Cancer Flashcards
Where are the main checkpoints within the cell cycle?
During G1 - Check cell has enough resources to go into cell division
Just before mitosis (G2) to check for DNA damage
Spindle assembly checkpoint
Name 2 things that must occur for mitosis to proceed in each cell cycle checkpoint.
G1 - Need enough growth factor and nutrition
G2 - DNA has to properly replicated and organelles have to properly replicated
Spindle assembly checkpoint - Attachment of spindle fibres to kinetochore and correct alignment of sister chromatids at the midline of the cell
State 4 specific features of apoptosis (as opposed to necrosis
Requires ATP No inflammation Regulated No cellular disruption Apoptosis can be physiological; necrosis is only pathological
Why can we give antioestrogens to treat breast cancers?
Around 70-80% of breast cancers are oestrogen receptor positive, with oestrogen stimulating the growth of the cancer. By targeting these oestrogen receptors and antagonising them, it would prevent the cancer from spreading and continuously growing. Some oestrogen receptor negative cancers also respond to antioestrogens (around 5-10%)
Tamoxifen is not strictly antioestrogenic. Give 3 other benefits of it in breast cancer treatment apart from its anti-cancer properties
Improves bone density therefore reducing risk of osteoporosis
Doesn’t cause atherosclerosis by decreasing LDL cholesterol
Doesn’t have many S/E
Why can we use antiandrogens in some prostate cancers
Cancerous prostate cells may present androgen receptors which would stimulate growth of the cancer when androgens bind
How does giving GnRH treat cancers and why would we combine this therapy with antiandrogens in prostate cancer
GnRH constantly stimulating the receptor subsequently leads GnRH receptor desensitisation and down-regulation. As a result, this would cause less FSH and LH release, leading to less formation of testosterone and other androgens by the gonads, therefore reducing total circulating androgen concentration.
The adrenals also produce androgens, which the GnRH agonists do not decrease the concentration
What can staging be used for
To see how far the cancer has spread
Name 3 cytological features looked for in staging
Tumour size
Lymph node involvement and which lymph nodes
Number of lymph nodes involved and which lymph nodes
Metastasis
4 ways to assess the grade of a cancer
Degree of differentiation
Increased nuclear:cytoplasmic ratio
Presence of necrosis
No. of abnormal mitosis
List two cancers and state how they affect physiological function specifically
Lung cancer causes ectopic ACTH leading to Cushings Syndrome
Pituitary adenoma causing bilateral hemianopia
Prostate pushing against urethra and causing difficulty urinating
Colon cancer causing iron deficiency anaemia
Give reasons why prostate specific antigens are elevated in prostate cancer
PSA is a component of seminal fluid, and normally is prevented from entering the blood via the basement membrane and basal cell layer. However, due to damage to the basement membrane and basal cell layers due to the prostate cancer, it causes there to be PSA which enters the blood, leading to the rise in PSA in cancer
Give some treatment methods for prostate cancer
GnRH agonist – continuously bind to the GnRH receptor on Gonadotrophic cells, leading to receptor downregulation and decreased release of LH and FSH. As a result, there would be less stimulation of the testes to form testosterone and other androgens, leading to decreased growth of the prostate cancer, as the cancer is initially androgen dependent
Anti-androgens – prevent androgens from binding to the androgen receptor and having their subsequent effect, leading to decreased cancer growth
What is androgen independence
Androgen independence is a severe stage in prostate cancer where there is growth of the cancer despite endocrine therapy being used, occurring on average around 13 months after diagnosis
Give three causes of androgen independence
Receptor responding to the lower concentrations of androgen or other androgens
Receptor responding to other compounds similar to androgen, like oestrogen
Decreased levels of co-repressors of the receptor
Ligand-independent activation of the androgen receptor
Name four things that causes a normal cell to become cancerous
Uncontrolled proliferation
Cell-cell adhesions downregulated
Cells develop motility
Increased levels of matrix metalloproteinase (MMP)
Name four cytotoxic drugs and briefly describe what they do
Chlorambucil – alkylating agent: donates alkyl group to guanine residues leading to crosslinking of DNA strands and preventing DNA uncoiling at replication
Cisplatin – pseudoalkylating agent: similar to above but donates platinum residue instead of alkyl group
Methotrexate – antimetabollites. Masquerade purine or pyramidine residues and inhibit DNA synthesis and cause DNA double stranded breaks and apoptosis and inhibit de novo nucleotide synthesis
Doxorubican – anthracycline: Inhibit transcription and replication by intercalating into DNA
Vinca alkaloids and taxanes – Vinca alkaloids prevent assembly of spindle fibres; taxanes prevent disassembly of the spindle fibres
Irinotecan/topotican and etoposide – topoisomerase inhibitors: therefore allowing permanent DNA strand breaks
State four ways of resistance to cytotoxic drugs
Drug efflux from cell increased by ATP binding casket transporters
Reduced drug influx into cell
Increase DNA base repair to remove DNA adducts
Upregulate DNA repair mechanisms
State two reasons why the cell cycle might terminate.
