Hallmarks of cancer

Question 1

Describe the current epidemiology of cancer. Why have incidence rates increased while mortality has fallen?

Answer 1

• • Every year over 12 million people worldwide are diagnosed with cancer and it’s currently the biggest killer in the UK.
• • 1 in 3 people will develop cancer at point in their lifetime.
• • Although there are variations in cancer types, there’s a broad trend of increasing incidence of cancer worldwide which is attributed to an increase in longevity.
• • Age is a cancer risk factor, the older you get, the more likely you will accumulate the set of mutations that will form a tumour cell.
• • 1 in 4 people will die from cancer – hopefully will drop in the future.
• • Approximately 200 different cancers exist.
• • Highest incidence cancer in women – breast cancer, highest incidence in males – prostate cancer. Lung cancer is prevalent too.
• • Lung cancer is leading cause of death related to cancer in both sexes.
• • While cancer rates have been increasing since 1975, but mortality rates have been decreasing – this is due to better diagnosis of tumours early on from screening programs which allows early treatment which gives higher chance of survival. More effective drug treatments have also been developed and there’s better prevention due to knowledge of risk factors.

Question 2

List the factors that can cause cancer.

Answer 2

1. Carcinogens – smoke, pollution.
   - - All mutagenic compounds are carcinogenic, but not all carcinogens are mutagenic.
   - - Some carcinogens can act to induce mutations in genes and hence are mutagenic, but others act to induce formation of tumours by non-mutagenic mechanisms and these are called tumour promoters.
2. Age – cancer is an accumulation of mutations over a period of time.
3. Heredity – some people can have a genetic predisposition to cancer, if they had parents suffering from cancer. E.g. small number of breast cancer cases (BRCA mutation).
4. Immune system defect – poor immune system due to AIDs/transplantation can increase risk of developing cancer.
5. Lifestyle – obesity, alcohol and tobacco consumption.
6. Environment – asbestos exposure, secondhand smoke, radiation.
7. Viruses and bacterial infection – e.g. HPV and cervical cancer.

Question 3

List the six original hallmarks of cancer.

Answer 3

The hallmarks of cancer are the rules of the transformation of a normal cell to malignant cancer that are shared in most, if not all cancers.

1. Self-sufficiency
2. Inhibition of anti-growth signals
3. Sustained angiogenesis
4. Metastasis
5. Limitless replicative potential
6. Evading apoptosis.

Question 4

Describe self-sufficiency as a hallmark of cancer.

Answer 4

That cancer cells are independent of growth signals.

• • Normal cells usually require growth factor signals, GF receptors and interactions/adhesions with other cells in order to proliferate. This is shown in cultured cells; they only grow when provided with GF signals.
• • This isn’t the case for tumour cells- they show a lot less dependence on these signals – ‘acquired growth signal autonomy’. Several mechanisms can explain this:

1. Many cancer cells can obtain ability to synthesise their own growth factors to which they are responsive. Or they can induce nearby cells to do so.
2. Growth factor receptors are overexpressed – making cells hyper-sensitive. This can also lead to ligand-independent signalling.
3. They can change the type of ECM receptor (integrins) they express, to one that favours pro-growth signals – integrins will transduce these signals into the cell.
4. They can alter intracellular pathways by activating oncogenes (produced from proto-oncogenes by mutations), usually in growth factors such as Ras which is mutated to release a flux of inappropriate mitogenic signals into the cell.
5. Additionally, cell-cell adhesions play a role – cancer cells can communicate with each other to promote growth.

–> Usually cell has defences against this – tumour suppressor genes but these are commonly inactivated in cancers.

Question 5

Describe insensitivity to anti-growth signals as a hallmark of cancer.

Answer 5

• • In normal cells, antigrowth signals (either soluble cytokines or immobilised inhibitors embedded in the ECM) act on transmembrane receptors to regulate proliferative homeostasis.
• • These signals can block proliferation by 2 mechanisms – either by forcing cells into G0 (temporary) or by inducing cells into the post-mitotic phases of the cell cycle (permanent).
• • In a lot of cancers, the cells experience disruption in this pathway, so cells are insensitive to anti-growth signals.
• • The most notable antigrowth signal being TGF-beta which will inhibit cell division by transcriptional repression of myc (an oncogene). Cancer cells switch this by inhibiting this action of TGF-beta and induce it to become a tumour promoter by inducing it to produce MMPs and angiogenesis.

Question 6

Describe angiogenesis as a hallmark of cancer.

Answer 6

• • Cellular nutrients and oxygen are delivered to mammalian cells via the bloodstream. A tumour will not grow much beyond a mere mm without a blood supply.
• • Tumour cells can release factors to induce the formation of new blood vessels - angiogenesis and thus provide the nutrients they need to promote their uncontrollable growth.
• –> VEGF – vascular endothelial growth factor
• • It’s signal protein that stimulates angiogenesis. Its overexpression can lead to tumour metastasising, as it will promote formation of new blood vessels near the tumour.
• • It is expressed by the cancer cell and binds to tyrosine kinase receptors on endothelial cells where it will cause activation of proteins that stimulate growth of new endothelial cells, eventually forming a new blood vessel.
• • VEGF is upregulated in cancers, and its expression can be increased by ras oncogene and inhibition of the VHL TSG.
• • Certain integrins can be expressed that promote angiogenesis (others can inhibit it).
• • Inhibitors of angiogenesis include thrombospondin-1 which also binds to transmembrane receptors on ECs. It is regulated by p53 (lost in a lot of cancers – causing levels to fall).

