The Hallmarks of Cancer

Question 1

what is a squamous cell carcinoma?

Answer 1

> derived from cells that seal the cavity or channel that they line

• most cancers of the anus, cervix, head and neck, and vagina are squamous cell
• skin as well

Question 2

What tissue type does the carcinomas arise from?

Answer 2

epithelial tissue

Question 3

what are adenocarcinomas?

Answer 3

> derived from cells that secrete substances into cavities or ducts that they line

• responsible for more than 80% of cancer-related deaths in western world
• tumours can be pure or a combination of both adenocarcinomas or squamous cell carcinoma

Question 4

what are non-melonoma skin cancers?

Answer 4

> 30% are SCC upper layer epidermis
- more tendency to metastise
basal cell carcinoma - cells in st basale

Question 5

describe the nonepithelial cancers

Answer 5

1) sarcomas = derived from various connective tissues
2) neuroectodermal - consists of cells derived from ectoderm that are not epithelium = nerve cells etc
3) Hematopoietic (blood tissue forming/leukemia/lymphoma)
4) melonoma - cancer of the melanocytes

Question 6

What are the progressive steps to cancer development (skin cancer for example)

Answer 6

> cellular changes are apparent at each stage arising from cumulative epi/genetic changes

• normal
• benign/ carcinoma in situ (basement membrane not invaded)
• locally invasive (carcinoma) -> invaded CT
• malignant carcinoma -> invaded blood stream and travels to different areas of the body

Question 7

What are the stages of tumour progression?

Answer 7

1) hypertrophy –> increase in size of cells
2) hyperplastic –> increase in number of cells
3) metaplastic –> change in type of cell
4) dysplastic –> disordered -> all over the shop
all above are reversible

5) neoplasia
- benign - localised and non-invasive
- malignant - spreading and invasive
not reversible

Question 8

what are the different types of tumours and some examples of these

Answer 8

> neoplasi is broad term for a tumour - abnormal, uncontrolled and irreversible - but usually benign

• adenomas are the name for abnormal growths in epithela tissue: eg adenomatous polyps (colon), warts, papillomas etc
• term carcinoma is usually applied to neoplasia that have acquired a degree of invasiveness -> break through the basement membrane and invading adjacent stroma.

Question 9

what are the unique properties of cancer cells?

Answer 9

> uncontrolled cell growth and proliferation
genetically unstable
possess an unusually high number of mutations including chromosomal abnormalities ( thats why they stain dark on slides as massive extra amount of chromosomes then usual)
abnormal cytoplasm:nucleus ratio
cytoskeletal abnormalities so appear abnormally shaped under a microscope

Question 10

describe the different types of mutagens

Answer 10

> viruses
- HPV contains dsDNA molecules which carry information required for both viral replication and virus-induced cell transformation

> UV radiation:
- results in formation of pyrimidine dimers, by cross-linking of adjacent pyrimidine bases (T=T or C=C)

> radiation:

• xrays and radioactive radiation tend to induce breaks in the dsDNA
• enhanced exposure of pop to such types of radiation results in higher incidence f leukemias and thyroid cancers

Question 11

What are the types of genes that have to be mutated to cause full cancer development?

Answer 11

a combination of mutations in one or more of these gene categories will lead to cancer

1) gain of function mutation in proto-oncogene (genes that tell cells to grow and proliferate)
2) loss of function mutation in tumour suppressor genes (genes turned off - leads to unchecked growth as nothing is saying to cell to stop growing)
3) Loss of function mutation in DNA repair enzymes

Question 12

What are proto- oncogenes?

Answer 12

• normal cellular genes that are involved in positive growth regulation of cells which are normally tightly reguated.
• they may turn into ONCOGENES (ie cancer causing genes) by a single mutation that either generates a hyperactive protein or results in overexpression of he gene product (receptors, growth factors etc that promote growth and proliferation)

Question 13

What are tumour supressor genes?

Answer 13

• the normal activity (normal inhibitors of cell growth) is required to keep cell proliferation in check
• slow down cell division
• repair DNA mistakes
• or tell cells when to die ( a process known as apoptosis or programmed cell death)
• mutation in these genes can lead to cancer cells growing out of control and cancer

Question 14

what are DNA repair enzyme examples?

