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34 Cards in this Set

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Matrix Metalloproteinases (MMPs)

- enzyme that breaks down ECM


- secreted by stromal cells


- macrophage injection in tumor cells will cause increase in MMPs


- important effect of EMT is MMP secretion

Lemellopodia

- cytoplasmic extensions used for cell movement


- leading end has integrins attach and pull


- lagging end has myosin contract the cytoplasm

Ras-like GTPases

- control alterations in cell shape and mobility


- "on" or "off" depending on GTP binding


- consist of Rho, Rac, and Cdc42 families

Rho Family GTPases

control cell movement via stress fibers and focal adhesion

Rac Family GTPases

cause lamellopodia formation

Cdc42 Family GTPases

cause filopodia formation

Alkylating Agents

damage DNA -> apoptosis


- cisplatin

Anti-metabolites

nucleotide analogs incorporated into DNA


- 5-fluorouracil

Taxanes

stabilize MTs during division to form a normal mitotic spindle


-Taxol

Topoisomerase Inhibitors

prevent DNA unwinding


- etoposide

Antineoplastics

intercalate and damage DNA


- Doxorubicin

Gleevec

targets Bcr-Abl kinase to treat myelogenous leukemia



Targeted Cancer Therapies

- Gleevec targets Bcr-Abl kinase for myelogenous leukemia


- Iressa targets EGFR in lungs


- Herceptin targets ErbB2 in breast

Essay 1: 3 reasons rare cancers have no treatment

1. Underfunded


2. No cell lines


3. Uncommon mechanisms

Essay 2: Target for Chemo?

B-catenin


- high levels of nuclear b-catenin are associated with p53 signaling and with EMT


- knock down to treat early stage cancers or for cancers that recur at high rates


- killing cells with high B-c would be generic, FAP


- 2014 Zhang et all, nuclear B-catenin post chemo in cervical squamos cell -> low survival

Essay 3: Blend two papers

Use method for determining active site on Akt in Liu article to determine binding importance of asparagines in HAS2 of Tian article. This would further show the link between the weird HAS2 sequence and enhanced levels of HMM-HA. Basically just mutate each site by changing AA and look at binding ability

Essay 4: New Hallmark of Cancer?

Deregulating Cellular Energetics


- argument against is its an effect of malignancy


- use glycolosis to avoid hypoxia (same reason angiogenesis is a thing)


- angiogenesis is partly used to get rid of glycolosis byproducts


- GLUT1 receptors are often upregulated


- warburg effect lends to proliferation

heterotypic interactions

signaling between stromal and epithelial cells

PDGF

- hetertypic interaction


- secreted by epithelia, received by stroma -> IGF-1 release


- signals fibroblast recruitment -> MMPs


- released in wound healing too


- myofibroblast recruitment -> desmoplastic


--- similar to wound healing



EMT

- loss of E-cadherin for N


- destabilized adherens junctions


- makes cells invasive


- seen at edge of carcinomas


- gain of vimentin


- highly promoted by TGF-B

Carcinoma Associated Fibroblasts (CAFs)

- combination of fibroblasts in desmoplastic region


- hugely important to tumor formation

VEGF

- Flt1 and Flk1 receptors on epithelial cells


- stimulates proliferation and capillary formation

angiogenic switch

- change from hypoxia -> apoptosis to hypoxia -> angiogenesis


- recruited inflammatory cells release MMPs to breakthrough ECM and allow VEGF to hit epithelia

Tsp-1

- secreted in extracellular space


- stimulates Fas-L production by epithelia cells -> apoptosis


- negative regulator of apoptosis


- only secreted during capillary growth


- shut off by Ras



Invasion-Metastatic Cascade

1. Primary Tumor


2. Localized Invasion ("malignant")


3. Intravasion


4. Transpo (lots of cells die)


5. Arrest in Capillaries


6. Extravasion (different methods, platelet push)


7. Formation of Micrometastases


8. Colonization (RLS, cells just sit there)

Vimentin

- replacement of cytokeratin of epithelial cells during EMT

TGF-B

- strong promoter of EMT


- exposure to Ras cells will quickly lead to EMT


--- later removal and cells will secrete own TGF-B


--- if TGF-B totally goes away then MET occurs


- NF-KB pathway is causing EMT

NF-KB

- pathway signalled by TGF-B that causes EMT


--- blocked by IkBa


- also used by TNF-a to promote EMT

CSF-1

- recruits tumor associated macrophages


- loss prevents basement membrane breakthrough



Hepatocyte Growth Factor (HGF)

- causes cell scatter which can lead to EMT

Twist

- transcription factor identified in Drosophilia that facilitates gastrulation normally


- induction can cause EMT


- induces metastases


- blocks anoikis

Slug

- transcription factor identified in Drosophilia that facilitates movement and morphological changes in wound healing


- induced in EMT


- inverse correlation with e-cadherin in breast cancer


- helps with invasiveness


- blocks anoikis

Bonapace

- inhibition of CCL2 used as treatment, but stopping treatment leads to IL-6 monocyte recruitment which causes more CD31 (endothelial) and Ki67 (proliferative) cells which leads to more metastases and increasing CTCs

Tian

Naked mole rats don't get cancer due to:


- HMM-HA


- decreased HA degradation (HAase) and increased production (HAS2)


- increased HA sensitivity


- increased HA affinity