LEC 43 Molecular Basis of Cancer Flashcards
Explain the basic properties of cancer cells and how they differ from normal cells List the major types of cancer and tissue of origins Discuss, with specific examples, the mechanism of action of the major conventional anticancer drugs and the molecular targets of new drugs
What are the 3 characteristics of cancer cells?
- Unregulated proliferation
- Invasion of surrounding normal tissue
- Spread, or metastasis, to more distant parts of the body
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What is a tumor?
any abnormal proliferation of cells, which may be benign or malignant
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What is a benign tumor?
remains confined to its original location
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What is a malignant tumor?
capable of both invading surrounding normal tissue and spreading throughout the body via circulatory or lymphatic systems
Only malignant tumors are properly referred to as cancers.
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What are carcinomas?
cancers that derive from epithelial cells
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What are sarcomas?
cancers that derive from connective tissue/muscle cells
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What is a leukemia/lymphoma?
cancer derived from blood-forming cells/cells of the immune system
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What is a glioma/retinoblastoma?
cancers derived from CNS/eye
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What is a basal-cell carcinoma?
- derived from a skin keratinocyte
- continues to synthesize cytokeratin filaments
- only locally invasive
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What is a melanoma?
- derived from skin melanocytes
- continues to make pigment granules
- often highly malignant
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What is tumor clonality?
- one of the fundamental features of cancer
- the development of a tumor from a single cell that begins to proliferate abnormally
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How does tumor development occur?
- initiates when a single mutated cell begins to proliferate abnormally
- additional mutations followed by selection for more rapidly growing cells w/i the population
- results in the progression of the tumor to increasingly rapid growth and malignancy
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What evidence is there that supports the multi-step nature of cancer progression?
- Most cancers develop later in life
- Almost always a long delay b/w cause and onset for cancers w/ a discernable cause (smoking/lung cancer; atomic bomb/leukemia)
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What are carcinogens?
agents that cause cancer
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What are some examples of causes of cancer?
broad terms
- Chemical carcinogens - damage DNA & introduce mutations
- Radiation - ionizing radiation that causes breaks in DNA or cross-linking DNA strands & introduces mutations
- Viruses/Bacteria - cause cancer by introducing foreign DNA into
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What major viruses are associated with causation of cancer in humans?
- Epstein-Barr virus (Mono) - lymphoma, nasopharyngeal cancer
- Hep B and C viruses - hepatocellular carcinoma
- HPV - cervical cancer
- Human T-cell Leukemia/Lymphoma virus type 1 - adult T-cell leukemia
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What is:
Autocrine Growth Stimulation
cancer cells produce growth factors to which they also respond, resulting in continuous self-stimulation of cell proliferation
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What is:
Reduced Adhesion
reduced adhesion to other cells and to extracellular matrix components
Promotes invasion and metastasis
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What is:
Invasion
malignant cells generally secrete proteases to digest extracellular matrix components, allowing invasion into adjacent tissue
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What is:
Angiogenesis
cancer cells secrete factors that promote the formation of new blood vessels
Supports growth of tumors & metastasis by access to circulatory system
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Describe how failure to differentiate leads to continued proliferation in some leukemias.
- different types of blood cells come from hematopoeitic stem cells
- their differentiation is blocked (no mature blood cells types formed)
- non mature leukemic cells continue to proliferate
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What are the two main mutational routes towards the uncontrolled cell proliferation characteristic of cancer?
- Make a stimulatory gene hyperactive. This type of mutation has a dominant effect – only one of the cell’s two gene copies needs to be altered. The altered gene is an oncogene, and its normal counterpart a proto-oncogene
- Make an inhibitory gene inactive and this type of mutation is usually recessive, both copies must be affected, and these genes are termed tumor suppressor genes
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How do transforming retroviruses acquire oncogenes?
Cellular proto-oncogene inadvertently captured by virus after excision from host DNA - e.g. capture of src by avian leukosis virus (ALV)
What are proto-oncogenes?
normal genes that encode proteins that function in signal transduction pathways that control normal proliferation
Oncogenes are abnormally expressed/mutated forms of proto-oncogenes
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How does a proto-oncogene become oncogenic
- Insertional Mutagenesis
- Chromosomal Translocation
- Gene Amplification
- Point Mutation
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What is insertional mutagenesis?
Some proto-oncogenes are activated by events that change their expression, but leave their coding sequence unaltered
ex: integration of proviral DNA adjacent to a cellular proto-oncogene
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How can c-myc become oncogenic?
If a virus inserts proviral DNA upstream of the proto-oncogenic c-myc, it turns it oncogenic
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In Burkitt’s lymphoma, how does a chromosomal translocation lead to cancer?
Translocation places c-myc gene under influence of enhancers from immunoglobulin heavy chain genes, leading to inappropriate c-myc expression
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Why is c-MYC overexpression tumorigenic?
- correlation between the tumorigenic phenotype and the activation of c-MYC by either insertion or translocation suggests that continued high expression of c-MYC protein is oncogenic
- Expression of c-MYC must be switched off to enable immature lymphocytes to differentiate into mature B or T cells; failure to turn off c-MYC maintains the cells in the undifferentiated (dividing) state
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Explain how a point mutation can lead to cancer.
using c-ras as an example
Mutation results in loss of GTPase activity, leading to persistent activation of MAPK (mitogen activated protein kinase) pathway d/t inability to inactivate Ras-GTP
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What are tumor suppressor genes?
normally act to inhibit cell proliferation and tumor development
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Why does loss of retinoblastoma (RB) protein cause excessive proliferation?
- RB typically is bound to E2F which prevents it from entering the nucleus to promote transcription
- If RB is absent, E2F is not prohibited from entering the nucleus and promotes uncontrolled cell growth
Phosphorylation released RB from E2F normally
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How does absence of the p53 Tumor Suppressor Gene lead to cancer?
- p53 is a DNA-binding protein that is elevated after DNA damage and promotes cell cycle arrest or apoptosis (transcriptional regulator)
- loss of p53 function causes cells with corrupted genomes to continue to proliferate, which promotes the transmission to daughter cells of mutations that may further promote tumor progression
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Tumor progression results from an accumulation of what?
Mutations
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How do most anticancer drugs generally act?
by inhibiting cell proliferation
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The most successful new cancer drugs interfere with what?
growth promoting kinases, especially tyrosine kinases
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