Pathology and Cancer therapy Flashcards
6 Hallmarks of Cancer
Evading Apoptosis Limitless reproductive potential Growth signals not required for cell survival, growth + differentiation Insensitivity to anti-growth signals Increased + sustained angiogenesis Tissue invasion + metastasis Defects in DNA repair
H Ras gene
Makes protein H Ras
Makes cell either grow or divide
Belongs to class of oncogenes- of mutated, causes cell to become cancerous
Antiproliferative signals
Soluble growth inhibitors
Immobilised inhibitors in ECM + surface of nearby cells
Antiproliferative cells MOA
Force cells out of active proliferative cycle, into G0
Cells induced to permanently stop proliferation and are induced into post mitotic state
Oncogene
A Cancer inducing gene, can transform cells
Tumour suppressor gene
Gene whose partial/complete inactivation leads to increased likelihood of cancer developing
Occur either in germ line, or genome of somatic cell
Responsible for constraining cell proliferation
e.g. p53
Limitless reproductive potential
Maintain telomeres- aren’t shortened, so can proliferate endlessly
Evading apoptosis
Loss of p53 –> thrombospondin-1
Angiogenesis
The formation of new blood vessels, including the development of endothelial cells which line the inside wall of blood vessels
Malignant cells + angiogenesis
Give off signals to stimulate angiogenesis
Secretion by malignant cells to degrade ECM
Collagenases/Proteases
Loss of p53
Tumour suppressor gene
Can facilitate both angiogenesis+ resistance to apoptosis
Normal –> hyperplastic epithelium
loss of APC
hyperplastic epithelium –> early adenoma
DNA hypomethylation
early –> intermediate adenoma
K-ras activation
intermediate –> late adenoma
loss of 18q TSG 9tumour suppressor gene)
late adenoma –> carcinoma
loss of p53
Cancer
collection of diseases characterised by uncontrolled growth, caused by changes to DNA
Tumour
a mass of tissue formed by an uncontrolled growth of cells, independent of surrounding structures
Neoplasm
an abnormal mass of tissue, the growth of which exceeds and is uncoordinated with that of the normal tissues and persist in the same excessive manner after cessation of the stimuli which evoked the change
Benign neoplasm
neoplasm that grows locally without invading adjacent tissue
Mesenchymal neoplasms
Chondroma= cartilaginous tumour Fibroma= fibrous tumour Osteoma= bone tumour
Epithelial neoplasms
Adenoma= tumour in glandular tissue
Papilloma= tumour with finger-like projections
Papillary cystadenoma= papillary and cystic tumour in glandular tissue
Polyp- a tumour that projects above a mucosal surface
Chondroma
cartilaginous tumour
Fibroma
fibrous tumour
Osteoma
bone tumours
Adenoma
tumour in glandular tissue
Papilloma
tumour with finger-like projections
Papillary cystadenoma
papillary and cystic tumour in glandular tissue
Polyp
a tumour that projects above a mucosal surface
Mesenchymal + epithelial benign neoplasm nomenclature
-oma
Malignant neoplasm
neoplasm that invades nearby tissue and spawns metastases
Mesenchymal malignant neoplasm nomenclature
-sarcoma
Epithelial malignant neoplasm nomenclature
-carcinoma
Mesenchymal malignant tumours
Chondrosarcoma
Fibrosarcoma
Osteosarcoma
Chondrosarcoma
Cartilaginous tumour
Fibrosarcoma
Fibrous tumour
Osteosarcoma
bone tumour
Epithelial malignant tumours
Adenocarcinoma
Squamous cell carcinoma
Undifferentiated carcinoma
Adenocarcinoma
Tumour from gland-forming tissue
Squamous cell carcinoma
squamous differentiation
Undifferentiated carcinoma
Carcinomas can arise from ectoderm, mesoderm or endoderm
Metastasis
process by which cells differentiate into specialised tissues and/or organs
Histogenesis
process by which cells differentiate into specialised tissues and/or organs
Well differentiated neoplasm
resembles mature cells of tissue of origin
Poor differentiated neoplasm
composed of primitive cells with little differentiation
Most common teratoma
Benign cystic teratoma of the ovary
Hamartoma
disorganised mass of tissue whose cell types are indigenous to the site of lesion
Choriostoma
Ectopic focus of normal tissue (heterotopia)
Malignant tumour MOA
Malignant change in the target cell, referred to as transformation
Growth of transformed cells
Local invasion
Distant metastases
Anaplasia
Structural differentiation loss
Pleomorphism
Shape + Size
Abnormal nuclear morphology
Hyperchromasia
High nuclear cytoplasmic ratio
Chromatin clumping
Prominent nucleoli