DNA damage during replication causing apoptosis of the cell
Incomplete spindle attachment during metaphase (metaphase-anaphase checkpoint) => mitotic arrest
Lack of nutrient and growth factors needed for growth
Name the two families of cell cycle inhibitors
INK4 – displace cyclin D from cdk 4/6
CIP/KIP – bind to cdk complex therefore preventing cyclin binding
What’s the difference between an oncogene and a proto-oncogene
Oncogene is a mutated form of the proto-oncogene which is aberrantly expressed, overly expressed and aberrantly active
Proto-oncogene = A gene which encodes protein that are involved in growth and differentiation
Describe three ways in which a proto-oncogene can become an oncogene
Point mutation
Proto-oncogene becomes under the influence of a gene amplifier due to chromosomal translocation
Gene amplification
Formation of a fusion or chimeric gene which forms a new protein that constitutively activates proliferation
Name four proto-oncogene/oncogene classes
- Cell death regulators and cell cycle regulatory proteins
- Intracellular transducers
- Growth Factor
- Transcription factor
- Intracellular receptors
- Growth factor receptor
Name four functions of tumour suppressor genes
Regulate cell cycle Regulate cell division Regulate cell growth Cell death regulator Cell-cell adhesion molecules Maintain cell integrity DNA repair Nuclear transcription factors
Why do you only need one mutated oncogene to cause neoplasia, but two mutated suppressor genes to cause neoplasia?
Oncogenes encode proteins promoting proliferation, so if they are abberantly expressed there is abberant proliferation. They act in a dominant way.
In contrast, tumour suppressor genes generally act recessively over the wild-type allele, as they act as a ‘brake’ on the cell cycle. Thus, if there is a mutated copy, the functioning copy is able to compensate so 2 mutations are required to cause neoplasia.
Describe four relationships between oestrogen/oestrogen receptor/prognosis/treatment (4 marks)
In women, if they have the oestrogen receptor, it is a better prognosis; in men it is a worst prognosis
70-80% of breast cancer is oestrogen receptor positive
Anti-oestrogens can be used as treatment for oestrogen receptor positive cancer and for 5-10% oestrogen receptor negative cancer
Give two side effects of tamoxifen, and name another drug used to treat breast cancer (3 marks
Increased risk of venous thrombosis
Increase risk of stroke
Increase endometrial cancer, fibroids and polyps
Luprolide (LHRH agonist)
Describe the six stages of apoptosis.
1) Initiation of apoptosis via intracellular or extracellular pathway
2) Microvilli contact, intracellular junctions break and chromatin begins to condense
3) Cell shrinks with epithelial closing around
4) Cell blebs violently and chromatin condensation continues
5) Apoptotic bodies formed
6) Apoptotic bodies phagocytosed by neighbouring cells or macrophages
What is the role of PTEN in apoptosis?
Without PTEN, PI3-Kinase converts PIP2 into PIP3. PIP3 activates the PKB/Akt pathway. PKB/Akt phosphorylates Bad onto 14-3-3, meaning Bax and Bak are bound to Bcl-2 and Bcl-xl on the mitochondrial membrane, preventing apoptosis. PTEN converts PIP3 into PIP2, preventing the activation of the PKB/AKT pathway. As a result, Bad is not bound to 14-3-3 leading to Bad displacing Bax and Bak from Bcl-2 and bcl-xl. Bax and Bak cause a pore to form in the mitochondrial membrane leading to cytochrome c leaving and activating the intrinsic pathway. PTEN is a tumour suppressor gene
What is a tumour suppressor gene, and give example
A gene which encodes a protein the inhibits the tumour phenotype. E.g. P53, PTEN, CIP/KIP
What is an oncogene, and give example
A mutated proto-oncogene that encodes proteins that lead to increases cell survival and proliferation. E.g. c-myc, V12 Ras, L61 Ras
Describe the sequence of events during ‘‘carcinogenesis’’.
- 1) Genetic mutation
- 2) Hyperproloferation of mutated cells
- 3) De-differentiation / loss of cell-cell contact
- 4) Loss of anchorage dependence and loss of contact inhibition of locomotion
- 5) Invasion and metastasis
What is meant by Anchorage Dependence Proliferation?
