molecular basis of cancer

Question 1

what are important characteristics of cancer cells?

Answer 1

1. replicative immortality
2. inducing angiogenesis
3. metastasis
4. high rate of cell division
5. genome instability & mutation
6. loss of anchorage dependence
7. lack of contact inhibition & density-dependent inhibition
8. avoid immune destruction

Question 2

why do cancer cells have replicative immortality?

Answer 2

• in most cancer/tumour cells, telomerase genes are reactivated, so telomerase is produced and maintains telomerase lengths so that the cancer cells divide indefinitely/are immortalised.
• whereas in most somatic cells, telomerase genes are switched off so they can only divide a limited number of times
• telomerase allows cancer cells to evade apoptosis

Question 3

what is angiogenesis and its significance in cancer development?

Answer 3

• ☆ angiogenesis is the process by which new blood vessels are formed. it is a tightly regulated process which occurs only when necessary, such as growth or repair. abnormal regulation may result in diseases like cancer
• to develop into larger, potentially metastatic tumours, a growing tumour stimulates the formation fo new blood vessels, or angiogenesis.
• these blood vessels increase blood flow to the tumour, supplying nutrientsand oxygen and removing toxic waste products. they also provide pathways for cancer cells to spread to other sites in the body.
• to stimulate the formation of new blood vessel, a tumour cell expresses angiogenesis-activating protein genes to produce angiogenesis activating proteins

Question 3

what is metastasis and its significance in cancer development?

Answer 3

• ☆ metastasis is a process where the primary tumour cells invade local tissues & blood vessels, establishing secondary tumours called metastases at distant sites.
• cancer cells invade surrounding tissues and penetrate through the walls of lympathic & blood vessels, gaining access to the bloodstream. cancer cells are then transported by the circulatory system throughout the body. cancer cells then leave the bloodstream and enter particular organs, where new secondary tumours at distant sites from the primary tumour are established

Question 4

what are benign and malignant tumours?

Answer 4

• benign tumours have few genetic mutations and do not cause serious health problems. they could be completely removed by surgery
• malignant tumours are invasive and could impair functions of organs. individuals with malignant tumours are considered to have cancer. systemic treatment like radiation or chemotherapy is required in conjunction with surgery to ensure complete eradication of all malignant tumour cells

Question 5

what are cell cycle checkpoints and their role in preventing cancer?

Answer 5

• ☆ cell cycle checkpoits are critical control points where stop & go ahead signal can regulate the cycle. checkpoints ensure the orderly progression of the cell cycle; if a malfunction occurs, signals are sent to the control system to delay progression into the next phase

Question 6

what are the differences between benign & malignant tumours?

Answer 6

shape & differentiation ⮕ benign tumour cells have SMALL & REGULARLY-shaped nucleus, and are well-differentiated. malignant tumour cells have LARGE and IRREGULARLY-shaped nucleus, and are poorly-differentiated.
nuclear:cytoplasmic volume ratio ⮕ benign tumour cells have low nuclear:cytoplasmic volume ratio while malignant tumour cells have high nuclear:cytoplasmic volume ratio (i.e. have big nucleus compared to cell)
rate of mitosis ⮕ benign tumour cells have LOW rate of mitosis compared to malignant tumour cells that have HIGH rate of mitosis
tumour boundary ⮕ benign tumour cells have a well-defined tumour boundary as tumour cells remain clustered together with a well-defined perimeter. malignant tumourcells have a poorly-defined tumour boundary as tumour cells may not cluster together due to their ability to metastasise

Question 7

what are the 3 cell cycle checkpoints?

not the most important

Answer 7

1. G1 checkpoint (assessment of cell growth) ⮕ checks for: growth factors (signal molecules), DNA damage, cell size & nutrients. apoptosis occurs if DNA is damaged & cannot be repaired
2. G2 checkpoint (assessment of DNA replication) ⮕ checks if DNA is replicated successfully without damage. apoptosis occurs if there is irreparable damage
3. M checkpoint (assessment of mitosis) ⮕ occurs at metaphase and checks if there is successful formation of spindle fibres & attachment of spindle fibres to the kinetochores of chromosomes. if spindle fibres are not formed or attachment is inadequate, mitosis is arrested

Question 8

what are cyclin-dependent kinases (Cdks) and what do they do in the cell cycle?

