2.9 - 2.10 Cancer Flashcards
What is the difference between normal cells to cancer cells?
What sort of changes is cancer caused by?
- Cancer is caused by genetic changes that affect gene expression or function.
- These can be caused by:
- Mutations (due to DNA damage)
- chromosomal abnormalities such as translocations
- Introduction of genes by viruses
What is cancer defined as?
A disease featuring abnormal and improperly controlled cell division resulting in invasive growths, or tumours, that may spread throughout the body
What is carcinoma?
Cancers of epithelial cells
Account for about 80% of human cancers (lung, breast, bowel, prostate, etc)
What is sarcoma?
Cancers of connective tissue
Bone, cartilage, fat, muscle vascular tissues
What is melanoma?
Cancers of melanocytes (pigment producing cells in the skin)
What are leukaemias?
Cancer of white blood cells
What are lymphomas?
Cancers of the lymphatic system
What are cancers of the cells of the nervous system (neurons and glia) known as?
Retinoblastoma, glioblastoma, medulloblastoma, neuroblastoma
What is the relationship between age and cancer?
Age increases cancer incidence
What is the relationship between mutagens and cancer incidence?
Exposure to mutagens increases cancer incidence
What is a tumor?
Abnormal growth of tissue
What is tumorigenesis?
Formation of tumors
What are benign tumors?
- Moles for example
- They generally stop growing or grow slowly
- Do not spread to other parts of the body
- Can still cause problems (e.g brain tumor) and progress to malignancy
What are malignant tumours?
- They can proliferate endlessly
- Can invade healthy tissues and spread to other parts of the body to create secondary tumors (metastasise)
- They can draw in blood vessels (angiogenesis) to get nutrients and oxygen for more growth
- Can interfere with body functions
What are the five hallmarks of cancer?
Which of the hallmarks of cancer are responsible for tumorigenesis?
Which of the hallmarks of cancer are responsible for metastasis?
How does cancer progression occur by accumulated mutations?
- The transition from a normal cell to cancerous involves successive mutations
- First mutation could give a slight proliferative advantage to the cell
- Second mutation greatly increase proliferation and start to affect the tissue structure
- Third mutation allow cells to break into their surrounding environment and metastasise
What are the two pathways to tumorigenesis?
In a normal tissue, the birth and apoptosis (i.e. death) of cells is balanced. If this balance is disturbed by INCREASED cell birth, or DECREASED apoptosis then tumors can form.
What is an oncogene?
A gene that, when mutation or expressed at high levels, helps turn a normal cell into a CANCER cell (this process is called transformation)
What is a proto-oncogene?
The normal form of the gene
What is a tumor supressor gene (TSG)?
A gene that acts to prevent a normal cell from turning into a cancer cell (also known as anti-oncogenes)
Typically what sort of proteins do proto-oncogenes?
Typically what is the normal role of proto-oncogenes?
Typically what is the type of proteins that tumor suppressor genes produce?
Typically what are the normal roles of tumor suppressor genes?
How many copies of proto-oncogenes do you need to be mutated in order to have an effect on the cell?
How many copies of the Tumor suppressor gene do you need to lose function for to have an effect on the cell?
What is Burkitt’s lymphoma?
An agressive cancer of the lymphatic system involving over-proliferation of B lymphocytes
What is Burkitt’s lymphoma caused by?
90% of cases involve a reciprocal translocation between chromosome 8 and 14
What causes cell proliferation in Burkitt’s lymphoma?
- Myc is a transcription factor, which promotes cell growth and proliferation by controlling expression of target genes in response to many signalling pathwyas
- Excessive Myc levels leads to hyper-proliferation of the lymphocytes
What are the symptoms of chronic myeloid leukaemia (CML)?
- Overproduction of granulocytes (leukemia cells)
- Reduced numbers of healthy white blood cells, red blood cells and platelets
- Leads to increased infection, anemia and easy bleeding
What is chronic myeloid leukaemia (CML) caused by?
- Most cases of CML involve a reciprocal translocation between chromosomes 9 and 22
- This results in the Philadelphia chromosome and a fusion between the c-abl (c-abelson) gene which encodes a kinase and the Bcr (Breakpoint cluster region) genes
- The Bcr-Abl fusion protein has increased kinase activity
What does the Bcr-Abl oncogene then do in causing CML?
- The BCR-ABL fusion protein oligomerizes through the BCR coiled-coiled domain
- Undergoes auto-activation of the ABL tyrosine kinase domain
- Results in constitutively active kinase, mis-regulation of the cellular signaling pathway that it mediates
How can a point mutation cause activation of a proto-oncogene?
- MAP is a transcription factor that turns on a lot of genes
- Valine position 600 gets mutated to glutamic acid and makes BRAF active
Name the genotypes for these cells
What are the two means of inactivating Tumor Suppressor Genes?
