Week 3 Flashcards
What is oncogenes and causes of it?
-mutated gene, has the potential to cause cancer
Cause of oncogene:
- Virus
- Chemicals
- Radiation
Explain what the Rous Sarcoma Virus is
It is a retrovirus ( any of a group of RNA viruses which insert a DNA copy of their genome into the host cell in order to replicate)
Gene v-src
- Involved in regulation of cell growth and differentiation
- Not needed for viral replication, but transforms cell leading to cancer
Something in the DNA inserted by the Rous sarcoma virus made the host cells cancerous, but what was it?
- virus picked up a passenger gene called V-src
- V-src was unmistakably similar, but not identical to a gene- C-src- that was discovered in the normal vertebrate genome. C-src had evidently been caught up accidentally by the retrovirus from the genome of a previously infected hostcell, and it had undergone mutation in the process to become an oncogene (V-src)
V-src oncogene
Virus v-src (oncogene, mutated)
- V-src is dominant= only need one copy
- Gain of function
V-src constitutively active tyrosine kinase
- Signalling molecule
- Cannot be regulated
○ Activates kinase signalling cascades
○ Decreased adhesion of cell to surface
○ Growth to high density
○ Loss of contact inhibition
○ Increased transport of metabolites
- Triggers uncontrolled growth
- Original proto-oncogene from vertebrates, cellular src (c-src)
○ C-src expression activated in human tumours
Explain Avian Leukosis virus
Cancer caused by a different mechanism from Rous
- Oncogene
Inserts viral DNA into host genome next to a proto-oncogene
- C-myc (DNA- binding protein) > transcription factor
Viral DNA
- Long tandem repeat sequences
○ Act as strong promoters or enhancers
○ Induces increased expression of c-myc
Receptors
What receptor and function?
Receptor Tyrosine kinases (RTKs)
- Receptors for growth factors
○ Transmembrane protein, intra- and extra-cellular domains
○ Signal transduction pathway
○ May be defective in cancers
§ Mutations can result in continually active receptors
§ i.e. Receptor activity in absence of ligand
Defective receptor tyrosine kinases:
- Erb-B family
○ Her2 (aka ErbB2= 25% of breast tumors)
Function
- Tyrosine kinase domains
- Binding of ligand > phosphorylation of tyrosine
○ Phosphorylate other intracellular signalling proteins
What is Erb-B
- Family of receptor tyrosine kinases related to epidermal growth factor receptor
○ Name derived from viral oncogene: erthyroblastic leukemia viral oncogene - When extracellular domain is missing
○ Receptor is always switch on….
= Uncontrolled growth
What is P53 (tumour suppressor)
- Regulates cell cycle
- Activates other transcription factors
- DNA binding site
- Recognises DNA damage
- “Guardian of the genome”
- can trigger growth arrest, DNA repair, or apoptosis
APC protein ( Adenomatous polyposis coli)
- Tumour supressor protein
- Inhibits myc gene expression
- Myc protein (transcription factor)
Induces expression of many genes required for cell to progress from G1 to S phase - Degradation of beta-catenin
- Beta catenin has 2 roles
- Cell-cell adhesion
- Drives transcription of target genes involved in cell proliferation
- Mutations that activate beta-catenin found in many cancers (oncogene)
APC mutations also cause cancer
- No control of myc or beta-catenin
Colorectal cancer
- Slow developing (over 10-35 years)
- Pre- cancerous growths
- Polyps - form on the inside of colon wall
- Cells in polyp contain mutations in APC gene
- If cells in polyp undergo mutation in Ras
- More uncontrolled cell division
- Another mutation occurs in p53
Malignant carcinoma
three mutations required
Colorectal cancer
- Inherit mutation in one APC gene (Familial adenomatous polyposis)
- Only one more mutation= formation of polyps
- Hereditary disposition to colonic cancer
- 10% cancer patients
- Develop cancer at an early age
- Other patients acquire 2 mutations during their life
Skin
Two types of skin cancer
- Melanoma of the skin
- Starts in melanocytes
- Non-melanoma skin cancer
- Basal cell carcinoma (BCC) and squamous cell carcinoma
Non-melanoma skin cancer (NMSC)
Basal cell carcinoma
- Most often found on head, neck and arms
- Due to exposure to UV radiation
- Leads to formation of thymine dimers, a form of DNA damage
- Basal cells invade the dermis
- Slow growing, usually do not spread
Non-melanoma skin cancer (NMSC)
Squamous cell carcinoma
- Scaly red patches, open sores, warts or elevated growths with a central depression; they may crust or bleed
- Mostly found on head, neck and arms
- Fast growing can spread
