Module 15 - Cancer Flashcards
Explain how genetic changes can lead to aberrant cell behaviour.
Genetic changes allows the accumulation of mutations that allow cells to divide uncontrollably and metastasized. This is called abberant cell behaviour, which is detrimental to neighbouring cells and the whole organism.
How is cancer classified based on cell origin?
- Carcinoma: cancers of epithelial cells
- Sarcoma: cancers of connective tissue
- Melanoma: cancer of melanocytes
- Leukaemia: Cancer of WBC
- Lymphomas: Cancer of the lymphatic system
- Retinoblawstoma, Glioblastoma, Medullablastoma, Neuroblastoma: cancer of the cells of the nervous system (neuron & glia)
Explain the link between old age, mutagens, and cancer progression.
Cancer incidence increases with age. Exposure to mutagens also increases cancer incidence.
Differentiate between benign and malignant tumors.
Tumors are abnormal growth of tissues. There are two type of tumors:
-
Benign Tumour
- grow slowly
- do not spread
- can progress to malignant
-
Malignant tumour
- can proliferate endlessly
- can invade healthy tissues and spread (metastasise)
- ca draw in blood vessels to get more nutrients and oxygen
- can interfere with body functions
How is tumorigenesis a balance between cell birth and death?
Define proto-oncogenes, oncogenes, and tumor suppressor genes.
Oncogene is a gene that when mutates or expressed at high levrld helps turn a normal cell into a cancer cell.
Proto-oncogene is the normal form of the gene.
TSG is a gene that acts to prevent a cell from turning into a cancer cell (also known as anti-oncogenes)
Explain the genetic mechanism of oncogene activation.
- Deletion or point mutation in coding sequence: hyperactive protein
- Regulatory mutation: overproduced protein
- Gene amplification: overproduced protein
- Chromosomal rearrangement
- nearby regulatory DNA sequence cause overproduced protein
- fusion lead to hyperactive protein
Explain the concept of Knudson’s two-hit model.
Inactivation of both copies of TSG is required to lead to lodd of function, hence promoting cell transformation. The first “hit” on the TSG can be germinal or somatic in nature. And a second “hit” is called a loss of heterozygosity and is somatic in nature.
Describe Burkitt’s Lymphoma.
Burkitt’s lymphoma:
- Translocation between chromosome 8 and 14
- Enhancer in chr 14 is translocated next to the c-myc proto-oncogene in chr 8, increasing its expression
- Myc is a transcription factor, which promotes cell growth and proliferation
- Excessive Myc levels lead to hyperproliferation of lymphocytes
Mention examples of TSGs and the normal role of the gene product.
Retinoblastoma (Rb): inhibits the cell cycle (preventing S-phase)
- E2F promotes cell-cycle progression by activating transcription of S-phase genes.
- It is normally held in an inactive complex by Rb.
- G1-Cdk phosphorylation of Rb inactivates it, liberating E2F and triggering S-phase
p-53:
- DNA binding transcription factor
- p-53 acts as a sensor for cell stress (DNA damage, telomnere shortening, etc) and respond by cell cycle arrest, senescence, apoptosis, and DNA repair.
Explain why inheriting one faulty copy of a TSG predisposes one to cancer.
By inheriting one faulty copy of a TSG, you only need to inactivate the other functional copy to lead to the functional loss of TSG. Compared this to having both healthy copies of TSG, to develop cancer both copies in the same cell must somehow be inactivated by mutation alone, which is rare.
Mention the hallmarks of cancer.
- sustaining proliferative signaling
- evading growth suppresors
- activating invation and metastasis
- enabling replicative immortality
- inducing angiogenesis
- resisting cell death
Describe Chronic Myloid Leukaemia.
Chronic myeloid leukaemia (CML)
- a cancer where cone marrow produces too much granulocytes
- reduced no. of healthy WBC, RBC, and platelets
- increased infection, anaemia
- translocation of Bcr gene in chr 22 to c-abl proto-oncogene in Chr 9
- leading to Bcr-Abl fusion gene (increased kinase activity)
- dimerization of the Bcr-Abl fusion protein (through the Bcr coiled-coil domain) causes the auto-activation of the Abl tyrosine kinase domain
Explain the main mechanism of melanoma proliferation.
45% of melanoma are casued by a point mutation (V6000E) which makes the BRAF protein constitutively active and activate the MAPK pathway without regulation, which lead to cell proliferation.
What is the Li-Fraumeni syndrome (LFS)?
It is a cancer predisposition syndrom where the molecular basis is a loos of function germline mutation in the p53 gene.
How does p53 protein levels regulated in response to DNA damages and proliferation of Myc? How does it repair them?
Binding of Mdm2 to p53 leads to ubiquitylation and degradation of p53; hence regulating its levels.
However, DNA damage may lead to the phosphorylation of p53 which prevents Mdm2 from binding, increasing p53 levels.
Another example is that excessive Myc (oncogene product) production lead to increased levels of Arf, which binds to Mdm2 (reducing its interaction with p53).
p53 acts through target genes such as Cdkn1a, which expresses the protein p21, which inhibits S-phase of cell cycle.
Describe epithelial cells.
Epithelial cells are stationary cells that are polarised and form cell-cell junctions to form a 2D sheet.
Explain how Twist and E-cadherin relate to the progression metastasis.
Twist drives Epithelial Mesenchymal Transitions (EMT) which causes stationary epithelial cells to become migratory, mesenchymal cells. It does this by inhibiting the epression of epithelial genes like E-cadherin and ß-catenin, which are expressed at the junctions of the cells. On the other hand, mesenchymal genes such as Vimentin is the one being expressed.
Loss of E-cadherin is a common feature of cancer cells as the cells are no longer bound to each other allowing it to metastasise. E-cadherin is repressed by Snail which is activated by Twist.
What is the APC (Adenomatous Polyposis Coli)?
It is a TSG. APC is also part of a complex that targets ß-catenin for destruction. LOH of APC leads to the overactivation of the Ent pathway (because ß-catenin is an activator) and causes tumor growths (called polyps).
What is K-Ras?
K-Ras is a small GTPase which is part of the MAP kinase pathway. Activation of this pathway leads to the increased expression of Myc.
How does Gleevec inhibit Bcr-Abl activity?
rBcr-Abl fusion protein is responsible for CML as it is constituively active through phosphorylation by ATP, promoting cell proliferation. Gleevec blocks this activation by occupying the ATP binding pocket of the kinase domain, preventing phosphorylation.