What are two key tumour suppressors?
What is retinoblastoma?
How does the Rb protein inhibit the cell cycle?
- E2F promotes cell-cycle progression by activating transcription of S-phase genes
- It is normally held in an inactive complex by Rb
- G1-Cdk phophorylation of Rb inactivates it, liberating E2F and triggering S-phase
- Without Rb then E2F is constantly activating S stage with tumours forming
How many faulty copies of Rb are needed to predispose one to cancer?
- Children that inherit a faulty copy of Rb are predisposed to retinoblastoma (and other cancers) and usually develop multiple tumors affecting both eyes
- Non-hereditary retinoblastoma is extremely rare because it requires two successive hits to the Rb gene and typically only produces a tumor in one eye
What is p53?
- Important tumour suppressor gene in human cancers. It is a DNA binding transcription factor
- Homozygous loss of p53 is found in many cancers
What does p53 sense?
- Cellular stress sensor
- Cells are subject to various stresses such as hyperproliferation (due to excess Myc), DNA damage, telomere shortening, or lack of oxygen. These increase levels of p53
- p53 then responds by stopping the cells from dividing, causing them to apoptose and make them repair damaged DNA
What is Li-Fraumeni syndrome?
- A cancer predisposition syndrome where the molecular basis is a loss of function germline mutation in the p53 gene
- Inheriting one faulty copy of p53 means you only need to lose the other copy to have no p53 function
- This greatly increases the risk of cancer and lowers median age at diagnosis
What happens to p53 in response to different cellular conditions?
- p53 is post translationally modified by other proteins in response to different cellular conditions. These can affect
- Stability of p53
- binding of other proteins to p53
- p53’s function as a transcriptional factor
What does Mdm2 do to p53?
- Mdm2 is a ubiquitin ligase which reduces levels of p53 to a low level
- Proteasome is a protein shredder regulated by ubiquitin proteins
- Mdm2 adds ubiquitin to p53 for degredation by the proteasome
How does DNA damage affect p53 activity?
How does excess Mcy affect p53 activity?
p53 is a transcriptional activator, it controls these things by turning on other genes
What is the structure of epithelial cells?
Epithelial cells are stationary cells that are polarised (along the apical-basal axis) and form cell-cell junctions with their neighbours to form a 2-dimensional sheet, or epithelium.
What is epithelial mesenchymal transition?
- At times epithelial cells lose their epithelial characteristics and become migratory, mesenchymal cells. This process is called an Epithelial Mesenchymal Transition, or EMT.
- EMTs are important during embryonic development, wound healing, and metastasis.
What is the role of Twist in metastasis?
- Twist was strongly expressed in metastatic lines but not 67NR
- Reducing twist levels in 4T1 cells prevented them from metastasing. This poved that the increased levels of Twist were the underlying cause
What is the journey of epithelial cells during metastasis via EMT?
- In early metastasis stages, epithelial tumor cells undergo EMT where they break free of epithelial state and invade surrounding tissue
- They enter the vasculature
- Twist is upregulated in many cancers and predicts poorer survival
What does Snail do to E-Cadherin?
What is E-cadherin?
- It is a cell to cell adhesion molecule
- It is the main component in adherens junctions
Which genes are expressed when cells udergo an EMT?
- Stop expressing epithelial genes like E-Cadherin and Beta-catenin
- Start expressing mesenchymal genes needed for migration like the intermediate filament protein, Vimentin
How does E-Cadherin levels relate to cancer?
- Loss of E-Cadherin is a common feature of cancer cells.
- Cadherin holds the cells together and once you lose it the cells start to migrate and move
- E-cadherin is a TSG
How is APC acting as a tumor suppressor gene?
- Inheritance of one faulty copy of Adenomatous Polyposis Coli (APC) gene predisposes one to colorectal cancer.
- APC is part of the complex that targets Beta-Catenin for destruction. B Catenin is a transcription factor
- Loss of Heterozygosity overactivates the Wnt pathways and causes tumor growths called polyps or adenomas
What does Ras do?
- Ras activates the MAP kinase pathway
- K-Ras is a small GTPase which is path of the MAP kinase pathway.
- Activation of this leads to increased expressions of Myc
What is a hypothetical path to colorectal cancer?
How does cancer show heterogenity and also evolve over time?
- Cancer cells can acquire new mutations, which are passes on to their progeny. Thus a tumor becomes genetically heterogeneous.
- Cancers evolve over time so that the cells with the most advantageous mutations become more prevalent
What does the Gleevec drug do in Chronic Myeloid Leukaemia which is caused by Bcr-Abl fusion protein?
How does Gleevec drug cause resistance in cancer cells?
Since the cell with the mutated Bcr-Abl gene is not affected by the drug, it will come to dominate the tumor. The tumor will now be resistant to the drug and could cause a relapse of the cancer.
