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Physiology of Disease > VHL in Kidney Cancer > Flashcards

VHL in Kidney Cancer Flashcards

1
Q

Oxygen is an essential component for life on earth

A

proving a fundamental element in the survival of aerobic organisms

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2
Q

In normal oxygen environments

A

mitochondria consume 90% oxygen available
34 ATP per glucose molecule
oxidative phosphorylation

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3
Q

Hypoxia

A

demand exceeds supply
high altitude and disease
oxygen sensing pathways to increase oxygen supply to tissues

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4
Q

HIF

A

hypoxia inducible factor
3 isoforms
degraded in normoxia
stabilised in hypoxia

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5
Q

HIF degradation

A

normoxia
10% oxygen
prolyl hydroxylase enzymes
proline residues to HIF1a
recognised by VHL
proteosomal degradation

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6
Q

HIF stabilisation

A

hypoxia
100% oxygen to the mitochondria
VHL cannot degrade HIF1a
HIF1b dimerisation in nucleus
Transcription of target genes
Increase oxygen

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7
Q

VHL

A

Von hippel lindau
VHL disease - kidney tumours
Loss or mutation
Pseudohypoxia

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8
Q

HIF1a and HIF2a binding to HRE

A

Hypoxia response elements
50 identified
Cancer hallmarks
VHL tumour suppressor protein
Kidney cancer

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9
Q

Kidney cancer

A

2-3% cases
650 in ireland each year
blood in urine
lump/pain in kidney
tiredness/weakness
can be early detected
hard to treat if metastatic

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10
Q

renal cell carcinoma

A

85% kidney cancers
ccRCC most common
histological appearance
lipid accumulation

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11
Q

VHL and ccRCC

A

90% of people with ccRCC have a mutation in VHL

No other gene perturbed to this level

Pseudohypoxia - cancer hallmarks

Relationship of VHL and ccRCC evident

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12
Q

HIF2 and HIF1a in Kidney cancer

A

HIF2 promotes (tumour promoter)
Agonism increased tumour volume and weight
HIF1 debated role
May act in early and redundant
HIF1 may be an oncogene

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13
Q

Ways HIF2 promotes cancer hallmarks in ccRCC

A

Raval et al. 2005

Plin2
Cyclin-D1
TGFa
VEGF
GAL3ST1

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14
Q

Plin2

A

increased lipid droplet formation - characteristic of ccRCC

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15
Q

CyclinD1 and TGFa

A

Cell proliferation

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16
Q

VEGF

A

Angiogenesis

17
Q

GAL3ST1

A

Platelet binding
Immune cell evasion
Robinson et al. 2019

18
Q

HIF2a inhibition with Belzutifam

A

Prevent dimerisation and transcription
FDA approved
Well tolerated
Highly specific
HIF2a inhibitor
Non-metastatic RCC and VHL disease

Physiology of Disease (4 decks)

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