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Block 1 Week 4 > Neural Crest Cells > Flashcards

Neural Crest Cells Flashcards

1
Q

most common malignancy & second leading cause of death in women in USA?

A

-breast cancer

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2
Q

HER2 and breast cancer?

A
  • seen in up to 20% of breast cancers (BRCA1/2= 1%)

- associated w/ aggressive phenotype

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3
Q

what is HER2? what pathway does it activate?

A
  • an oncogene (ERBB2 is gene)
  • is a transmembrane tyrosine kinase receptor in EGFR family
  • activates 2 pathways
    1) PI3K-AKT-mTOR (apoptosis)
    2) MEK/ERK (proliferation)
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4
Q

How activate HER2 normally(pro-otoncogene) vs when its hyper activated (oncogene)?

A
  • proto: requires a ligand mediated heterogeneity or homo dimerization
  • oncogene:activates in ligand-independent manner
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5
Q

two mechanisms of HER2 amplification?

A

1) chromosomal region contains multiple copies of HER2 (hyper trxn)
2) multiple chromosomes w/ normal amount of HER2 trxn/copies being made

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6
Q

two mechanisms of gene amplification?

A

1) double minute chromsomes
2) homogenous stained regions

-not independent, most likely arise in same fashion & can be acquried by same mechanism

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7
Q

how make homogenous stained regions & how do they cause gene amplification??

A

-when have a normal amount of the chromosome, but the region with the gene of interest is being transcribed more than normal (amplified)

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8
Q

glioblastomas and what are result of?

A

most common adult primary malignant brain tumor

  • very aggressive, poor prognosis
  • most have amplified EGFR gene, with half expressing the EGFRvIII variant 7
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9
Q

glioblastomas and what are result of?

A

most common adult primary malignant brain tumor

  • very aggressive, poor prognosis
  • most have amplified EGFR gene, with half expressing the EGFRvII (variant 7)
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10
Q

healthy pathway of EGFR? hyperactive pathway?

A
  • usually phosphorylates ERK pathway, leads to proliferation
  • hyperactivated get:
    1) hyperproliferation
    2) increased invasion
    3) elongated irregular shape
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11
Q

neuroblastoma (NB)

A
  • most common extracranial solid tumor in kids

- bad prognosis for advanced stage or relapsed disease

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12
Q

MYCN amplification

A
  • seen in 25% NB tumors
  • is trxn factor
  • expressed early in development up through a few weeks following birth
  • after it is restricted to adult B cells
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13
Q

What does MYCN trxn factor do in the cell?

A

1) controls expression of genes that increase cell proliferation
2) changes chromatin structure by DNA hypermethylation (causes proliferation)

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14
Q

N-MYC & neuroblastoma

A

-not cause of neuroblastoma, but if see MYCN amplification in neuroblastoma know its a severe/aggressive form and prognosis is bad

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15
Q

two ways N-MYCN gene can be amplified?

A
  • homogenous stained regions

- double minute chromosomes

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16
Q

what are the cytogenetic hallmarks of genomic amplification in cancer?

A

1) double minute chromosomes
2) homogeneously staining regions

-50% of cancers have these marks

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17
Q

survival of neuroblastoma and the N-MYC gene?

A
  • see that >10 copies of N-myc shows decreased survival

- <10 copies of N-myc shows an increase in survival

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18
Q

how form double minute chromosomes?

A
  • done via the episome model
  • have a DNA segment that is excised from an otherwise intact chromosome, circularized (often multiple of this DNA segment in the circle) & amplified
  • makes many copies of the chromosome so amplify the protein product
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19
Q

ecDNA? where found?

A
  • extrachromosomal DNA
  • double minute chromosomes are an example; are nuclear and circular
  • found ~50% human cancers; varied by tumor type, never found in normal cells
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20
Q

neural crest cells & vertebrates?

A
  • w/o vertebrates wouldn’t have survived/evolved
  • key to increase the size of skull that protects larger brain
  • provide key features of jaw for predatory life style
  • provide pigmentation
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21
Q

General movement of neural crest cells

A

1) in neural ectoderm/non-neural ectoderm border in the neural plate
2) elevate w/ the neural fold
3) become part of the dorsal neural tube, migrat out and make cranial ganglia (neural crest cells) & extomesenchyme

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22
Q

What is Ectomesenchyme?

