T8

Question 0

Differ between malignant and benign tumours.

Answer 0

Malignant tumours spread (metastasize) into the territory of other cells whilst benign tumours are contained within territory of source tissue.

Question 1

What two heritable properties define cancers?

Answer 1

1. Reproduction in defiance of normal cell growth/reproduction
2. Colonization/invasion of territories normally reserved for other cells

Question 2

What are the two general categories of cancers and what two cancer types don’t fit in either category?

Answer 2

Carcinomas arise from epithelial tissue, sarcomas from muscle/connetive tissue. Cancers of hemopoietic cells, in addition to cancers of nervous system.

Question 3

Is a cancer necessarily a result of change in DNA sequence?

Answer 3

No, an epigenetic change may change gene expression leading to neoplasia. These include affecting heteromerization and gene silencing through methylation of cysteine.

Question 4

What defines progression of cancer from on aberrant cell to a tumour?

Answer 4

Gradual development of degree of mutation, so that the parent cell may have had a few mutations whilst advanced daughter cells have aquired further mutations, changing the nature of the growth.

Question 5

How can a cancer be likened to a species evolving?

Answer 5

Both follow the same rules for a successful proliferation:

1. mutation rate
2. number of reproducing individuals
3. rate of reproduction
4. selective advantage

Question 6

What does genetic instability infer on cancerous cells?

Answer 6

That the DNA maintenance genes may be mutated in a way that increases incidence of further mutation in the cancer cell genome. This may or may not increase the malignancy of the cancer, depending on how much the DNA changes (approaches the optimum level of mutation/aquired properties).

Question 7

Name two normally occurring cellular functions that if disturbed (up/down-regulated) can lead to neoplasia.

Answer 7

Cell division and apoptosis

Question 8

How can cells with inactivated DNA-damage response mechanisms develop into cancers when the completion of their cell cycles sigbificantly slow down?

Answer 8

Accumulation over time of mutated cells eventually form a high-number basis, the division of which can be detected. This explains in part why cancers develop over many years before being detected.

Question 9

How are replicative cell senescence mechanisms modulated in cancer cells?

Answer 9

Checkpoint mechanism, for example mediated by p53, is disabled through mutation of p53-gene so that replication continues despite de-capping of telomeres. Another modulation is the maintenance of telomerase activity, even when the activity would normally have been discontinued.

Question 10

How is the cancer cell population maintained and enlarged?

Answer 10

Through divison of cancer stem cells into cancer strm cells or transit amplifying cells. These progress through mutations and epigenetic changes into malignant cancer stem cells.

Question 11

Outline the steps leading to metastasis formation.

Answer 11

1. Cancers cells manage to escape into the blood through the ‘leaky’ blood vessles supplying the tumour, or a lymph vessle.
2. Cancer cells adhere to endothelium, penetrating it and forming a micrometastasis.
3. Parenchym is infiltrated and a full metastasis, cancer colony, is formed.

Question 12

How does tumour angiogenesis lead to evolving of aggressive cancers?

Answer 12

The vessles formed are leaky and partyl malformed, leading to areas of hypoxia in the tumour. This makes for selection of cells that better withstand these hardh conditions. Metastasizing of these cells is more effective as they survive better in harsh conditions.

Question 13

What is HIF-1α and what is its role in tumours?

Answer 13

Hypoxia inducible factor-1α, mediates tumour angiogenesis in hypoxic conditions.

Question 14

What is the role of thre stroma for the tumour?

Answer 14

Throug extracellular signaling the stroma and tumour work together. The stroma induces tumour growth and the tumour excretes protein signal and proteases to modify the ECM.

Question 15

List 9 properties that contribute to cancerous growth.

Answer 15

1. Self-sufficiency, no need fot survival sigbals
2. Insesitive to anti-proliferation signals
3. Less prone to apoptosis
4. Defective intracellular control mechanisms that respond to stress or DNA damage
5. Induction of help from normal stromal cells
6. Induction of angiogenesis
7. Metastasization
8. Genetic instability
9. Recruit ways of stabilizing telomeres

Question 16

Are all carcinogens chemicals?

