L30-33: Cancer

Question 1

What percentage of cancers involve inherited (germ-line) mutations?

Answer 1

5-10%

Question 2

Immune checkpoint blockade

Answer 2

Tumour cells turn off activated T cells when they attach to specific T cell receptors. Immune checkpoint inhibitors prevent tumour cells from attaching to T cells so T cells stay activated. Can target T cells or tumour cells.

Question 3

Classic immunohistochemical markers

for cancer - Proliferation markers

Answer 3

PCNA (proliferating cell nuclear antigen)

Ki-67 (aka MIB-1)

Question 4

PI3K pathway

Answer 4

PI3K converts PIP2 to PIP3
PTEN inhibits this conversion
Mutations in p110 and pTEN cause this pathway to drive without any negative regulation

Question 5

Evasion of apoptosis mechanisms

Answer 5

1. Reduced Fas (CD95) receptor level
2. Inactivation of death-induced signaling complex
3. Up-regulation of BCL2 (antiapoptotic)

Question 6

Tumour cells and telomeres

Answer 6

Tumour cells reactivate telomerase, maintaining telomere length for each generation, thus staving off mitotic catastrophe and avoiding senescence / achieving immortality, even though they have an unstable genome

Question 7

Metastasis

Answer 7

1. Detachment of tumor cells from each other
2. Degradation of ECM
3. Attachment to novel ECM components
4. Migration of tumor cells

Question 8

Stochastic model/ clonal evolution

Answer 8

• Multiple subclones co-­exist (may have different sizes)
• All cells have equal but low probability of initiating tumour growth.
• Strong influence of the microenvironment (extrinsic factors)

Question 9

Cancer Stem Cell model

Answer 9

• Distinct classes of cells exist within a tumour
• Only a small definable subset has intrinsic ability to initiate tumour growth.
• Hierarchical organisation with CSC as the source of other cells

Question 10

Define: Cancer stem cell

Answer 10

Ability to generate heterogeneous tumors with higher efficiency once injected at high dilution (down to single cells) in recipient animals

Question 11

Self-­renewal

Answer 11

Ability to go through multiple cycles of cell division while maintaining at least one stem cell. At least one daughter cell is exactly identical to cell of origin.

Question 12

Multipotency

Answer 12

Potential for differentiation into progeny that can’t self-­renew

Question 13

Cancer stem cell vs. cell of origin

Answer 13

A stem cell can give rise to a cell of origin of cancer (first mutated cell) but also gives rise to other progenitors. A cell of origin can also come from a uncommitted progenitor

Question 14

Properties cancer stem cells share with normal stem cells

Answer 14

1. Expression of “specific” markers that enrich cells with
   tumourigenic potential
2. Self-renewal
3. Multipotency -­ Potential for differentiation into phenotypically diverse mature cell types
4. Regulated by similar signalling pathways

Question 15

EMT

Answer 15

Epithelial–Mesenchymal Transition (EMT):
loss of epithelial characteristics and acquisition of mesenchymal features (decreased adhesion and polarity, increased motility, invasiveness, increased resistance to apoptosis).
• Important roles in developmental processes (Gastrulation, formation of placenta, somites, heart valves, neural crest, urogenital tract, morphogenesis of multiple organs)
• In cancer, EMT is involved in invasion, metastatic dissemination and acquisition of therapeutic resistance.
• EMT process (during development and cancer) is highly sensitive to signals that cells receive from their stromal microenvironment.