Question 7

Describe metastasis as a hallmark of cancer.

Answer 7

• • A primary tumour is formed, and they invade near the blood vessels. Some part of the tumour force their way into blood vessel by squeezing into vasculature and circulate around the body.
• • They then leave the blood vessel (by intravasation/extravasation) and invade another part of the body where they could successfully set up secondary tumour.
• • Affected proteins include cell adhesion molecules (CAMs), integrins, proteases such as MMPs and urokinase – which allows cells to become less adhesive to ECM so they can invade the BM and enter blood vessels.
• • Metastasis is the cause of 90% of cancer deaths.

Question 8

Describe limitless replicative potential as a hallmark of cancer.

Answer 8

• • All cells have a finite replicative limit - Hayflick limit, the no. of times they will divide before they enter a state of senescence.
• • Number of divisions are dictated by the telomere length, as telomeres become shorter after each division until they are too short entering CRISIS and cell cannot divide any further. The telomeres are now too short to protect ends of chromosome.
• • Cancer cells have no replicative limit: In tumours, the telomere length is maintained.
• -The telomerase activity is promoted (this enzyme lengthens telomeres so it never reaches critical point) and it immortalises malignant cells and prevents them going through crisis – leading to a loss of chromosomal integrity – fusion, disarray etc.
• • Cancers that do not express telomerase will instead use the alternative telomere lengthening process.

Question 9

Describe evasion of apoptosis as a hallmark of cancer.

Answer 9

• • Apoptosis is a rapid programmed cell death, which is induced in unhealthy or useless cells.
• • It is different from necrosis where the cell contents are released into surrounding tissues which will induce an inflammatory response – which actually aids tumorigenesis!!.
• • P53 – a TSG, usually detects uncontrollable growth, DNA damage, stress (e.g. hypoxia) –> all conditions seen in tumours, and upregulates Bax (a protein that promotes apoptosis) but its function is lost in many cancers.
• • Cancers also evade apoptosis by several other mechanisms (look at lectures.)

Question 10

What are the two emerging hallmarks of cancer?

Answer 10

1. Reprogramming cellular energetics

2. Avoiding the immune system

Question 11

Describe reprogramming cellular energetics as a hallmark of cancer.

Answer 11

• • Cancer cells also reprogram their metabolism in order to aid their growth and division.
• • Cancerous cells tend to limit their metabolism to glycolysis the same way normal cells do when there’s no oxygen. This is referred to as ‘aerobic glycolysis’ (the Warburg effect).
• • This process seems rather limiting (18-fold lower efficiency of ATP production); therefore they have to upregulate factors such as glucose transporter GLUT1 which increases uptake of glucose into cytosol which makes this process less inefficient.
• • Upregulation of glucose transporters has been shown to be linked to activated oncogenes and mutant TSGs – e.g. P53. Also aided by the hypoxic conditions most cancerous cells tend to function in – which upregulates glucose transporters and several enzymes of glycolysis.
• • The limiting to glycolysis could be due to the products of glycolysis being converted into macromolecules and organelles for creating new cells.

Question 12

Explain evading the immune system as an emerging hallmark of cancer.

Answer 12

• • There must be some mechanisms by which tumour cells can avoid the immune system, especially since cancers can arise easier/quicker in people with immunosuppression.
• • Tumour cells have antigens which immune system detect and induce apoptosis.
• • Some cancer cells express less of the antigen or there is so much cancer burden that the immune system can’t keep up.
• • Tumour cells can also secrete factors to weaken the immune system – supress CTLs and NK cells.
• • Hypothesis – highly immunogenic cancer cells are eliminated by the immune system leaving weakly immunogenic variants which go on to grow and generate tumour and can’t be detected.

Question 13

What are the two enabling hallmarks of cancer?

Answer 13

1. Genomic instability

2. Tumour-promoting inflammation

Question 14

Describe genomic instability as an enabling hallmark of cancer.

Answer 14

• • Tumour progression can be thought of as a series of clonal expansions, each of which is activated by chance acquisition of mutant genotype.
• • The genomic instability seen in cancer cells is due to increased sensitivity to mutagenic agents and defects in surveillance/repair systems. E.g. P53 – caretaker of genome.
• • These defects in genome surveillance/repair are advantageous for the tumour as they can increase rate at which cancerous cells can adapt favourable genotypes to aid their growth.

Question 15

Describe inflammation as an enabling hallmark of cancer.

Answer 15

• • Inflammation is one of the first responses to tissue damage, which is often seen in cancers.
• • It’s now clear that inflammatory factors actually aid tumour growth.
• • Tumour cells have been found to be infiltrated with innate immune cells and hence inflammatory conditions.
• • Tumour cells can also secrete pro-inflammatory cytokines themselves.
• • The cancer can make the immune system promote its own growth – induce inflammation to recruit macrophages and other innate immune cells to create an inflammatory response.
• • One of the aims of inflammation is to promote the tissue to return to its normal state. It does this by producing growth and survival factors that will promote tumour growth.
• • Inflammatory cytokines activate the NFkB signalling pathway which will induce expression of anti-apoptotic proteins such as Bcl-2.
• • They can also release ROS which is mutagenic and promotes genomic instability.