Dysplasia
abnormal growth, some but not all hallmarks of malignancy present - may develop into malignancy
Local effects of neoplasm on host
Destruct vital structure
Obstruct or perforate a hollow organ
Cause haemorrhage, thrombosis or infection
Invade nearby or distant structures
Systemic effects of neoplasm on host
Weight loss Fever Anaemia Immunosuppression Paraneoplastic Syndrome
Paraneoplastic Syndrome
the set of symptoms caused by non-metastatic malignant disease
Cushing’s syndrome
Production of ACTH by tumour cells
Prevalent in small-cell lung cancer and pancreatic carcinoma
Lambert-Eaton Myasthenic Syndrome (LEMS)
Impaired release of acetylcholine causing muscle weakness, drooping of eyelids and double vision
Prevalent in lung cancer
60% of LEMS patients have lung cancer
Goals of cancer therapy
Cure
Control (stop new growth)
Palliation
Low radio-sensitivity cells
Nerve cells
Muscle cells
Intermediate radio-sensitivity cells
Osteoblast
Endothelial cell
Fibroblast
Spermatids
High radio-sensitivity
Spermatogonia Lymphocytes Stem cells Intestinal mucosa cells Erythroblast
Types of radiation therapy
External beam radiation (gamma photons, neutron beams)
Radioimmunoconjugates (antibody-targeted)
Radioconjugates (isotope tagged to bone-seeking material
Free isotopes (131I, Gallium)
First line chemotherapy
most effective drug first
Adjunctive chemotherapy
After the tumour has been controlled by surgery or radiotherapy
Neo-adjuvant chemotherapy
Before treatment with surgery or radiotherapy
Nitrogen mustard gas
chemotherapy
causes direct DNA damage by adding methyl onto guanine
most active in resting cells
Antimetabolites
chemotherapy
interfere with synthesis of purine/pyrimidine bases
mostly active against cells in S phase
Antifolates
type of antimetabolite
Topo i inhbitor
chemotherapy
induce single and double strand breaks
Topo ii inhibitor
insert planar ring between adjacent bases, concentrating drug in nucleus until S phase
Drugs interfering with microtubule assembly
Vinca alkaloids
Taxols
Monoclonal antibodies
-mab
target specific antigen
specificity is relative
Small molecules (tyrosine kinase inhibitors)
-nib
target oncogene production
inhibit signalling at key steps
Adjuncts
glucocorticoids
biphosphonates
oestrogens/anti-androgens/SERMS
Chemotherapy imperfections
Lack of selectivity
Toxicity to host- dose levels are well below what is needed to kill effectively
IV- hospitalisation
Selective Oestrogen receptor modulators (SERMs)
Tamoxifen (Nolvadex)
Toremifene (Fareston)
Oestrogen receptor inhibitor and destroyer
Fulvestrant (Faslodex)
Oestrogen synthesis inhibitors- aromatase inhibitors (Als)
Anastrozole (Arimidex)
Letrozole (Femara)
Exemestane (Aromasin)
Tyrosine Kinase inhibitors
-nib Imatinib Dasatinib Lapatinib Gefitinib
Monoclonal antibodies MOA
Efficient carriers for delivery of anti-tumour agents
Antigen cross-linking- target GFR (antagonise ligand-receptor signalling)
Activation of death receptors
Monoclonal antibodies as carriers
Accumulate in solid tumours- no lymph drainage so not taken away
Tumour blood vessels leaky so can pass through, compared to normal where can’t
Growth factors
EGFR (epidermal) IGF-1R (insulin-like growth factor-1 receptor) FGFR (fibroblast) PDFGR (platelet-derived) VEGFR (vascular endothelial)
Monoclonal antibodies activation of death receptors
Cross-link surface antigens on tumour cells + antibody agonists
Activate specific receptors
Intracellular calcium ion increase
Activate caspase 3 + 9 (involved in cell apoptosis)
Monoclonal antibodies
-mab
Alemtuzumab
Cetuximab
Rituximab
CD20
Glycosylated phosphoprotein
Expressed on surface of all B cells beginning at pro-B phase
Type 1 CD20 antibody
Prominent Fc-FcR interaction
Rituximab
Type 2 CD20 antibody
Strong induction of direct cell death
Tositumomab, Obinutuzumbab
Growth factor oncogene
EGF
HER2
Growth factor receptor oncogene
EGF
VEGF
Signal-transduction proteins oncogene
K-ras
B-raf
Transcription factors oncogene
c-myc
Anti-apoptotic proteins oncogene
Bcl-2
EGFR overexpression
Colorectal cancer (27-77%)
Pancreatic (30-50%)
Lung (40-80%)
Non-small cell lung (14-91%)
Ras mutation
Pancreatic 90%
Papillary thyroid 60%
Colon 50%
non-small cell lung 30%
B-Raf mutation
Melanoma 70%
Papillary thyroid 50%
Colon 10%
Point mutation within a control element in tumour suppressor gene
Bax (pro-apoptotic)
Point mutation within the tumour suppressor gene
p53 (prevents cells leaving G1)
