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HemOnc Week 2 > ICL 7.4: Clinical Challenges of Cancer > Flashcards

ICL 7.4: Clinical Challenges of Cancer Flashcards

1
Q

Name 5 processes in the body where cell migration is a critical driver

A
  • embryogenesis
  • inflammation
  • tumorgenesis
  • metastasis
  • wound healing

Cell migration is super important in promoting and allowing these processes to occur!

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2
Q

What are the three types of adhesion molecules involved in leukocyte-endothelial interaction during inflammation?

A
  1. Integrins
  2. Selectins
  3. IgG superfamily molecules

Tumor cells will use these same molecules during invasion/metastasis!!

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3
Q

What are integrins?

A

They’re adhesion molecules on leukocytes

Involved in cell rolling/arrest

They are transmembrane receptor heterodimers (alpha and beta)

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4
Q

What are selectins?

A

Adhesion molecules on leukocytes and endothelial cells

Involved in trapping and rolling of cells

selectins are the receptors and their ligand is fucosylated sialoglycoconjugates on glycoproteins = S-Lewis X

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5
Q

What are IgG molecules?

A

A family of adhesion molecules

Mostly endothelial cells and includes ICAMs and VCAMs

Involved in firm adhesion and diapedesis of cells

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6
Q

What’s the CD designation for P-selectin?

A

CD62P

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7
Q

Whats the CD designation for E-selectin?

A

CD62E

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8
Q

What’s the CD designation for L-selectin?

A

CD62L

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9
Q

What are B1 integrins? What’s their CD designation?

A

CD29

This integrin mostly binds to ECM substrates like dibronectin, collagen and lamin in

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10
Q

What is the CD designation for B2 integrins?

A

CD18

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11
Q

What is LFA-1?

A

When CD18 aka a B2 integrin is paired with an alpha integrin called CD11a it’s called LFA-1

The ligand for this integrin is ICAM 1-5

When different alpha units pair with CD18 B2 integrin they have different ligands

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12
Q

What cells express CD11a?

A

It’s a pan-leukocyte marker

It’s expressed by B and T lymphocytes, monocytes, macrophages, neutrophils, basophils, and eosinophils

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13
Q

Which cells express CD11b?

A

Strongly expressed by most granulocytes, monocytes/macrophages, and NK cells

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14
Q

Which cells express CD11c?

A

Highly expressed in monocytes or macrophages, NK cells and hairy cells

Moderately expressed in granulocytes

Weakly expressed in lymphocyte subsets

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15
Q

What’s the CD designation for B3 integrins?

A

CD61

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16
Q

What is αIIbβ3?

A

CD41CD61

It’s a receptor for fibronectin, fibrinogen, vWF, vitronectin and thrombospondin

It has a crucial role in coagulation

Mutations that impair its role in coagulation result in thrombasthenia

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17
Q

What is αVβ3?

A

CD51CD61

It’s a type of integrin that is a receptor for vitronectin

It’s a marker for angiogenesis

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18
Q

What is the CD designation for sialyl Lewis-X?

A

CD15s

Sialyl Lewis-X is the ligand for E and P-selection

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19
Q

What are the steps of the adhesion cascade?

A
  1. Rolling

Selectins grab onto S-Lewis X which causes rolling

  1. Leukocytes activation and arrest

Integrin/VCAM or integrin/ICAM interactions mediate this

  1. Crawling and transmigration

Integrins bind to CAM, ECM or PCAMs

20
Q

What is leukocyte adhesion deficiency?

A

Rare primary immunodeficiencies affecting the immune system — LAD syndromes are characterized by defects affecting how leukocytes respond and traffics to the site of a wound of infection

Patients develop increased susceptibility to developing recurrent bacterial/fungal infections

LAD I»>LAD II, III

The different types of LAD can hit different parts of the adhesion cascade like rolling, activation or adhesion

The adhesion cascade is very linear aka everything has to go in order - so if any one stage is messed up then the down stream response will be interrupted and inflammation won’t happen or the tumor won’t be able to spread

Rolling —> activation —> adhesion —> transmigration

21
Q

What step of the adhesion cascade is LADI associated with?

A

Adhesion

22
Q

What step of the adhesion cascade is LADII associated with?

A

Rolling

23
Q

What step of the adhesion cascade is LAD III associated with?

A

Activation

24
Q

What is the inheritance pattern of LAD?

A

Autosomal recessive

25
Q

What is the clinical presentation of LAD?

A

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….

26
Q

What causes LAD?

A

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

27
Q

What is the most prevalent type of LAD?

A

LAD I&raquo_space;> LAD II, LAD III

28
Q

What characteristics do all LADs have?

A

Neurophilia

Periodontitis

29
Q

What is a unique characteristic of LADI?

A

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

30
Q

What does PECAM do?

A

It mediates transmigration

31
Q

What part of the adhesion cascade does LAD II effect and how?

A

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

32
Q

What part of the adhesion cascade does LAD III effect and how?

A

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

33
Q

What part of the adhesion cascade for LADI effect and how?

A

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

34
Q

What do chemokines do?

A

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

35
Q

What are the levels of CD18, CD61, CD15s and CD29 in LADI?

A

CD 18 is low or a sense because it’s a B2 integrin problems

CD61, CD15s and CD29 levels are normal

CD29 = integrin B1

36
Q

What are the levels of CD18, CD61, CD15s and CD29 in LADII?

A

CD15s levels are low or absent because its an S-Lewis X problem

CD18, CD61, and CD29 are normal

37
Q

What are the levels of CD18, CD61, CD15s and CD29 in LADIII?

A

CD15s levels are normal

CD18 and CD29 levels are low/defective

CD61 levels are low in platelets

LADIII effective many different integrins!

38
Q

What are some cell and tissue-based obstacles to epithelial cell invasion and metastasis?

A
  • 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

39
Q

How does a tumor spread and progress?

A

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

40
Q

What are the basic steps of tumor cell intravasation and extravasation to a secondary tumor site?

A

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

41
Q

How does EMT and MET play a role in tumor metastasis?

A

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

42
Q

Can you gather information from circulating tumor cells (CTC) as to the genetic state of a tumor and whether a targeted therapy would work?

A

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

43
Q

How do clustered CTCs get into the bloodstream?

A
  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

44
Q

What do clusters of CTCs indicate?

A

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

45
Q

How many cells that are capable of metastasizing actually are successful?

A

Metastasis isn’t actually that efficient of a process

46
Q

How can cell-free DNA be used as a diagnostic test for tumor status?

A

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

HemOnc Week 2 (14 decks)

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