Lecture 30: From tumor biology to clinical care

Question 1

List factors 1-3 of the hallmarks of cancer and their therapeutic potential examples

Answer 1

1) Sustaining proliferative signalling i.e EGFR inhibitors
2) Evading growth suppressors i.e cyclin-dependant kinase inhibitors
3) Avoiding immune destruction i.e Immune activating anti-CTLA4 mAb

Question 2

List factors 4-6 of the hallmarks of cancer and their therapeutic potential examples

Answer 2

4) Enabling replicative immortality i.e telomermase inhibitors
5) Tumor promoting inflammation i.e selective anti-inflammatory drugs
6) Activating invasion and metastasis i.e Inhibitors of HGF/c-met

Question 3

List factors 7-10 of the hallmarks of cancer and their therapeutic potential examples

Answer 3

7) Inducing angiogenesis i.e inhibitors of VEGF signalling
8) Genome instability and mutation i.e PARP inhibitors
9) Resisting cell death i.e Proapoptotic BH3 mimetics
10) Deregulating cellular energetics i.e aerobic glycolysis inhibitors

Question 4

What is neoplasm/neoplasia/”tumour”

Answer 4

Abnormal and excessive growth that is uncoordinated with that of the normal surrounding tissue

Question 5

What is benign vs. malignant?

Answer 5

Does not spread vs has the potential to metastasize

linked to stage

Question 6

What is adenoma vs adenocaricinoma?

Answer 6

Benign tumour of the epithelial cells vs malignant tumour of the epithelial cells

Question 7

What is dysplasia?

Answer 7

(lack of control)
- Abnormal cell growth, often associated with microscopic appearance of variability between cells, reduced cellular differentiation and maturation

Question 8

What is anaplasia?

Answer 8

(Cant differentiate)

- Reduced differentiation

Question 9

What is metaplasia?

Answer 9

• Replacement of one type of mature differentiated cells with another

Question 10

What is proliferation?

Answer 10

Division of cells, controlled by signalling pathways, often becomes uncontrolled in cancer

Question 11

What is tumour evolution?

Answer 11

Mutations and epi-genetics accumulate in the somatic cells of a tumour, these changes are retained by tumour cells if they provide a competitive advantage in terms of survival, proliferation, migration, resistance to immune response or treatment

Question 12

What is tumour heterogeneity?

Answer 12

Genetic, epi-genetic, and gene expression differences between distinct regions of a tumour, which may possibly result from tumour evolution

Question 13

What is invasion?

Answer 13

Local spread of tumour

Question 14

What is metastasis?

Answer 14

Spread of tumour to distinct sites i.e lymph nodes

Question 15

What is grade?

Answer 15

How aggressive and unlike the originating cell type the cancer looks like under the microscope, especially in terms of proliferation and anaplasia.

Question 16

What is stage?

Answer 16

How far a cancer developed and spread, in terms of primary tumour growth and invasion, and in terms of distant metastasis

Question 17

What is tumour stroma?

Answer 17

Non-tumour cells within and around a tumour that support the tumours survival and growth

Question 18

How is the regeneration of the colon mucosa achieved?

Answer 18

Genetically programmed signalling pathways control cellular proliferation and differentiation

i.e its very complex and requires many factors

Question 19

How can DNA be influenced by cell signalling?

Answer 19

Many receptors and signals to impact the nucleus but hormones can freely diffuse in

Question 20

What are some microscopic cellular features of dysplasia?

Answer 20

• Pleomorphism: Variation in size and shape between cells
• Hyperchromatic nuclei and increase in the nucleus/cytoplasm ratio
• loss of tissue architecture

Question 21

What do anaplasia and dysplasia represent?

Answer 21

Failure of normal signalling pathways in cells due to genetic or epi-genetic changes, you can think of this as a loss of cellular social responsibility.

Question 22

What are the two sets of genes help generate out of control cells?

Answer 22

Changes to tumour suppressor genes - inactivating proteins ‘not enough break’

Changes to proto-oncogenes - overactive proteins ‘too much throttle’

Question 23

What are some examples of tumour suppressor genes?

Answer 23

RB1, TP53, BRCA1/2, APC

Question 24

What are some examples of proto-oncogenes?

Answer 24

EGFR, RAS, BRAF, CCND1

Question 25

Describe how cancer is initiated?

Answer 25

• Cancer is initiated and progresses through the accumulation of genetic changes that disrupt the signalling pathways that regulate cells
• (Somatic changes)
• 5-10% sig inheritance component

Question 26

What is one of the hallmarks of cancer and why?

Answer 26

Evading the immune system

- Required for cancer cells to survive and proliferate

Question 27

Summarise of key molecules and cells involved in cancer elimination by the immune system;

Answer 27

• Antigen presentation (MHC class 1, display tumour antigens from within cancer cells)
• NK cells
• CD4
• CD8

Question 28

Describe 1-4 mechanisms of tumour immune resistance?

Answer 28

1) Reduced HLA class 1 expression
2) Antigen loss
3) Antigen processing system loss
4) Increase resistance to immune attack

Question 29

Describe 5-8 mechanisms of tumour immune resistance?

Answer 29

5) Release immune inhibitors
6) Amino acid depletion
7) Activate immune inhibitory T cell types
8) Express immune inhibitors on cancer cell surface i.e CD80

Question 30

How does trastuzumab act?

Answer 30

• Causing Her2 receptor lysosomal degradation
• Blocking Her2 PI3K/AKT intracellular signalling
• Encouraging immune attack

More effective in those with amplified Her2

Question 31

What is the Her2 receptor?

Answer 31

• Her2 receptor is on the surface of epithelial cells that turns on intracellular signalling pathways (including the PI3K and MAPK pathways)

Question 32

What happens to Her2 in cancer?

Answer 32

20-30% of breast cancers the Her2 gene is amplified, this turns on cell division and tumour growth