A
  • made of neural crest cells
  • contribue to production of bone & cartilage of the face
  • is how neural crest cells contribute to the jaw
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23
Q

What do neural cells make/contribute to?

A 
contribute cranially:
1) neurons &amp; glia of cranial ganglia
2) cartilage &amp; bone
3) connective tissue 
contribute to trunk:
1) pigment cells
2) sensory neurons &amp; glia
3) sympathy adrenal glands
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24
Q

Are neural crest cells pluripotent?

A
  • do have many derivatives so are described as multipoint

- NOT pluripotent like stem cels

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25
Q

neural crest gene regulatory network?

A

1) at neural/non-neural ectoderm border receive induction signals from BMP
2) triggers Border Specifiers as neural fold appears
3) triggers NCC Specification as tube closes w/ neural crest cells in dorsal region
4) Migration (out of dorsal region) and Differentiation

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26
Q

historical understanding of induction of neural crest cells (NCC)? (classic induction)

A
  • thought were differentiated as ectoderm cells b4 folding started; but they give rise to mesoderm derivates (bone, cartilage etc)
  • thought communication between Meso-Ecto or Non-Neur-Neural Interactions allowed the NCC to develop mesoderm features
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27
Q

current understanding of induction of neural crest cells?

A

-recognize a cascade of events initiated by signaling molecules which induce a relay of expression of various TF that ultimately lead to mig & Diff of NCC.

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28
Q

new mechanism of neural crest cells induction?

A
  • instead of late induction of NCC on ectoderm, it happens before gastrulation
  • future NCC cell are tagged & retain early epiblast function including ability to make both ecto & meso
  • allows NCC to have functions in both germ layers
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29
Q

neural crest migration

A
  • NCC undergo an epithelial to mesenchymal transition (EMT)
    1) leave the dorsal neural tube
    2) emigrate into adjacent territory
    3) do widespread stereotypic migration
    4) near/at final location differentiate
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30
Q

NCC migration & other tissues/cells?

A
  • unlike other cells, NCC don’t avoid other tissues/cells

- migrate through them, like invasive cancer

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31
Q

describe neural crest cells

A
  • arise early in development
  • migrate extensively & differentiate into a range of derivatives
  • they are multipotent , & often thought of as stem cell-like cells.
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32
Q

How do NCC do EMT (Epithelial-Mesenchymal Transition)?

A
  • to be in epithelia had to maximize contact w/ neighbor cells (rectangle shape, attach to basement, cell-cell interactions)
  • get signals to down-regulating adhesion molecules (detach), then signals to move away (delamination)
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33
Q

plasticity of NCC during migration?

A
  • stay plastic for long time during migration, typically don’t differentiate until reach terminal destination
  • can change plan IF given specific signals
34
Q

what promotes down regulation of adhesion molecules? what are the adhesion molecules being down regulated?

A
  • promoted by Slug & Snail family trxn factors

- cadherin & adhesions

35
Q

what is mesenchymal tissue?

A
  • embryonic connective tissue that is derived from the mesoderm and that differentiates into connective tissue & other things
36
Q

Neurocristopathies

A
  • Disorders of neural crest cell development, mess up pigmentation, facial features etc
  • failure to make enough NCC or messed up NCC migration leads to these
  • up to 1/3 cranial malfunctions caused by neural crest defects
37
Q

Treacher Collins syndrome

A
  • a Neurocristopathy
  • defects in cranial neural crest cell formation
  • cause craniofacial anomalies
38
Q

syngnathia?

A

-defects in neural crest cell differentiation

39
Q

NCC & cancer?

A
  • NCC have capacity
    1) expand/proliferate,
    2) Migrate aggressively,
    3) differentiate into a wide range of derivatives
  • make it perfect pathway for cancer spread
40
Q

Neural Crest Cell Derived Cancers

A

1) Melanoma – melanocyes/skin cancer

2) Neuroblastoma – nerves/nervous tissue

41
Q

NCC & cancer metastasis

A
  • do EMT & MET*
    1) invasion EMT occurs in metastatic primary epithelial tumors (eg breast)
    2) tumor cells break through epithelial w/ same signals and enter blood
    3) transport through circulation, arrest in micorvessicle of various organs
    4) do invasive MET to break into new tissue
    5) form micrometastsis then macrometastsis in new tissue
42
Q

Who regulates EMT and MET?

