Cancer Mechanism Of Resistance and Development of Metastases Flashcards
How does cancer normally spread?
- Local invasion- infiltrate, invade and destroy surrounding tissue
- Example: colorectal cancer perforates colon wall, ovarian cancer grows into fallopian tubes (not metastatic cancer)
What is metastasis
When the primary cancer spreads to other cells in the body
Secondary involvement = metastases
Example: teratoma removed from the brain that normally originates from sex organs so it resembles primary malignancy
What are the steps to developing invasive cancer cells?
- Normal
Acquired DNA damage- chemicals, radiation, viruses
2. DNA damaged cell Mutations in DNA repair Genes affecting cell growth Genes regulating apoptosis Inactivation of tumour suppression gene
- Altered neoplastic cell
Expression of gene product
Loss of regulatory genes
4. Clonal expansion Self sufficiency Insensitive to growth signals Evasion of apoptosis Endless replication Neoangiogenesis EMT program activation Stomal microenvironment cross talk and release of inflammatory factors Invasive and metastatic phenotype
What are the routes for metastatic spread?
- Lymphatic spread to lymph nodes elsewhere- Lymphadenopathy
- Haematogenous spread via blood
veins are more easily invaded than arteries
portal system invasion- lung metastases
inferior vena cava (IVC)- lung metastases
crossing blood brain barrier- brain metastases - Through body walls into abdominal or chest cavities
Describe the soil and seed hypothesis?
- The tumour forms at the primary site known as the seed
2. It enters the blood stream through ‘intravasation’ and into brain parenchyma known as soil via ‘dissemination’
What is Transcoelomic spread?
Moving across the peritoneal cavity where surfaces/organs of the abdominal and pelvic cavities are covered by peritoneum
Associated with inflammatory response and fluid build up due to presence of cancer cells in cavity- ascites
Example:
Ovarian cancer goes across peritoneum leading to ascites
Lung cancer across pleural cavity leads to pleural effusion
Give examples of typical cancer spreading
Breast cancer: spreads to liver, lung, brain, bone
Lung cancer: spreads to liver, brain and adrenal gland
Melanoma: spreads to lung, liver, brain, bone, skin
How do we diagnoses metastases
Using CT scan, tumour markers, biopsy, cytology
black and white spots on imaging
What are the common complications from bone metastases and what cancers does it normally originate from
Hypercalcaemia- bisphosphonates used to reduce this
Very painful and can lead to fractures
Can cause spinal cord compression
Originates from: Radiotherapy manages symptoms
Renal
Breast
Prostate Ca
How do you treat spinal cord compression
Dexamethasone 8mg BD with PPI cover
Radiotherapy to bone
Rare to use chemo (takes too long)
Pain relief
Laxatives- common side effect is constipation as nerves to bowel/bladder often affected
How do you treat brain metastases
Dexamethasone 2-8mg OD with PPI cover
Seizure causes means anti-epileptic use
can trigger CTZ
Anti-emetics often needed
May require anxiolytics
Headaches and dizziness often occur
How do you treat lung metastases
Dexamethasone 2-8mg OD with PPI cover to limit inflammation
Salbutamol to open airways
Linked to haemoptysis- coughing up blood
May need tranexamic acid to reduce bleeding
Can cause superior vena cava obstruction (SVCO)
How do you treat superior vena cava obstruction
Dexamethasone 8mg with PPI cover
Chemotherapy especially if SCLC is very chemorpsponsive
Radiotherapy if not chemo sensitive
Stent
Pain relief
Anti-coagulants if clot expected
How do you treat liver metastases and what can it lead to
Dexamethasone 2-4mg OD useful for pain
Can lead to liver capsular pain
Jaundice + pruritus
May help with creams but anti-histamines may cause drowsiness so beware
Ascites- drainage
What is primary chemotherapy resistance
Decreased drug activity- present prior to drug exposure, tumour insensitive to initial treatment
What is acquired chemotherapy resistance
Resistance develops during or after treatment
How do you develop acquired resistance
One hallmark is increased genetic instability and mutation rates
Dividing cancer cells acquire mutations at a higher rate
Sensitive cells are killed by chemo but the resistant cells survive and continue multiply
Tumour becomes populated with resistant cells
How do you combat acquired resistance
Using a combination of chemotherapy drugs with differing mechanisms of action
What are the three mechanisms of resistance
Impaired delivery of anticancer drugs- reduced uptake and increased efflux
Changes to receptor- no longer can bind
Changes to metabolic pathway within the cell
Give examples of genetic changes that induce resistance
Oncogene- genes that gain function when mutated
Tumour supressor gene- gene loses function when mutated
EGFR- oncogene- promotes angiogenesis
p53 tumour supressor gene- supresses apoptosis to promote cancerous growth
Give examples of multi-drug resistance
Simultaneous resistance to many structurally and functionally unrelated drugs
ATP resistance efflux pumps with broad specificity
Increased efflux leads to reduced intracellular concentration
MDR1 gene- code for p-glycoprotein
PGP (P-glycoprotein) implicated in MDR (multidrug résistance) leading to increased drug efflux
Defective apoptotic pathways
Reduced drug uptake
How do you design a regime to target cancer
Want drugs with different mechanisms of action like FEC
What does FEC stand for and what does each of them do
Fluorouracil- inhibition of thymidylate synthase, preventing DNA synthesis
Epirubicin- forms a complex with DNA by intercalating between base pairs
Cyclophosphamide- forms DNA and RNA cross-links (not cell cycle specific)
Describe how doxorubicin works
Works on S phase in DNA cycle
Substrate for p-glycoprotein to cause DNA damage and apoptosis
Resistance occurs due to over expression of MDR1
Resistant cells increase rate of DNA repair
Modulates drug uptake
