Cancer and its Hallmarks

Question 1

What is cancer?

Answer 1

A group of diseases in which cells divide and grow uncontrollably, forming a malignant tumour

Question 2

What is meant by the hallmarks of cancer?

Answer 2

Characteristics that the cell acquires, allowing them to become malignant. Help us understand essential properties of cancer cells

Question 3

How common is cancer and what factors influence this?

Answer 3

1/2-3 chance of developing cancer in our lifetime. Influenced by age, sex, geographic location, type of cancer, socioeconomic status, ethnicity

Question 4

Describe the development of cancer

Answer 4

Incidence increases with age, showing that cancer is the result of an accumulation of mutations. 3-7 “events” required for normal cell to become malignant - transformation. The events are genetic alterations

Question 5

How can mutations lead to the development of cancer?

Answer 5

A mutation in a protein which checks the DNA for damage causes it to become non functional. Damaged DNA not detected and hence not repaired before replication, leading to more mutations etc.

Question 6

Describe what is meant by a carcinoma

Answer 6

Cancer arising from epithelial cells covering the external and internal surfaces of the body. Adenocarcinomas develop within a gland or organ, and squamous cell carcinomas develop from the epithelia in the top layer of skin/covering of certain organs. Most common cancer (80-90%)

Question 7

Describe what is meant by a sarcoma

Answer 7

A much more rare cancer, arising from the supporting tissues, such as bone, cartilage, fat, connective tissues, and muscles

Question 8

Describe what is meant by myeloma

Answer 8

Cancer arising in the immune system, from antibody producing plasma cells

Question 9

Describe what is meant by leukaemia

Answer 9

Cancers of the blood, arising in immature blood cells growing in the bone marrow and accumulating in large numbers in the blood stream. Acute and chronic. Lymphocytic and myelogenous (rbc and platelets)

Question 10

What is meant by the term carcinogen?

Answer 10

Helps in causing cancer by promoting DNA damage

Question 11

How does age result in an increased incidence of cancer?

Answer 11

It takes time for accumulations to build up in the genome, meaning that later on in life we have a higher proportion of mutations that can lead to cancer

Question 12

How can someone be genetically predisposed to cancer/

Answer 12

Cells need mutations to become malignant. If somebody already has an inherited mutation in their genome, it can make other mutations more likely to occur

Question 13

What role does the immune system play in cancer?

Answer 13

Immunocompromisation increases the likelihood of certain cancers such as lymphoma and cancers caused by diseases eg. HPV

Question 14

How do body weight and diet impact cancer risk?

Answer 14

Diet high in red meat, processed meat, sat fat, dairy associated with a higher risk of cancer. Alcohol increases risk by directly promoting DNA damage and negatively affecting absorption of important nutrients and breakdown of hormones

Question 15

How can the environment increase cancer risk?

Answer 15

Radiation from sun can cause DNA damage

Question 16

How can viruses and bacteria increase the risk of cancer?

Answer 16

Viruses can alter genetics by their activity. Cerival, genital, anal cancers - HPV. Primary Liver cancer - Hep B/C. Lymphomas - Epstein-Barr. T cell leuk - Human T cell leuk virus.
Bacterial infection of Helicobacter Pylori can lead to stomach lining inflammation increasing cancer risk.

Question 17

Describe what is meant by Hallmark 1: Self Sufficiency in Growth Signals

Answer 17

Cancer cells do not need external growth signals (mediated by cell-surface receptors) in the form of GFs to grow

Question 18

Describe the 3 ways that cancer cells are self sufficient in growth signals

Answer 18

Producing their own GFs, leading to a positive feedback loop - glioblastomas produce their own PDGF and sarcomas their own tumour GF-a.
They overexpress receptors making them hypersensitive to GFs, and grow in response to GF levels that wouldn’t usually cause growth. Epidermal GF receptor overexpressed in stomach, brain, breast cancer.
They can produce downstream responses to signals even when there is no signal. Mutant Ras is present in about 25% of tumours, activating SOS-Ras-Raf-mAPK pathway

