Cancer biology Flashcards by Jasmine Callacher

What is neoplasia?

new, uncontrolled growth of cells that is not under physiologic control, can be benign of malignant

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What are the histological differences in bengin and malignant tumours?

in benign tumours the tumour is contained in a capsule with nothing escaping the basement membrane

malignant tumours distinguished by messier, disorganised growth, with cells branching down and growing where they shouldn’t and have an invasive phenotype

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What is hyperplasia?

increase in the amount of tissue caused by an increase in the reproduction rate of its cells, often a preneoplastic event

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What is metaplasia?

change in form of cellsthe, the conversion of a mature differentiated cell into another form of a mature cell type, often following injury or insult

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What is dysplasia?

a change in the structure and shape of cells

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What is anaplasia?

structural differentiation loss in cells

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In which type of cell do most tumours start?

What are some of the possible reasons for this?

Epithelial cells

they cover large surfaces e.g. organs and are alot closes to the envrioment so form the first line of defense
they are also often in secretory areas so need to be frequently repalced

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What are tumours of epithelial origin called?

What are the two major categories?

Carcinomas

squamous cell carcinoma - covers and lines the tissue
adenocarcinoma - glandular or secretory function

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What are tumours that derive from mesenchymal cell types (mostly connective tissue) called?

sarcomas

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What are tumours that derive from blood-forming hematopoeitc tissues called?

Hematopoeitic malignancies

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What are tumours that derive from cels in the central and peripheral nervous system called?

neuroectodermal tumours

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Are tumours thought to be monoclonal or polyclonal?

What part of the tissue are tumours thought to originate from?

monoclonal

stem cells

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What is the evidence that supports tumour cells being either monoclonal or polyclonal?

tumours that look heterogeneous the pattern of X-inactivation is conserved suggesting they are monoclonal.
the G6PD enzyme has various forms, and can migrate from various cells. Tumours form heterozygous patients were found to express only one variant of the cell
in tumour cells such as multiple myeloma there are only one type of immunoglobin rather than the many you would expect to see in normal plasma cells, this suggests the tumour came from one cell that expressed that particular immunoglobin
chromosomal rearrangements found only in one cell can then be present in all tumour cells

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Who came up with the ‘cancer is bad luck’ theory?

How did they come to this conclusion?

Tomasetti and Voglestein, 2015

looked at the incidence of different cancer types and estimated the cancer risks for certain tissues
they then correlated this with the number of divisions that the stem cells would undergo in their lifetime
sad the majority of cancer due to random events and only 1/3 due to environment

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Briefly describe some examples the support the role of environmental factors in cancer occurrence?

Seventh-day Adventists (no smoking, red meat or drinking) have a cancer rate about half of the general population

Breast cancer incidence in the US is 6X higher than China

Japanese people who moved to Hawaii. In Japan they had high incidence of stomach cancer but when they moved to Hawaii incidence of stomach cancer reduced and prostate and breast cancer increased

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What are non-genotoxic agents?

Carcinogens that do no cause genetic mutations

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What is the Ames test?

A method for testing if a substance is mutagenic or not

Mix bacteria with the suspected agent

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What are the two major strategies for detecting and removing miscopied nucleotides?

DNA polymerases have proofreading activity (3’-5’ exonuclease activity);

Mismatch repair (MMR)!

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What are the 4 stages of the cell cycle?

G1: cell preparing to divide
S: components of the cell are being copied
G2: gap phase 2
M: mitosis phase where the cell splits in two

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In mammalian cells, what proteins provide the MutS activity and what proteins provide the MutL activity?

In what disease are on of these four genes mutated?

MutS: a dimer of MSH2/MSH6

MutL: a dimer of HLH1/PMS2

Lynch syndrome

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What is Myc?

A transcription factor

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On what chromosome is Her2 found?

Chromosome 17

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Drugs that target specific cancer markers. What drug is used in the treatment of:

CML
Her2 expressing breast cancers

Gleevect/Imatanib

Trastuzamab/Herceptin

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What are the two isoforms of the pyruvate kinase gene?

M1 or M2 (PKM1 or PKM2)

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What induces expression of TIGAR?

P53

Name the three mechanisms behind the increased risk of breast cancer with oestrogen.

Increased inflammation Increased hormonal exposure Increased production of insulin like growth factor

What is a SERM?

selective oestrogen receptor modulator

What does an APC mutation result in high levels of?

Beta-catenin

What percentage of colon tumours suffer APC mutations as an early step?

90%

What layer of the bowl does: - Ulcerative collitus - Crohns disease affect?

Inner layer of the bowel wall All layers of the bowel wall

What are the two mechanisms by which IBD increases risk of colon cancer?

Increased production of cytokines ROS production

If Ras is bound to GDP what happens? If Ras is bound to GTP what happens?

It is inactive It is active

Which Ras mutation is associated with lung cancer?

K-ras

Iressa/Gefitinib can be used in the treatment of lung cancer with what mutation?

EGFR mutations

What do Taxels mainly target?

