ICL 7.4: Clinical Challenges of Cancer Flashcards

Question

What is the clinical presentation of LAD?

Answer 1

Increased susceptibility to developing recurrent bacterial/final infections Leukocytosis Localized bacterial infections that are difficult to detect until they have progressed to an extensive level secondary to lack of leukocyte recruitment at the site of infection The bacterial and fungal infections are gross looking....

Answer 2

Mutations of specific genes encoding adhesion proteins/receptors that are necessary for leukocytes to travel from the bloodstream to the site of an infection or inflammation Some patients with mild LAD syndrome have deficient levels of these proteins but retain some residual protein activity

Answer 3

LAD I >>> LAD II, LAD III

Answer 4

Neurophilia Periodontitis

Answer 5

Delayed separation of the umbilical cord Usually the umbilical cord should separate at 2 weeks of life but people with LAD I have delayed separation and lots of bleeding and hardened skin when it does happen

Answer 6

It mediates transmigration

Answer 7

Rolling LAD II is impaired fucosylation of sialylated carbohydrate ligands which prevents selectin binding Cytokines induce the endothelial expression of selectins But in LADII P-selectin and E-selectin on the ECM can’t bind to the S-Lewis X proteins on the leukocyte So integrins on leukocytes have normal expression and function but the selectin ligand has defective fucosylation CD15s levels are low or a sense while CD18, CD61 and CD29 levels are normal

Answer 8

Activation LAD III impairs cytokine signaling which prevents integrin activation There’s defective signaling of B1, B2 integrins on leukocytes and alphaIIbB3 integrin on platelets Integrin receptors on the leukocyte don’t get activated so then they won’t be able to later bind to ICAM on the ECM CD18 levels are low/defective CD61 levels are low in platelets CD15s levels are normal CD29 levels are low/defective

Answer 9

Tight adhesion LADI has an absence of CD18 which prevents formation of functional B2 integrins There is reduced or absent expression of B2 integrins on leukocytes but normal expression and function of selectin ligands CD18 is low or a sense while CD61, CD15s and CD29 levels are normal

Answer 10

When cells start rolling they add chemokins which are signals that drive activation of integrins and other membrane signals to allow for firm adhesion of the cell

Answer 11

CD 18 is low or a sense because it’s a B2 integrin problems CD61, CD15s and CD29 levels are normal CD29 = integrin B1

Answer 12

CD15s levels are low or absent because its an S-Lewis X problem CD18, CD61, and CD29 are normal

Answer 13

CD15s levels are normal CD18 and CD29 levels are low/defective CD61 levels are low in platelets LADIII effective many different integrins!

Answer 14

- epithelial cells - dense basement membrane - connective tissue Cells use MMPs to get through all of this! Also cells are really pliable so they can squeeze through

Answer 15

They do this by altering their E-cadherin expression E-cadherin is what zips cells up and connects them so if you get rid of it, single cells can escape from the collective tumor and invade EMT is when you lose E-cadherin and go from epithelial cells to mesenchymal cells that are happy existing as single cells Epithelial tumors undergo EMT and then intravasation and then extravasion into the underlying tissue These tumor cells are using the normal mechanisms that the immune system uses to infiltrate through the tissue! After the tumors extravasates into the tissue at the secondary site, they undergo MET to zip back up into epithelial cells and they do this by turning E-cadherin back on OVERALL: EMT —> intravasation through the basement membrane into the blood —> transport through circulation to secondary site —> extravasation from blood vessel into tissue of secondary site —> MET —> micrometastasis

Answer 16

EMT —> intravasation through the basement membrane into the blood —> transport through circulation to secondary site —> extravasation from blood vessel into tissue of secondary site —> MET —> micrometastasis Mimics the inflammation cascade so it uses the same exact cell-ECM and cell-cell adhesion molecules

Answer 17

EMT breaks down tumors into single cells so they can travel around the blood while MET zips them back up into a tumor at a secondary site

Answer 18

YES CTCs are really important genetic information because if we can isolate them we can use technology to sequence the DNA of the cells to try and understand how they have been changed genetically Then we can predict if we have a targeted therapy against that mutation or mutant protein This is good so you’re not just giving the patient a ton of different medications to hope something works Also this is non-invasive and just needs a blood sample instead of a sample from the tumor itself

Answer 19

1. Intravasation as single cells, coalesce into clusters within blood stream 2. Intravasation as single cells, proliferate within bloodstream and stay clustered 3. Collectively intravasation into blood stream = a whole group of cells intravasates together which is crazy! Cancer cells can enter the blood stream as single cells OR clusters of cells — often they will then aggregate within the blood stream into larger clusters

Answer 20

If CTCs are found in clusters its indicative of worse prognosis Clusters of different degrees of compactness, classified as very tight, tight and loose showed variable expression of cytokeratins Cluster formation is associated with disease progression and shorter overall survival

Answer 21

Metastasis isn’t actually that efficient of a process

Answer 22

cfDNA is released predominantly by cell death into the blood stream, although active secretion may have a role A lot of tumor cells are apoptotic so cfDNA gets released from them! We look at alterations in the DNA that we know are specific to a certain type of tumor or cancer Foundation One is the assay used to assess cfDNA so you can see which genes have been mutated to predict which therapy will work best for that tumor