Question 19

Describe what is meant by Hallmark 2: Insensitivity to Growth Signals

Answer 19

Cancer cells are resistant to growth inhibitors from the ECM, environment, neighbouring cells. Growth inhibitors usually act on cell cycle clock, interrupting mitosis

Question 20

How is retinoblastoma protein related to Insensitivity to antigrowth signals

Answer 20

Retinoblastoma protein is a protein that activates a checkpoint when there is a reason the cell shouldn’t divide (DNA damage). When RB is mutant, it won’t activate the checkpoint and the damaged cell continues to divide. RB is a tumour suppressor.

Question 21

Describe what is meant by Hallmark 3: Evading apoptosis

Answer 21

p53 is a tumour suppressor that identifies irreparable DNA damage and signals to the cell that apoptosis should occur. Mutant p53 (and others like it) result in apoptosis not being initiated when it should be - DNA damage, oncogene overexpression, external signals

Question 22

Describe what is meant by Hallmark 4: Limitless Replicative Potential

Answer 22

Cancer cells don’t have a Hayflick limit (60-70 doublings) due to their overexpression of telomerase allowing the lengthening of their telomeres and replicative immortality

Question 23

Describe what is meant by Hallmark 5: Sustained Angiogenesis

Answer 23

Tumours may be able to release GFs such as Vascular Endothelial GF that activate angiogenesis, and also they may be able to downregulate endogenous inhibitors of angiogenesis

Question 24

Why is angiogenesis important for cancer cells?

Answer 24

Angiogensis is the branching of new blood vessels from existing ones. Allows the supply of cells with adequate O2 and nutrients and waste removal. All cells must be 100uM from a vessel.

Question 25

Describe what is meant by the angiogenic switch

Answer 25

Balance between pro- and anti-angiogenic factors tilts towards pro-angiogenesis

Question 26

Describe what is meant by Hallmark 6: Tissue invasion and metastasis

Answer 26

Cancer cells are able to break away from the site of origin and invade surrounding tissues, spreading to distant body parts. Responsible for about 90% of cancer deaths

Question 27

How do cancer cells metastasise?

Answer 27

Pioneer cells spawn from primary tumour masses and invade adjacent tissues. Can travel to distant sites via the circulation. Newly metastasised tumours are amalgams of cancer cells and supporting cells from host

Question 28

How do cancer cells break away from their site of origin?

Answer 28

Downregulation of E-cadherin which is the connecting molecule between cells, forming bridges between cells and also contacting intracellular molecules. On colonisation of a new site, cells can reverse this process and reestablish contact with neighbouring cells

Question 29

How can cancer cells adapt to different environments?

Answer 29

During this process, migrating cancer cells contact new environment with different ECM. To accomodate this, they alter their integrin subunit expression. Integrins facilitate cell adhesion but have substrate preferences, which cancer cells upregulate to facilitate invasion. Some integrins can facilitate matrix degredation by proteases and this facilitates invasion through stroma, vessels, epithelia

Question 30

Describe what is meant by emerging hallmarks and what are they?

Answer 30

Pivotal characteristics of cancer cells. Deregulation of cellular energetics, and avoiding immune destruction

Question 31

Describe what is meant by enabling characteristics and what are they?

Answer 31

Characteristics allowing cells to acquire hallmarks. Genome instability and Tumour-promoting inflammation

Question 32

How do therapies exploit the hallmarks?

Answer 32

Therapy involves responses to the hallmarks either on their own or in combination. eg. telomerase inhibitors, selective anti inflammatory drugs, VEGF singalling inhibitors.

Question 33

What are the 6 hallmarks of anti-cancer drug resistance?

Answer 33

Reduced expression/mutation of drug targets
Drug pump upregulation
Drug detox mechanism activity increased
Redcue apoptosis susceptibility
Alter proliferation level
Increase DNA damage repair ability