A

Snail, Zeb and Twist families of proteins

-(mostly snail)

43
Q

epithelial cell components?

A

1) cell-cell adhesions
2) motility is low
3) E-cadherin/catenin

44
Q

mesenchymal cell components

A

1) cell-matrix interaction
2) motility high
3) N-cadherin/vimentin
4) MMPs/collagen

45
Q

Melanoma

A

-cancer originates from melanocytes NCC

46
Q

what are the 3 common skin cancers?

A

1) Basal cell carcinoma
2) Squamous cell carcinoma
3) Melanoma
- first 2 more common, not aggressive
- Melanoma is very aggressive

47
Q

benign melanocytic neoplasm?

A
  • Congenital Naevi
  • are childhood pigmented lesions (present at birth); frequently lead to melanoma
  • risk increases as you age
  • SOX10 positive
48
Q

Multiple congenital melanocytic nevi may reflect what?

A
  • a mosaic RASopathy

- reflecting postzygotic activating mutations inNRAS (which often leads to cancers)

49
Q

How is Melanoma classified (2 types)? common ages in the 2 types?

A

1) CSD:skin chronically sun damaged (head/neck)
- >55 years
2) Non-CSD: covered by clothes; less UV exposure
- according to sun exposure
- <55 years

50
Q

where are BRAF V600E mutations found?

A

-only in Non-CSD melanomas (covered areas)

51
Q

why age distinction between CSD and Non-CSD?

A
  • suggest that Non-CSD, have areas rarely exposed to the sun so have limited protection, therefore when are exposed have a lot of DNA Damage= cancer at younger age
  • in CSD skin often exposed to sun, more protections, requires very slow accumulation of DNA damage to reach cancer (>55 years)
52
Q

Where do CSD & non-CSD melanoma present?

A
  • Present mutations in key signalling pathways that govern
    1) proliferation
    2) growth and metabolism
    3) cell identity
    4) resistance to apoptosis
    5) cell cycle control
    6) replicative lifespan
53
Q

acronym for melanoma skin cancer?

A 
-ABCDE
A) asymmetry 
B) borders 
C) color 
D) dimensions 
E) elevation
54
Q

SOX 10

A
  • master regulator of NCC development & involved in multiple steps of the process
  • critical for maintaining proliferation & multipotency of NCC
  • influences differentiation into melanocytes in the skin; neurons, glia and Schwann cells in PNS
55
Q

SOX 10 in melanoma

A

-is super activated leading to excessive proliferation

56
Q

loss of Sox10 activity?

A
  • counteract mutant Nras driven congenital naevi & melanoma formation w/o effecting other NCC function
  • suppresses melanoma’s neural crest stem cell properties, counteracts proliferation & cell survival, & abolishes in vivo tumour formation
57
Q

NEUROBLASTOMA, what is it due to?

A
  • most common cancer in infants < 1 year
  • develops at any site of sympathetic nervous system tissue; causes pain
  • due to failure of neurocrest cell precursors
58
Q

where do most causes of neuroblastoma arise?

A
  • the abdomen; either adrenal gland or retroperitoneal sympathetic ganglia
  • adrenal glands are populated by a lot of NCC, so common place for it to arise
59
Q

what does neuroblastoma look like?

A
  • firm nodular mass palpable in the flank or midline causing abdominal pain
  • has variable degrees of neural differentiation, from undifferentiated to mature ganglion cells
60
Q

where does neuroblastoma metastasis to? does it metastasis at all?

A

-metastasis to the long bones, skull, BM, liver, lymph nodes & skin

61
Q

what genes involved in neuroblastoma?

A

-Mutations in ALKandPHOX2Bgenes have shown increased risk of getting familial&sporadic neuroblastoma

62
Q

MYCN gene and neuroblastoma?

A
  • MYCN gene amplification shown in 25% of neuroblastoma cases
  • associated w/ severity of disease NOT the cause of the disease
63
Q

MYCN gene function and role?