Answer 14

> nucleotide excision repair
- removes lesions of the DNA - ie dimers caused by uv
- scans DNA and cuts out a section around fault which is then filled in by DNA pol
repair of double stranded breaks

> mismatch repair

• coupled to DNA replication, located at rep fork
• scans new daughter strand for mismatches and recruits other enzymes to fix faults

Question 15

What are the hallmarks of cancer?

Answer 15

1) self-sufficiency of growth
2) insensitivity to antigrowth signals
3) evading apoptosis
4) limitless replication
5) angiogenesis
6) tissue invasion and metastasis

Question 16

Describe the self sufficiency of growth hallmark

Answer 16

> receptor proteins are overexpressed so the cancer cell has excessive growth signal receptors
growth signal receptor proteins are mutated so that they are constantly switched on
the cells make excessive amounts of normal growth ligands which keep surface receptors switched on
mutations affecting catalytic enzyme:
- structure: changes so that the receptors form dimers without the ligand
- overexpression: too many receptors on cell surface so that they come into contact which eachother without the ligand stimulus
- autocrine signalling: receptors mutate to respond to their own signalling molecule instead of the correct signalling molecule

Question 17

describe insensitivity to antigrowth signals hallmark

Answer 17

> cells need to be connected to the ECM to carry out their tissue specific roles
when disconnected, antigrowth signals are not recognised as cells are transformed
cancer cells also grow and proliferate when the presence of growth signal is minimal
loss of surface proteins
enhanced expression of proteases that contribute to ECM breakdown
- behaves like a wound
example: strong epithelial cells held together by desmosomes transition into mesenchymal cells which can penetrate the blood stream a lot easier, have no adhesion cell to cell

Question 18

describe evading apoptosis hallmark

Answer 18

> failure of apoptosis results in cancer
cells differentiating where they shouldn’t be but no cell death
failure or mutation in Tumour suppressor genes
most frequently in protein P53

P53 normal function:

• sensing of DNA ds breaks
• induction of the synthesis of cell cycle inhibitors (p21 or waf-1) - cell cycle arrest
• induction of the synthesis of DNA repair enzymes
• induction of cell suicide by apoptosis (is DNA damage cannot be repaired
• P53 is activated in various other cell stress conditions, such as oxidative stress or hypoxia

P53 loss of function:

• mutations of gene (missense or nonsense mutations)
• complexing with a mutant p53 protein
• complexing with proteins originating from oncogenic DNA viruses

p53 deficient cells fail to undergo apoptosis
- can be an inherited defect

Question 19

describe limitless replication hallmark

Answer 19

> cancer cells evade replicative senescence (irreversible arrest of cell proliferation and altered cell function) through overproduction of certain proteins
this must work in combination with an avoidance of telomere shortening
- this shortening is what tracks how old a cel is and how many replications it has gone through
- if it does not shorten, cell effectively immortal

Question 20

describe angiogenesis hallmark

Answer 20

> tumours will not grow without blood supply
dialogue with other cells is replaced with a monologue about only that tumour, so that the focus for blood supply is on it
tumours resemble wounded tissues that do not heal to the body
many of the signalling processes involved in cancer progression are similar to those that occur during wound healing
capillaries within tumours are leaky, unlike those in normal tissues
release angiogenic factors that promote blood vessel formation

Angiogenesis process

• tumour secretes VEGF (angiogenic growth factor)
• neighbouring blood vessel epithelial cells respond to this factor and transition to mesenchymal cells ( EMT transition) -> migration and proliferation
• these mesenchymal cells proliferate and join the tumour, creating a tube (vessel) to the tumour

Question 21

describe tissue invasion and metastasis hallmark

Answer 21

> primary tumours cause 10% of cancer deaths
circulating tumour cells are the most dangerous
breast cancers often spawn metastatic colonies promiscuously in many tissues throughout the body, including brain, liver, bones and lungs

three ways tumours spread:

1) through the surrounding tissue -> in situ, versus through basement membrane and into blood stream
2) through lymph system -> invades a few lymph nodes and these go through bloodstream
3) through blood to other parts of the body

EMT very important for carcinoma:

• well differentiated adenoma - cells group together and maintenance of intracellular adhesion resists transition to invasive phenotype
• if EMT occurs, adenoma transitions into invasive carcinoma (mesenchymal state)