Neoplasia II: Oncogenesis & Pre-malignancy

Question 1

What are some hallmarks of cancer?

Answer 1

-Limitless replication potential
-Sustained angiogenesis
-Evasion of apoptosis
-Self-sufficiency in growth signals
-Tissue invasion & metastasis
-Insensitivity to growth inhibition

Question 2

How do cells accumulate these hallmarks of cancer?

Answer 2

By one of two mechanisms:

Activation of oncogenes

Inactivation of tumour suppression genes

Question 3

What is oncogenesis?

Answer 3

Development of cancer

Question 4

What is a proto-oncogene?

Answer 4

A normal gene whose product promotes cell growth.

Question 5

What is an oncogene?

Answer 5

A dysregulated proto-oncogene causing cell to grow autonomously

Question 6

What is an oncoprotein?

Answer 6

The product of an oncogene

Question 7

How do proto-oncogenes become oncogenes?

Answer 7

Through mutations, chromosomal rearrangements, & gene amplifications.

Question 8

How are oncogenes classified?

Answer 8

They’re classified according to where they are in the signalling pathway, so they may act as either:

-Growth factors
-Growth factor receptors
-Signal transducing proteins
-Nuclear proteins

Question 9

How do oncogenes maintain the self-sufficiency of growth signals?

Answer 9

They over-express growth factors so that its receptors are constantly stimulated (autocrine activation).

Or

They can also be self-sufficient through inappropriate activation of the receptor, either through ligand-dependent activation or ligand-independent activation

Question 10

Give some examples of self-sufficiency of growth signals and which cancer was caused.

Answer 10

slide 23

Question 11

What is an example of a signal transduction protein in oncogenesis?

Answer 11

Ras

Question 12

What is Ras bound to in its inactive form?

Answer 12

GDP

Question 13

What happens when Ras is activated through upstream signalling?

Answer 13

It phosphorylates to become bound to GTP and it then induces further donwstream signalling to progress the cell through its cell cycle

Ras is then returned to its inactive state

Question 14

What happens when there are mutations in Ras?

Answer 14

If it fails to return to its inactive state, it renders this protein to be continuously stimulating downstream proteins, therefore progressing the cell inappropriately through the cell cycle.

Question 15

What are some examples of gene translocations in neoplasia?

Answer 15

Gene translocation as a mechanism of oncogene activation is relatively common in tumours of the haematopoietic system.

Question 16

Give an example of gene amplification in oncogenesis.

Answer 16

Amplification of N-myc gene seen in neuroblastomas

Over-expression of oncoprotein may result from the duplication of DNA Sequences.

Question 17

What is the normal function of tumour suppressor genes?

Answer 17

To regulate cellular proliferation

Question 18

How are tumour suppressor genes classified?

Answer 18

Gatekeeper genes- inhibit proliferation/induce apoptosis of cells with damaged DNA

Caretaker genes- maintain integrity of genome

Question 19

How are tumour suppressor genes inactivated?

Answer 19

-Mutation
-Deletion
-Transcriptional silencing

Question 20

What is the most widely dysregulated tumour suppressor gene in cancer?

Answer 20

p53 known as the guardian of the genome

Question 21

What is retinoblastoma?

Answer 21

Rare, intra-ocular tumour that affects 1 in 20,000 infants

60% of cases are sporadic (occurs occasionally)

40% of cases are familial (runs in the family, less likely due to chance)

Knudson’s two hit hypothesis - in tumour suppressor genes, both alleles need to be inactivated before it has a significant impact on tumour progression.

Question 22

What is the role of p53?

Answer 22

A transcription factor that regulates cell-cycle and DNA repair genes.

It is activated in a response to a number of cell/DNA damaging stimuli

Question 23

Once P53 is activated, what are the 2 possible pathways that could occur?

Answer 23

1 - if the stimuli wasn’t damaging enough, there is G1 arrest and repair is initiated.

2 - If the stimuli was damaging, repair fails and cell undergoes apoptosis

Question 24

What are some examples of other tumour suppressor genes that are commonly dysregulated in cancer?

Answer 24

look at slide 45

Question 25

What happens when there is abnormal p53?

Answer 25

The protein cannot direct the cell following damage to G1 arrest or apoptosis.

Any damage that is not lethal will accumulate in the cell.

Question 26

Why are APC mutations significant?

Answer 26

Beta-catenin needs to translocated to the nucleus as a transcription factor to exert its effects.

Because APC usually binds beta-catenin (cell cycle/Tumour promoter).

This is to stop it translocating to the nucleus to exert its effects but when there is mutations in APC, it can’t do that so beta-catenin is active in inappropriate circumstances

Question 27

What is BRCA?

Answer 27

-breast cancer (gene) which is usually mutated in 50% of women with breast cancer.

-Forms a complex with RAD51.

-Any mutations in BRCA can cause mutant DNA

Question 28

What is another important caretaker tumour suppressor gene?

Answer 28

Xeroderma pigmentosum (XP)

Important in nucleotide excision pathway of DNA repair.

Any hereditary XP mutations can cause cancers at young ages

Question 29

What are 2 additions to the updated hallmarks of cancer?

Answer 29

Immune evasion: Cancers develop antigens which are recognised by the immune system, particularly cytotoxic T cells. Cancers have developed ways to avoid detection from the immune system.

altered metabolism: Cancers adapt to a more glyc

Question 30

What does the regulation of apoptosis depend on?

Answer 30

Ratio of death antagonists (e.g. bcl-2) to agonists (e.g. bax) determines the cellular response to an apoptotic stimulus.

Question 31

What is initiation in oncogenesis?

Answer 31

The event that induces the genetic alteration that gives the transformed cell its neoplastic potential.

Question 32

Is cancer a multistep process?

Answer 32

yes

Question 33

What is promotion in oncogenesis?

Answer 33

Event that stimulates clonal proliferation of initiated cell.

Question 34

Do all carcinomas have an adenoma precursor?

Answer 34

No

But carcinoma have pre-malignant phases, dysplastic

Question 35

Histology

Answer 35

look at slides