Cancer 2

Question 1

benign tumour characteristics

Answer 1

Generally self contained and localised

well defined periphery

slow growing

expands outwards from central mass

Question 2

Malignant tumour characteristics

Answer 2

Not self contained or localised

presence of invading cells at periphery

able to spread

have capacity for rapid growth

Question 3

what is bad about metastic tumors ?

Answer 3

Hard to treat surgically

impair organ function

chemo resistant

Question 4

lymph nodes role in cancer metastases

Answer 4

Lymphatic system is a common pathway for the initial spread of solid tumour

pattern of lymph nodes involvement follows natural route of drainage

can also spread through the body wall into abdominal and chest cavities

involvement of lining of cavities results in inflammatory response, accumulation of fluid and inflammatory cells

Question 5

Oestrogen signalling involving nuclear ER

Answer 5

1. Oestrogen diffuses into the cell. E.ligand bunds to the hydrophobic pockets of the nuclear ER
2. ER conformational changes -> helix 12 region of ER protein fully seals pockets contianing E.ligand
3. Hsp90 “chaperone proteins” are lost and the 2 oestrogen bound receptors dimerise
4. Oestrogen bound ER dimees bind directly to the ERE in the DNA promoter of oestrogen sensitive genes driving their expression
5. After binding of the dimer to ERE, gene expression is regulated by AF-2 and AF-1
6. When oestrogen is blund to the ER, AF-2 reguon recruits co-activators. These bridge the ER to rhe cell transcription machinery -> transcription of ERE containing gene
7. AF-1 also recruit co-activators (after Phosphorylation)
   8) Both AF-2 and AF-1 activity are reguired for max gene exprssuon whifh promotes proliferation and cell surival -> ER+ cancer growth

Question 6

What do Non steroidal antioestrogens do ?

Answer 6

Compete with oestrogen for ER binding
Tamoxifen is a trans isomer of the substituted triphenylethylene with a bulky side chain
Reduces growth of early or advanced

Question 7

How does Tamoxifen have antioestrogenic effects?

Answer 7

Similar structure to oestrogen so competes for ER binding
Binding causes conformational changes, hsp90 loss and receptor dimerisation
Bulky side chain furthers alters conformation and displaced helix 12 so that the pockets can’t fully seal -> results in no recruitment AF-2 coactivators

Question 8

How does Tamoxifen have oestrogenic effects?

Answer 8

on uterus mainly

AF-1 is still phosphorylated by kinases and recruits its co-activators

Due to persistent AF-1 activity, transcription and proliferation still occur

SERM behaviour depends upon the tissues content (balance of corepressors and coactivators)

Question 9

Steroidal Antioestrogens

Answer 9

Derivatives of 17-Beta oestradiol with a long unbranched hydrophobic 7 alpha aklylsulphyl side chain

Steroidal (100x affinity v tamoxifen)

Potent competitive inhibitor of oestrogen binding to ER but also gives catastrophic decrease in ER level and activity

Faslodex has no oestrogenic activity

Question 10

Faslodex MOA

Answer 10

Competes with oestrogen binding at ER

Long side chain causes impaired ER dimerization, decreased nuclear localisation of ER

Also fully prevents helix 12 closure-> blocks co-activators recruitment silencing both AF-2 AND AF-1 activity -> no ER gene proliferation

Question 11

What are Immune checkpoint inhibitors

Answer 11

Monoclonal antibodies which target the co-inhibitory receptors on T cells or their ligands on tumour cells, to re-engage immune system and restore anti-tumour response

Question 12

What is CTLA-4 and its role?

Answer 12

Transmembrane glycoprotein receptor unregulated on the surface of active T cells to prevent overstimulation by the TCR
Competes with CD28 to bind to CD80 and CD86 on surface of APC-> prevents T cell activation (not able to kill tumour cells)
Blocking binding with an anti-CTLA-4 antibody enables T cell activation

Question 13

Explain the PD-1 and PD-L1 interaction

Answer 13

PD-1 is a surface receptor on activated T cell
It regulates effector T cell by inactivation by binding to PD-L1 and PD-L2
tumour cells express PD-L1
Blocking the binding with an anti PD-L1 or anti PD-1 will enable T cell activation
PD-L1 inhibitors do not affect PD-L2 and therefore are more precise and have less side effects

Question 14

What is LAG-3

Answer 14

Interacts with MHC iii causing inhibition of cytotoxic T cells to prevent autoimmunity and tissue damage
T cells in tumour over-expression LAG-3-> tumour growth favoured
Block LAG-3 favours immune activation

Question 15

What is TIM-3

Answer 15

Is an inhibitory checkpoint receptor promoting immune tolerance
High TIM-3 levels = poor prognosis
TIM-3 blockade favours activation against cancer cells

Question 16

Describe the hallmark proliferative signalling

Answer 16

Proliferative signaling in cancer refers to the aberrant activation of signaling pathways that promote uncontrolled cell growth and division. Normally, cells have tight regulation over their proliferation, but in cancer, these regulatory mechanisms are disrupted, leading to excessive cell proliferation and tumor formation.

Growth factor receptor signaling: Receptor tyrosine kinases, such as the Epidermal Growth Factor Receptor (EGFR), can be overexpressed or mutated in cancer cells. This leads to enhanced signaling through pathways stimulating cell proliferation and survival.

Gefitinib works by selectively inhibiting the tyrosine kinase activity of the EGFR protein. By binding to the EGFR, it prevents the activation of downstream signaling pathways that are responsible for promoting cell proliferation and survival. This inhibition helps to slow down or halt the growth of cancer cells with EGFR mutations.