Answer 8

• cyclin-dependent kinases, Cdks, phosphorylate their substrates by transferring phosphate groups from ATP to the substrates.
• Cdks need to be bound to cyclin to be activated, forming cyclin-Cdk complexes that are also called maturation-promoting factor (MPF)
• MPFs promote mitosis by phosphorylating substrates that control the orderly progression of the cell cycle
• in many cancers, when cell cycle control genes like cyclin and/or Cdk genes are mutated, this results in the over-expression of cyclins & Cdks. cells that have escaped precise cell cycle control can proliferate indefinitely.

Question 9

what is the function of a tumour suppressor gene?

Answer 9

tumour suppressor genes are a family of normal genes that code for proteins that prevent uncontrolled cell division ⮕ loss of such proteins allows a cell to divide through the absence of suppression in cell division

functions of tumour suppresor proteins (coded for by tumour suppressor genes)
1. take part in cell signalling pathways to inhibit the cell cycle
2. halt cell division if DNA is damaged (cell cycle arrest)
3. triggers DNA repair mechanisms, preventing cells from accumulating DNA damage
4. initiate apoptosis if DNA damage cannot be repaired
5. maintain cell-to-cell adhesion

Question 10

what kind of mutation ?

under what circumstances will no functional gene product be produced by tumour suppressor genes?

Answer 10

a loss of function mutation, defined as a mutation that results in abolished protein function, must occur.

if one copy of a tumour suppressor gene is lost, cell cycle activity remains normal as the other copy of the gene is still able to produce sufficient quantityof the normal gene product to regulate the normal cell cycle.
so in order to abolish the function of TSGs totally, both copies of the TSG must be mutated so that no functional gene product can be produced.

this is a loss of function mutation, and mutated TSGs act in a recessive manner (since both copies need to be mutated)

Question 11

what is an example of a tumour suppressor gene?

Answer 11

the p53 gene is a tumour suppressor gene.

it is critical as it is involved in apoptosis, maintenance of genetic stability AND cell cycle control

Question 12

describe the role of p53 protein (coded for by p53 gene) in the cell cycle and how it prevents cancer.

Answer 12

p53 protein is a transcription factor that binds to DNA to trigger transcription of genes involved in cell cycle inhibition. (high levels of p53 proteins indicate that DNA is damaged)

p53 protein prevents cancer by:
- activating DNA repair proteins when DNA has sustained damage ⮕ ensures damaged DNA is not replicated
- arresting growth by holding the cell cycle at the G1/S regulation point upon DNA damage recognition ⮕ ensures damaged DNA is not replicated and gives time for the cell to repair DNA damage. [activated p53 protein binds to specific DNA control elements & promotes transcription for relevant genes like p21, which stops the cell cycle by binding to proteins involved in cell cycle progression like Cdks]
- initiating apoptosis when DNA damage proves to be irreparable. [p53 protein activates ‘suicide’ genes that ensure cells with damaged DNA does not continue to proliferate

loss of function mutation to both copies of p53 gene = defective/missing p53 protein = unable to inhibit cell cycle when DNA is damaged = cells containing damaged DNA proliferate indefinitely (UH-OH!!)

Question 13

what is the function of a proto-oncogene?

Answer 13

proto-oncogenes code for gene products that promote normal cell division.
proto-oncogene products include:
1. growth factors that stimulate cells to divide
2. growth factor receptors, membrane proteins that bind to growth factors
3. protein kinases that phosphorylate & thus activate proteins
4. inhibitors of apoptosis, which reduces rate of cell death
5. transcription factors which control rate of transcription

Question 14

what kind of mutation ?

under what circumstances will defective proto-oncogene products be formed?