Diagnosis
Asymmetry, irregular
Boards (uneven)
Colour ( variegated)
Diameter (greater than 6mm)
Evolving (changing, growing over time)
Characteristics of cancer cells
- Grow continuously
- Lack of control, increased rate
- De-differentiated
- Loss of specialised function
- Lack contact inhibition
-
Altered cell surface characteristics
- Less adhesive
- Invade other tissues
-
Metastasis
- Break through basal lamina and enter circulation
- Secrete a protease > digests basal lamina
Metastasis
- Development of secondary malignant growths at a distance from a primary site of cancer (via blood supply)
- Reduced cell to cell adhesion and cell-matrix adhesion molecules
- Mechanism of metastasis
- If cell-cell or cell-matrix contacts are disrupted
- Tumour cells degrade extracellular matrix and then get between endothelial cells and into capillary
- Cancer cells secrete proteases to digest matrix and establish themselves at new site
- Selectins on endothelial cells recognise carbohydrate groups on cancer cells and allow cancer cells to adhere to endothelial cell at new site in body
Stages of metastasis
E-cadherin
- Cell linker molcules
- Links cells together at side
- Also connects to cytoskeleton
- Also connects to cytoskeleton within cell
- Beta catenin links E-cadherin to cytoskeleton
What happens to E-cadherin in cancer cells
In many cancers
- E-cadherin expression is reduced, OR
- E-cadherin is located in the cytoplasm, not the membrane
Intergins
- Allow cell to attach to extracellular matrix
- Linker molecules
- form heterodimers
- enable cells to link to extracellular matrix at basal surface (keep cells in position)
- Recognise different extracellular matrix components such as collegen, laminin, fibronectin, vitronectin
- Also bind to cytoskeleton
Integrins and their role in cancer
What happens to cells with lost e-cadherin or integrins?
- Loss of E-cadherin or integrins can lead to cultured cells becoming more motile
What are the two main types of proteases?
Two main types
- Serine proteases; eg.plasminogen
- Metalloproteinases (require zinc and calcium) e.g. Collagenase and stromelysin
- Also secrete protease inhibitors
There is a balance to regulate the composition of the extracellular matrix
How are proteases secreted and example?
Both types of proteases are secreted in an inactive form as proenzymes
Serine protease precursor plasminogen > active protease plasmin by plasminogen activators
How metalloproteinases classified?
Metalloproteinases are classified by substrate specificity
What happens to proteases in cancer?
What is angiogenesis?
The development of new blood vessels
Whats the connection between tumours and angiogenesis?
What are the benign forms of cancer?
- Fibrodenoma
- lobular or ductal hyperplasia (can develop into carcinoma in situ)
What are the malignant?
- Invasive lobular carcinoma (ILC)
- Invasive ductal carcinoma (IDC)
What are the 5 main molecular subtypes of breast cancer?
What are some cancer treatments?
Traditional
- surgery
- chemotherpay
- radiation therapy
Systemic
- angiogenesis inhibitors
- immunotherapy
Targeted
- horomone therapy
- monoclonal antibody
Chemotherapy
- non-specific intracellular poisons
- Systemic therapy
- cytotoxic by means of interfering with cell division (mitosis)
Effects: damage to normal cells that divide rapidly
- Bone marrow, digestive tract and hair follicles
Radiation Therapy and cons with using it
Used in conjunction with chemotherapy
- Ionizing radiation (leads to the formation of free radicals)
Damage DNA
-Has both indirect and direct action
What are the characteristics of a tumour microenvironment?
- Decreased blood supply
- Deficient in oxygen
- Decreased effectiveness of radiation therapy
What is avastin and what does it do?
Cancer drug treatment
- Approved for certtain tumours- glioblastoma, colorectal
- inhibits growth of blood vessels
- Adverse events - bleeding, pulmonary embolism
- Adaptive resistance
Name the hormonal and antibody drug selection for breast cancers
What are benign tumours?
- Remain localised and do not spread
- Usually do not cause problems unless they grow in a confined space i.e. the brain
What is malignant tumours?
- Often have irregular structures, large variable nucleus, little cytoplasm
- Invade surrounding tissues
What are the two hormones involved in human breast?
- Estrogen
- Progesterone
Name two beign breast cancers
- Fibrodenoma
- Lobular or ductal hyperplasia (can develop into carcinoma in situ)
Name malignant breast cancers
- invasive lobular carcinoma (ILC)
- Invasive ductal carcinoma (IDC)