A
  • N-myc is a transcription factor, regulates neural crest cell proliferation, survival, migration and and differentiation and
  • over expressed in neuroblastoma
64
Q

Medullary thyroid carcinoma (MTC)

A
  • 25% are familial (fMTC); described as multiple endocrine neoplasia syndromes (MEN2)
  • inherited as autosomal dominant cancer
  • characteritized by MTC & hyperparathyroidism (HPT)
65
Q

What are the 3 ways fMTC appear?

A

1) MEN2A
2) MEN2B
3) FMTC

66
Q

MEN2A

A
  • (60-90%); MOST aggressive
  • Late onset (50 to 70 years old)
  • seen in Medullary thyroid cancer, Pheochromocytoma, or benign adrenal gland tumor
67
Q

MEN2B

A
  • (5%); middle aggressive
  • benign tumor of nerve tissue on tongue, lips & throughout GI tract
  • muscle, joint & spinal problems
  • Early onset, shortly after birth
68
Q

FMTC

A
  • (5 to 35%); least aggressive
  • Familial medullary thyroid carcinoma only (MTC only)
  • has no other pathologies
69
Q

what does RET encode?

A
  • first proto-oncogene implicated in an inherited cancer susceptibility syndrome
  • encodes a transmembrane receptor tyrosine kinase expressed in tissues & tumours derived mainly from NCC
  • autophosphorylates & activates MAPk (proliferation) & PI3K/AKT (survival) pathways
70
Q

RET & fMTC?

A
  • GermlineRETmutations have been identified in ~95% of all MEN 2
    1) 98% of MEN 2A probands
    2) 97% in MEN 2B
    3) 85% in FMTC
71
Q

What happens when RET is mutated?

A
  • leads to RET’s constitutive activation, so causes over proliferation & evasion of cell death
  • in MEN2A see missense mutations in multiple cysteine codons
72
Q

RET receptor configuration?

A
  • requires a multicomponent complex to trigger activation
  • RET has to bind one of four GFR before binding one of four members of the glial cell line-derived neurotrophic factor family of ligands
  • bind into a heterohexameric complex
73
Q

What is GFR family of proteins?

A

-family of GPI-linked coreceptors

74
Q

Rhabdomyosarcoma and 2 types

A
  • soft tissue sarcoma arising from cells of mesenchymal or skeletal muscle lineage
  • localize to head, neck & muscles of eye, GI tract & retroperitoneum
  • rare childhood cancer
  • 2 types: ARMS & ERMS
75
Q

Rhabdomyosarcoma due to (2 variations)

A

chromosome rearrangment (translocation)

  • between chrom 1 & 13; causes a fusion of
    1) Pax 3-FOX01 (common)
    2) Pax7-FOX01 (less common)
76
Q

PAx 3 vs Pax 7

A
  • on diff chromosomes, have same spot for recombination w/ chrom 13 where FOX01 is
  • have similar sequence, when fused with FOX01 will produce same protein
  • both have pair, homeo & transactivation domain
77
Q

How distinguish Pax 3-FOX01 vs

Pax7-FOX01? How do they act?

A
  • almost impossible to if just look at Pax-FOX product, due to insane similarity between the two
  • fusions act as trxn factors which results in expression of oncogenic fusion protein
78
Q

t(2;13)(q35;q14),

A
  • chromosomal translocation found in ARMS; result sin PAX3-FOX01 fusion trxn factor
  • is most common
  • results in the expression of an oncogenic fusion protein.
79
Q

what does PAX03-FOX01 fusion protein consist of?

A
  • consists of the paired & homeodomains of the PAX3 trxn factor w/ the potent transcriptional activation domain of FOXO1
  • so have same amount of chromosome, but now are hyperactively transcribing it due to FOX01 presence, now have cancer
80
Q

what is major driver of malignancy in NCC cancer?

A
  • the reactivation of neuro-crest potentials (undifferentiated cells)
  • capacity to proliferate more than other cells, migrate & EMT, & plastic differentiation capacity lead to cancer metastasis
81
Q

ARMS?

A
  • Alveolar rhabdomyosarcoma, kids <10
  • more aggressive, more prone to metastasis & carries poorer prognosis
  • tumors carry one of several characteristic chromosomal translocations like t(2;13)(q35;q14)
  • results in PAX3-FOX01 fusion trxn factor that hyper-transcribes gene, hyperactive protein and lead to rhabdomyosarcoma

Block 1 Week 4 (7 decks)

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