Answer 16

No. Ex. radiation is classified as carcinogenic.

Question 17

Name a commo, rapid, test for mutagens.

Answer 17

The Ames test.

Question 18

How come most carcinogenic chemicals are relatively inert as such?

Answer 18

They are converted enzymatically, ex. by liver cytochrome P-450, into more potent forms that induce mutation.

Question 19

What combinations of tumour initiator and promotor exposure can lead to cancer?

Answer 19

1. One initiator and immediate rapid succession of multiple promoters
2. One initiator and delayed rapid succession of multiple promoters
3. Multiple, far spaced, initiator exposures

Question 20

What are common tumour promoters?

Answer 20

Phorbol esters such as TPA (tetradecanoylphorbol acetate which activate PKC and phosphatidylinositol signaling pathway.

Question 21

What is the first sign of initiator + promoter exposure in skin cancer?

Answer 21

Formation of a papilloma.

Question 22

Are infections, for example by viruses, directly responsible for cancers?

Answer 22

Usually no. They mostly promote cancer formation. Ex. HIV virus weakens the immune response, making it easy for herpes virus HHV-8 to infect and directly cause Kaposi’s sarcoma. Hepatitis B and C cause inflammation in the liver, increasing the chance of cancer formation. Also parasite may promote cancer formation.

Question 23

What is a suggested most potent carcinogen?

Answer 23

Aflatoxin B1

Question 24

Define cancer-critical genes.

Answer 24

Genes who alteration of which frequently leads to cancer.

Question 25

What classes can cancer-critical genes be divided into?

Answer 25

1. Proto-oncogenes (overexpressed mutant form called oncogenes) 2. Tumour supressor genes(loss-of-function genes) 3. DNA maintenance genes (mutation results in genomic instability)

Question 26

How do proto-oncogenes and tumour supressing genes differ in their activation into carcinogenic form?

Answer 26

Proto-oncogene mutation usually results in a dominant oncogene, whilst the mutation of a tumour supressor gene is usually recessive and need to by homozygous for it to take effect.

Question 27

Why is Ras an oncogene in many cancer cells?

Answer 27

The mutation of Ras makes it unable to hydrolize GTP to GDP causing chronic activation and subsequent cancer.

Question 28

What's so special about Rb gene and protein in oncology?

Answer 28

The Rb gene is commonly missing not only in retinobladtoma but aldo in many other forms of cancers. It is a tumour supressing gene.

Question 29

Whilst a tumour supressing genes function may fail through loss of heterozygosity, are DNA sequence alterations the only possible way for tumour supressing gene alteration to occur?

Answer 29

No. Epigenetic changes may pack the gene into heterochromstin or silence it through cytosine methylation.

Question 30

In what three ways may overexpression of a gene occur?

Answer 30

1. Point mutation or deletion leads to a hyperactive protein or protein overproduction 2. Gene amplification (multiple gene copies) caused by error in DNA replication 3. Chromosomal rearrangement leading to overproduction or production of hyperactive protein

Question 31

How is EGF and Myc related to tumour formation?

Answer 31

Deletion of part of the extracellular domain of the EGF receptor leads to ligand-independent activation. Myc overexpression leads to cellular proliferation past normal boundries.

Question 32

Outlone the Rb mediated control of cell proliferation.

Answer 32

Rb inhibits E2F and is itself inhibited by cyclin D-Cdk4 complex which is inhibited by p16

Question 33

What part of the PI3/Akt pathway is usually affected when a cell exhibits the Warburg effect?

Answer 33

Then PTEN phosphatase which regulates Akt.

Question 34

The mutation of what apoptosis-controlling gene allows cancer cells to survive?

Answer 34

Bcl2

Question 35

What affects p53 and what are the consequences of it.

