Lecture 3: : Cancer therapeutic challenges

Question 1

Describe heterogeniety in cancer cells

Answer 1

Tumours have many different cell types with different characteristsics. They have normal cells, cancer cells and mutations, extracellular matrix, immunomodulatory cells.
Some cells can be resistant to chemotherapy, some resistant to radiation, some are EGFR mutant. Hypoxia also makes cells resistant to chemotherapy.

Question 2

What are the factors that determine the rate at which a tumour proliferates?

Answer 2

• Access to nutrients
• Oxygen
• Genetics
• Tumour microenvironemnt
• Distance to blood vessels

Question 2

What are the grades in cancer?

Answer 2

Grade 1 is an early tumour. The higher the grade, the more proliferative

Question 2

What is the name of the dye used to show images of spheroids?

Answer 2

Pimonidazole

Question 3

What are the markers which tell if a cell is proliferating?

Answer 3

Ki67, Mcm2 and geminin

Question 3

How do cells become hypoxic?

Answer 3

As the cells move away from the capillary, they cant get enough ocygen from the capillary because oxygen cant diffuse as far, so the cells become hypoxic. They are radiation and chemithetpay resistant

Question 4

What does hypoxia do to the cell?

Answer 4

the cell becomes gnomically instable, tissue invasion and metastasis, evade the immune system, induce angiogenesis, limitless replicative potential, induce or evasion of apoptosis, insensitivity to anti growth signals, self sufficiency in growth signals, glycolysis.

Question 5

What effect does tumour hypoxia have on cancer biology?

Answer 5

They upregulate gene expression that produces changes to the cell phenotype (the way it looks and behaves). It changes cell signalling, proliferation, metabolism, metastasis, angiogenesis, DNA repair, induces cancer stem cells and this is all results in treatment resistance.

Question 6

Why is hypoxia a bad thing in cancer?

Answer 6

1. No or poor blood supply means problems getting drugs delivered into the full area of the tumour
2. Hypoxia activates genes which called for drug effects pumps these throw out chemotherapy drugs
3. Hypoxia activates antiapoptotic proteins so cells don’t die when given chemotherapy or radio therapy
4. Radiotherapy and chemotherapy require oxygen to work best which is not present in hypoxia
5. In hypoxia cells often stop dividing. So therapies which target dividing cells wont work
6. Hypoxia causes genomic instability which drives mutations, this increases the aggressiveness of a tumour cell

Question 7

What is the tumour microenvironment?

Answer 7

Cancer cells exist in an environment. This environment influences what the cells do, how they behave and what genes they express. The environment different within tumours and between tumours of the same type

Question 8

What are cancer stem cells?

Answer 8

Cells with stem like properties – these are called cancer stem cells. These are very different from normal tumour cells. They don’t self-renew, they don’t grow, they are very different to chemo and radiotherapy, they can rapidly repopulate a tumour, some say these cancer stem cells are the key barriers to therapy success.

Question 9

What are the characteristcis of cancer stem cells?

Answer 9

• Minor population in tumour; 0.1 – a few percent
• They are self renewing so have infinite proliferative potential
• They have enhanced resistance to drugs, radiation and cell stress
• They are tumorigenic so give rise to other cell types in the tumour
• Associated with metastisis and relapse

Question 10

Where do cancer stem cells live?

Answer 10

In specific niches – hypoxic, inflammatory environment with low pH

Question 11

what are the strategies to target cancer stem cells?

Answer 11

• Blocking cancer stem cell pathway
• Disrpting the microenvironemnt
• Ablation of propective markers
• Disruption of self protection

Question 12

What are the mechasnisms of drug resistance in cancer?

Answer 12

1. Cancer cells upregulate drug efflux pumps – these pump the cancer drug back out the cell
2. Altered apoptotic pathway – cancer cells upregulate pro survival signals and downregulate the genes that are required for the cells to undergo apoptosis
3. Decreased drug uptake – cancer cells limit the amount of entry points a drug can enter the cell. Proteins (porins) are made which prevent the uptake of drugs into cells
4. Alter drug targets – cancer cells either stop expressing or cause alterations in the receptor so the drug isn’t taken up
5. Altered DNA repair – if the DNA is damaged, cancer cells release proteins to repair the DNA
6. Cancer cells also evolve to metabolise or breakdown drugs in the cell to harmless forms eg CYP450, glutathione 5 transferases
7. Cancer cells can also increase their ability to repair DNA damage many cancer drugs cause eg the drug temozolomide is the main treatment for brain tumours – it methylates the DNA so the cell can’t divide cancer cells upper up regulate the enzyme MGMT watch basically un-methylayes the DNA freeing it up so the cancer cell can then go on and divide
8. Cancer cells can also change cellular targets: many cancer drugs old and new will target a specific protein overexpressed in the cancer or a receptor on the surface or a kinase which is overexpressed. Many of these drugs work by binding the protein in a pocket which has a particular shape. Cancer cells acquire mutations in these pockets which changes the shape so the drug can no longer fit and therefore stop or inhibit the protein. Some antibodies work by binding cell surface receptors cancer cells can down regulate these so there is no target for the drug or again by mutation change the shape so the antibody does not recognise the receptor for drugs which may be targeting enzyme cancer cells can up regulate their production of the enzyme so there is simply too much of it to be attacked by the drug eg androgen ablation therapy for prostate cancer.
9. Cancer cells can also make more proteins which act as inhibitors to apoptosis. They upregulate genes which make proteins which made the cells survive regardless of damage caused by drugs or radiation. Ie. cancer cells upregulate genes such as BCL2 and NF Kappa B which promote survival and inhibit cell apoptosis. Also cancer cells can switch off the cell cycle checkpoints and alter the surveillance which would send damaged cells for cell death so no matter what killer therapy the cells get the cells develop mechanisms to not die but cope with any damage or avoid apoptosis