Microtuble assembly, but there are many methods by which they can induce cell death

What are the 5 steps of metastasis?

``` Invasion Intravasiation Transport Extravasiation Metastatic colonisation ```

What is the cadherin marker expressed normally in epithelial tissue? What cadherin marker is expressed in metastasis?

E-cadherin N-cadherin

On what chromosome is the BCR gene found? On what chromosome is the Abl gene found?

22 9

What type of leukaemia is associated with the Philadelphia chromosome?

CML

What is the most frequent from of BCR-Abl?

P210

Where do most mutations occur in p53? What happens as a result of mutation?

The DNA binding domain Makes p53 less likely to bind a specific sequence and instead binds all over switching genes on

What is responsible for the recruitment of ubiquitin ligase to p53?

MDM2

What percentage of cancers did Voglestine and Tomasetti say were down to random mutation?

66%

In which period of the cell cycle are cells responsive to mitogenic growth factors and TGF-b?

In non-smokers a mutation in what is often the cause of non-small cell lung carcinoma?

EGF mutation

What type of receptor is the PGDF receptor?

Tyrosine kinase

Briefly describe what happens when a ligand binds a tyrosine kinase.

- Ligand binds causing conformational change - Two RTK bind and form an oligomer - The two tyrosine kinase domains phosphorylate each other - Once phosphorylated they recruit and bind other proteins and phosphorylate them inducing a signal transduction cascade

What type of receptor is a EGF receptor?

receptor tyrosine kinase

What type receptor is a TGF-b receptor?

Serine/threonine receptor

What is the most important step in DNA MMR?

Identifying which of the 2 DNA strands is the newly replicated strand

What type of kinase is ATM? What is it's role?

Serine/threonine kinase the kinase that activates the signal transduction cascade that leads to repair

What does PEL stand for?

Primary effusion lymphoma

What is the name of the enzyme that catalyses the last step of glycolysis?

Pyruvate kinase catalyses conversion of phosphoEnolPyruvate to pyruvate

What transcription factor is involved in controlling expression of proteins involved in splicing PKM? What are the names of the proteins?

Myc hnRNPA – heterogenous nuclear ribonucleoprotein A PTB – polypryrimidine tract binding protein

Is Myc a protooncogene or tumour supressor gene?

Protooncogene

Which oligomer of PKM2 is often found in cancer cells?

the dimer

What induces TIGAR expression? What does TIGAR do?

p53 inhibits phosphofructokinase (which catalyses one of the steps of glycolysis) leading to a redirection of glucose awards the pentosephosphate shunt and increased NADPH

List some examples of in vivo stresses that can induce senescence.

- telomere dysfunction - oxidative stress - DNA damage - oncogene activation - cytotoxic drugs

What is seen at the ends of chromosomes in normal cells?

Telomeric repeat binding factor 2 (TRF2)

What percentage of human cancers express telomerase?

90%

What does telomerase do?

adds additional copies of the 5’TTAGGG3’ to the end of a chromosome

What is TERT

the catalytic subunit of the enzyme telomerase, which, together with the telomerase RNA component (TERC), comprises the most important unit of the telomerase complex

Name a telomerase inhibitor and briefly describe how it works.

Imetelstat - a hybrid oligonucleotide identical to the RNA part of the telomerase enzyme It binds the RNA template to prevent telomerase ends and stabilising them

Give an example of a SERM. What disease are they used to treat?

Tamoxifen Breast cancer

What percentage of colon cancer cases are thought to be due to familial risk factors?

10 - 30%

What happens to a tumour grown in avascular tissue?

It grows very slowly

What happens to HIF-alpha in normoxic conditions?

It is ubiquitinated by VHL leading to its degradation. So don't get activation of transcription factors and angiogenesis doesn't occur

What happens to HIF-alpha in hypoxic conditions?

It is not ubiquitinated by VHL so is not degraded and is free to bind to HIF-beta. Binds to a response element and alters transcription leading to VGEF production and angiogenesis.

What type of receptor is the VGEF receptor? What happens when VGEF binds to its receptor?

Tyrosine kinase It leads to a signal transduction cascade leading to angiogenesis and survival and proliferation of tumour cells

How does p53 relate to the angiogenic switch?

p53 is an important TSG mutated in over 50% of cancers, of of its target genes is thrombospondin 1 which is an inhibitor of the angiogenic switch

What type of protease is upregulated in almost all tumour types?

matrix metalloproteinases

What are mesenchymal cells?

Mesenchymal stem cells are multipotent stromal cells that can differentiate into a variety of cell types, including osteoblasts (bone cells), chondrocytes (cartilage cells), myocytes (muscle cells) and adipocytes (fat cells which give rise to marrow adipose tissue).

Name two molecules important for intravasiation.

MMPs - to degrade the basement membrane TAMs (tumour assisted macrophages) - guide tumour cells to vessels

What molecule expressed in endothelial cells is important for attachment?

E-selectin

What does CAM stand for?

Cell adhesion molecule

What do CAMs and cadherins do?

mediate cell recognition/ interaction and hook cells into place

What do integrins do?

Integrins bind cell to extracellular matrix

What induces EMT?

Signals from the tumour stroma

What is E2F? What acts as its enforcer?

a transcription factor that turns on genes needed for S-phase retinoblastoma protein