Answer 35

Hyperproliferayive signals (overexpressed Myc), DNA damage, telomere shortening and hypoxia. Effects are cell cycle arrest, senescence and apoptosis.

Question 36

Give an example of how replication of damaged DNA increases the risk of tumour formstion.

Answer 36

Chromosome breakage so that a telomere is lost makes for sister chromatid end-to-end joining after replication. 'Separation' of the sistet chromatids leads to formation of one chromosome with two copies of specific genes.

Question 37

What is the mechanism of papillomavirus tumour formation?

Answer 37

The two oncogenes E6 and E7 bind key tumour supressor proteins Rb and p53.

Question 38

What are the key difficult points in metastasis formation?

Answer 38

Entry into blood or lymph and survival of tumour cells in colonized tissue. Traveling and exiting of tumour cell from a blood vessle is easy.

Question 39

What is a possible marker for a good metastasizing ability of a tumour?

Answer 39

The Rho-family GTPase RhoC. It helps mediate actin-based cell motility.

Question 40

What is a key feature of the EMT (epithelial-to-mesenchymal transition)?

Answer 40

A change in the E-cadherin gene which nornally serves to keep cells bonded together through adherens junctions.

Question 41

Name an affected oncogene found in up to 40% of coloractal cancer cells.

Answer 41

K-Ras.

Question 42

How does loss of heterozygosity of Apc trigger tumour formation and what type of cancer may this mechanism often be found?

Answer 42

Apc is an inhibitory protein for the Wnt-signaling pathway. Apc binds nirnally to β-catenin, inhibiting it from entering thr nucleus. When β-catenin is free to enter the nucleus in a stem cell the stem cell population expands uncontrollably leading to tumour formation. Loss of Apc activity also leads to increased frequency of mitotic spindle defects. The mechanism is usual in FAP (familial adenomatous polyposis coli).

Question 43

What is another possible way for cancer, ex. colon cancer, to arise apart from defective signaling pathways?

Answer 43

Malfunction of the DNA mismatch repair system.

Question 44

Outline a theoretical histological progression of colorectal cancer with relevant biomolecular signal defects.

Answer 44

1. Normal epithelium progresses through loss of Apc to hyperplastic epithelium 2. Development into early adenoma 3. Early adrnoma turns into intermediate adenoma through activation of K-Ras 4. Development into late adenoma adter loss of Smad4 and other tumour supressors 5. Loss of p53 causes carcinom 6. Other unknown alterations lead to invasion and metastasis

Question 45

What common activation patterns may be expected for wrparate tumours?

Answer 45

The sltered signal pathways and the order in which they are altered serm to correlate.

Question 46

How is PARP inhibition an effective treatment of cancer?

Answer 46

It inhibits a pathway for DNA strand breakage repair. Whilst normal cells have many paths for breakage repair many cancers, like those that have inactivated Brca1 and Brca2 genes that function in DNA recombinant events, only have one accessible pathway (PARP mediated). When it is blocked the tumour cell dies.

Question 47

What role does Mdr1 play in tumour drug resistance?

Answer 47

Mdr1 codes for a plasma-membrane-bound transport ATPase that excretes lipophilic substances, such as drugs, from the cell.

Question 48

What is the phenomenon of oncogene addiction?

Answer 48

A tumour with oncogene addiction is highly dependent on one overproduced or hyperactive protein. Blocking the production of thsi protein combats the cancer.

Question 49

Give an example of a small molecule that can inhibit specific oncogenic proteins.

Answer 49

Gleevec fits into the ATP binding groove of the Brb-Abl-fusion protein, inhibiting it from activating signal protein for cell proliferation/survival.

Question 50

How does inhibition of the VGEF-receptor (vascular endothelial growth factor) combat cancer?

Answer 50

The inhibition of the effects of VEGF makes for poor angiogenesis in the tumour and thus lessened blood supply.

Question 51

Why is multi-drug therapy a more efficient way of treating cancer, compared to successive drugs?

Answer 51

It disallows drug resistance and following selection to occur in the cancer cells.