Answer 14

a gain in function mutation must occur.

a mutation of one of the two copies of a proto-oncogene into an oncogene is sufficient to cause abnormal cell proliferation. the oncogene acts in a dominant manner (since only 1 copy needs to be mutated). this is a gain in function mutation, leading to genes to gain function, eg being over-expressed or coding for hyperactive proteins which lead to uncontrolled cell division

Question 15

what is an example of a proto-oncogene?

Answer 15

the ras gene is a type of proto-oncogene

Question 16

describe the role of ras protein (coded for by ras proto-oncogene) in the cell cycle and how a gain in function mutation of the ras gene leads to cancer.

Answer 16

normally:
- the ras protein, when activated, relays signals from a growth factor receptor to a series of protein kinases in the phosphorylation cascade.
- the last protein kinase of the pathway activates transcription of genes encoding proteins that stimulate cell division
- the pathway is normally activated only when a growth factor binds to its receptor in the plasma membrane, causing cell division

when there is a gain in function mutation:
- gain in function mutations in the ras gene leads to changes in the 3D conformation of the ras protein
- causes GTP to remain bonded to the ras protein as a ras-GTP complex and thus the ras protein is in a constant active state, even in the absence of a growth factor (stimulant).
- results in an increased rate of cell signalling, transcription and consequently stimulates the cell cycle
- so a hyperactive ras protein leads to excessive cell division

Question 17

what are the 2 types of change that could happen to cancer-critical genes?

Answer 17

quantitative change, eg overproduction/no production/underproduction
qualitative change, eg hyperactive product/change in 3D shape of product

Question 18

why is cancer development a multi-step process?

Answer 18

• there needs to be a gradual accumulation of mutations in cancer-critical genes in a single cell lineage to achieve increasing genetic instability
• both alleles of TSGs like p53 need to be mutated in a loss of function manner while one mutation in a proto-oncogene like ras needs to occur in a gain in function manner
• which will lead to uncontrolled cell division, which allows the cell to possess an unstable genomeand accumulate more mutations, allowing it to escape normal growth restraints
• these mutations allow cancerous cells to activate telomerase, angiogenesis, and metastasize, leading to cancer

Question 19

how does the activation of telomerase contribute to the development of cancer?

Answer 19

• once telomeres, regions of repetitive & non-coding DNA at the ends of chromosomes, are shortened to a critical length, the cell stops dividing and goes into replicative cell senescence
• telomerase is a ribonucleoprotein complex that adds telomere repeat sequences to the 3’ ends fo DNA
• telomerases are usually not expressed in most human somatic cells
• once telomerase genes are activated, telomerase is produced and maintains telomere lengths, allowing cancer cells to divide indefinitely, avoid hayflick’s limit and evade apoptosis

Question 20

how does angiogenesis contribute to the development of cancer?

Answer 20

• a tumour requires more nutrients and oxygen due to its more rapid proliferation. a growing tumour is thus able to stimulate angiogenesis, the formation of new blood vessels, to ensure its relentless growth
• these blood vessels allow increased blood flow to the tumour, supplying nutrients & oxygen, and removing toxic waste products. they also provide the pathways for cancer cells to spread to other sites in the body (metastasise)
• many cancer cells produce angiogenesis-activating proteins that overcome the effects of angiogenesis inhibitors that normally restrain the growth of blood vessels

Question 21

describe the angiogenic process.

i.e. how angiogenesis occurs

Answer 21

1. a tumour cell releases angiogenesis-activating proteins that attract endothelial cells and promote their proliferation
2. endothelial cells secrete protein-degrading enzymes (matrix metalloproteinases, MMPs)
3. MMPs break down the blood vessel wall and the components of the extracellular matrix, allowing endothelial cells to become organised into new networks of blood vessels

Question 22

what is metastasis and how does it occur?