The cell would have needed to bind to ECM, e.g. via integrins, in order for it to proliferate
Describe differences between benign and malignant tumours
• Benign: o Well differentiated o Encapsulated o Normal mitosis therefore normal nuclear: cytoplasmic ratio o Do not invade and metastasise o Slow growing • Malignant: o Well to poorly differentiated o Not encapsulated o Increased mitosis therefore causing increased nuclear: cytoplasmic ratio o Can invade and metastasise o Fast growing
Name two death receptors
Fas Death Receptor (1-4)
Briefly explain the adenoma - carcinoma change in bowel cancer
Normal colon – APC gene mutation, causing to polyps to form within the bowel. K-ras mutation with hypomethylation of DNA forming an adenoma. P53 gene mutation forming a carcinoma, which can metastasise
Give 3 common clinical symptoms of bowel cancer
Per rectal bleeding Change in bowel habits Constitutional, e.g. weight loss Per rectal mucous Bloating Unexplained iron deficiency anaemia
What is Duke’s staging? How does it relate to the progression of colorectal cancer and what is the clinical significance? (4)
- Dukes staging is the staging system specific for colon cancer, going from Duke A to Duke C2
- Duke A would have the best prognosis, with prognosis subsequently decreasing going from Duke A to Duke C2, due to greater growth and lymph node invasion
- Dukes’ A - confined within the bowel wall (including the muscle)
- Dukes’ B – growth beyond the muscularis propria
- Dukes’ C1 - metastasis in lymph nodes, apical LN negative
- Dukes‘ C2 – apical LN positive (distant metastatic spread)
- Highlights the possible treatment options available to try tackle the cancer
- The worse the stage, the worse the prognosis
Outline integrin’s structure.
They are heterodimer complexes of alpha and beta subunits
They associate extracellularly via their head and each of the tail regions spans the plasma membrane
Describe outside-in signalling of integrins
A cell can receive information about its surrounding via adhesion to the ECM
The ligand binds and opens the legs of the complex, allowing cytoplasmic signalling molecules to bind
Describe inside-out signalling of integrins.
Growth factors can generate signals inside the cell, which can act on the integrin complex and alter its affinity (this is important in bloodclotting)
What is the cell lineage of ALL?
Lymphoid: Lymphocytes, so B-cells, T-cells and NK cells
How does ALL kill someone
ALL could lead to the formation of immature B-cells, T-cells and NK cells. As a result, due to the lack of maturity of these cells, they would not be able to respond as effectively to infections, in comparison to their mature counterparts. As a result, this would likely increase the likelihood of infection occurring and also decrease the prognosis of the infection. As the body would not be able to respond to and clear the infection, it could subsequently cause death
How does ALL lead to bone pain, thrombocytopenia and anaemia?
ALL would lead to unregulated and subsequently increased division of the haematopoietic stem cells. As a result, this would lead to bony pain due to the constant division and accumulation of cells, causing overcrowding
As the haematopoietic stem cell is constantly dividing to form lymphocytes, there would be less stimulation to form RBC and platelets (=out-crowding). As a result, this would subsequently lead to thrombocytopenia and anaemia
Explain how ALL can sometimes cause hyperuricaemia. Is this clinically significant? If so, how?
ALL could cause renal failure. As uric acid, formed normally from cell turnover, is excreted in the kidneys, less would be secreted, leading to hyperuricaemia. This is significant as it could cause gout
What are 3 genomic causes of leukaemogenesis
- Mutation in known proto-oncogene
- Creating novel gene (chimeric or fusion gene)
- Dysregulation of a gene where translocation brings it under the influence of a promotor or enhancer of another gene
- Loss of function of a tumour suppressor gene
What does leukaemia literally mean and what are the 4 main types?
- Leukaemia translates to white blood
- 4 types: Acute Lymphoblastic Leukaemia, Chronic Lymphocytic leukaemia, Acute myeloid leukaemia and Chronic myeloid leukaemia
Describe 3 cellular features that allows a normal cell to become cancerous
- Mutation to permanently switch on oncogene
- Mutation to permanently switch off tumour suppressor gene
- Increased production of VEGF for angiogenesis
Describe 2 features to allow cancer cells to invade
- Gain motility
- Dysregulation of cell-cell adhesion
- Production of matrix metalloproteases to degrade ECM
Name three types of Skin cancer
- Malignant Melanoma
- Squamous cell carcinoma
- Basal cell carcinoma
Describe the mechanism in which UV light causes pathogenesis of skin cancer (2 marks
UVB and UVA both induce dimerization of pyrimidines
UVA also causes formation of free radicals which damage DNA and the cell membrane
What is epidermodysplasia verruciformis and what is the characteristic feature?
A rare autosomal recessive condition characterised by a genetic predisposition to HPV induced warts which can progress to squamous cell carcinoma
