or arrestii. Telomere shortening

1. Haflick limit

2. Another round of cell mitosis just can’t take place3. telomere shortening doesn’t occur at the same rate 4. telomere shortenining doesn’t happen in cancer cells

c. Cell death isn’t just mitosisi. Mitotic catastrophe drives deploy of microtubules required to pull apart

sister chromatidsii. Autophagy helps eliminate cancer cells

iii. Necrosis and entosis can contribute to help remove cancer cells6. Trating cancer

a. Ioninzing radiation exposed to celli. Results in DNA damage

1. p53 recognizes damage and do its duty of arrest/repair or deathii. even if p53 is not working, the cell will recognize damage, arrest, mitotic

failure, catastrophe, and the tumor will regress in size. 1. If you don’t make a severe mutation to allow cell death, the cell

will continue to divide and go through mitosisb. KO studies of p53 and treated with chemotherapy drugs

i. 5-flurouracil, etoposide, adriamycin, are all cancer drugs1. DKO = no p53

a. As if chemo has not even been done2. +/- = one mutated gene3. control

7. Cell divisiona. Will top dividing after Haflick limitb. With optimum genetic instability, there will be a change in the cells that will

make them more likely to become oncogenic with a second hit.i. These do not need to be malignant generally

ii. May end up with cell that is neoplastic and malignant and form metastasis in other parts of the body.

8. Therapies for cancera. If you can’t mutate the dna with treatment, cancer smart bombs are an option

i. Nanoparticles – filled with chemotherapy drugs1. Package a concentrated amount of chemo drugs into or on the

nanoparticles and develop a way to give to a specific cancer cella. Whats on the surface that we can target there?b. Cells are targeted to particular tissues because thy have

receptors that recognze addressinsi. often integrin type receptors or cell adhesion

(CAMs) that bind specific tissues and target to particular site.

2. Prostate Cancera. Docetaxel on the NPs and recognize aptomers, or short

strands of RNAi. We can target aptomers to specific proteins

1. PSMA – prostate receptor mucosal addressing

2. Endocytosis and a mechanism for killing of prostate cancer cells

3. A problem with chemo is specificity of the drugii. Take immune cells from individuals, aggressive mealnoma patients, and

virally infect the cells with constructs that target them to epithelial cells, or melanoma cancer cells.

1. Irradiate and kill off the rest of the person’s functional immune system

a. Hope to only have these virally infected immune cells active for treatment

b. Inject super active immune cells into individual, targeting cancer cells more effectively.

c. 2/17 people have shown continual remission. So not very successful.

d. Because using own immune system, don’t have to worry about rejection

9. Hallmarks of Cancer/tumoregenic cellsa. Avoidance of apoptosisb. Sustained angiogenesis, where they can recruit endothelial cells to enhance

blood vesicles around tumorsc. Lack of growth factor dependeance

i. Loss of contact inhibition as welld. Unlimited mitotic potentiale. Increased cell signaling, which supports iunlimited mitotic potentialf. Tissue invasion/metastasisg. Inflammation

i. Kime et all 2009 - Nature1. Macrophages, usually phagocytic cells, can contribute to tumor

progression because cytokines secreted help drive cell mitosis of cancer cells

2. Change ECM protein expression, supporting tumor survival/growth