Answer 22

metastasis is the ability of cancer cells to enter the circulatory system and travel to distant sites, where secondary tumours/metastases are formed

invasion refers to the acquired ability of cancer cells to perform direct migration and penetration to neighboring tissues

metastasis process:
1. cancer cells invade surrounding tissues and penetrate through the wals of lymphatic & blood vessels, gaining access to the bloodstream
2. cancer cells are transported by the circulatory system throughout the body
3. cancer cells leave the bloodstream and enter particular organs, where new secondary tumours at distant sites from the primary tumours ar established

Question 23

what are causative causes of cancer?

Answer 23

1. polycylic aromatic hydrocarbons (PAHs) in cigarette & tobacco smoke
2. heterocyclic amines in charred meat
3. ionising radiation/ultraviolet radiation
4. inherited mutations in proto-oncogene/tumour suppressor gene
5. age (?)
6. viral infections

Question 24

describe how polycylic aromatic hydrocarbons (PAHs) in cigarette & tobacco smoke may lead to cancer

Answer 24

1. PAHs enter the lungs and spread throughout the body via the blood stream
2. PAHs can bind to DNA of cells and form an adduct, damaging DNA.
3. this damage can typically be repaired, but if not repaired, the adducts cause mistakes in DNA synthesis during normal cell division.
4. this introduces mutations into the DNA sequence, leading to gene mutations.
5. PAHs tend to form adducts at several sites on the p53 gene, which prevent the production of functional p53 protein in affected cell, leading to uncontrollable cell division which leads to tumour formation

polycylic aromatic hydrocarbons are insufficient to trigger cancer. additional mutations in other genes and processes like telomerase reactivation, angiogenesis and metastasis is required to cause cancer

Question 25

describe how heterocylic amines (HCAs) and polycylic aromatic hydrocarbons (PAHs) in charred meat may lead to cancer.

Answer 25

1. when charred meat is consumed, HCAs & PAHs spread around the body system via the bloodstream
2. HCAs bind to DNA and cause mistakes in DNA synthesis during normal cell division, which introduces mutations into the DNA sequence. this leads to gene mutations
3. PAHs form adducts on the p53 gene, causing mutations that prevent the production of functional p53 proteins, which in turn leads to uncontrollable cell division and tumour formation

heterocylic amines are insufficient to trigger cancer. additional mutations in other genes and processes like telomerase reactivation, angiogenesis and metastasis is required to cause cancer

Question 26

describe how ionising radiation may lead to cancer

Answer 26

1. ionising radiation may result in the production of free radicals of water
2. these free radicals can interact with cellular DNA to produce double stranded breaks, leading to chromosomal rearrangements and deletions, affecting cancer critical genes
3. the cell may thus experience uncontrollable cell division which may lead to tumour formation

ionising radiation is insufficient to trigger cancer. additional mutations in other genes and processes like telomerase reactivation, angiogenesis and metastasis is required to cause cancer

Question 27

describe how ultraviolet radiation may lead to cancer

Answer 27

1. excessive exposure to UV rays produces a covalent attachment between adjacent pyrimidines in one strand, or base pair substitutions/insertions/deletions in cellular DNA
2. may cause mutations in cancer critical genes which may eventually lead to tumour formation

UV ray exposure is insufficient to trigger cancer. additional mutations in other genes and processes like telomerase reactivation, angiogenesis and metastasis is required to cause cancer

Question 28

describe how viral infections may lead to cancer

Answer 28

tumour viruses can integrate their genetic material into DNA of host cells and transform a normal cell into a tumourigenic cell by:
- inactivating TSGs/converting proto-oncogene into an oncogene
- directing expression of viral proteins that can inactivate p53 and other TSGs to render a host cell more susceptible to cancer
- introducing an oncogene into a normal cell

a viral infection is insufficient to trigger cancer. additional mutations in other genes and processes like telomerase reactivation, angiogenesis and metastasis is required to cause cancer