LEC 43 Molecular Basis of Cancer

Question 1

What are the 3 characteristics of cancer cells?

Answer 1

1. Unregulated proliferation
2. Invasion of surrounding normal tissue
3. Spread, or metastasis, to more distant parts of the body

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Question 2

What is a tumor?

Answer 2

any abnormal proliferation of cells, which may be benign or malignant

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Question 3

What is a benign tumor?

Answer 3

remains confined to its original location

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Question 4

What is a malignant tumor?

Answer 4

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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Question 5

What are carcinomas?

Answer 5

cancers that derive from epithelial cells

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Question 6

What are sarcomas?

Answer 6

cancers that derive from connective tissue/muscle cells

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Question 7

What is a leukemia/lymphoma?

Answer 7

cancer derived from blood-forming cells/cells of the immune system

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Question 8

What is a glioma/retinoblastoma?

Answer 8

cancers derived from CNS/eye

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Question 9

What is a basal-cell carcinoma?

Answer 9

• derived from a skin keratinocyte
• continues to synthesize cytokeratin filaments
• only locally invasive

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Question 10

What is a melanoma?

Answer 10

• derived from skin melanocytes
• continues to make pigment granules
• often highly malignant

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Question 11

What is tumor clonality?

Answer 11

• 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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Question 12

How does tumor development occur?

Answer 12

1. initiates when a single mutated cell begins to proliferate abnormally
2. additional mutations followed by selection for more rapidly growing cells w/i the population
3. results in the progression of the tumor to increasingly rapid growth and malignancy

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Question 13

What evidence is there that supports the multi-step nature of cancer progression?

Answer 13

1. Most cancers develop later in life
2. 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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Question 14

What are carcinogens?

Answer 14

agents that cause cancer

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Question 15

What are some examples of causes of cancer?

broad terms

Answer 15

• 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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Question 16

What major viruses are associated with causation of cancer in humans?

Answer 16

• 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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Question 17

What is:

Autocrine Growth Stimulation

Answer 17

cancer cells produce growth factors to which they also respond, resulting in continuous self-stimulation of cell proliferation

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Question 18

What is:

Reduced Adhesion

Answer 18

reduced adhesion to other cells and to extracellular matrix components

Promotes invasion and metastasis

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Question 19

What is:

Invasion

Answer 19

malignant cells generally secrete proteases to digest extracellular matrix components, allowing invasion into adjacent tissue

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Question 20

What is:

Angiogenesis

Answer 20

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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Question 21

Describe how failure to differentiate leads to continued proliferation in some leukemias.

Answer 21

• 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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Question 22

What are the two main mutational routes towards the uncontrolled cell proliferation characteristic of cancer?

Answer 22

• 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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Question 23

How do transforming retroviruses acquire oncogenes?

Answer 23

Cellular proto-oncogene inadvertently captured by virus after excision from host DNA - e.g. capture of src by avian leukosis virus (ALV)

Question 24

What are proto-oncogenes?

Answer 24

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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Question 25

How does a proto-oncogene become oncogenic

Answer 25

1. Insertional Mutagenesis 2. Chromosomal Translocation 3. Gene Amplification 4. Point Mutation ## Footnote Slide 24

Question 26

What is insertional mutagenesis?

Answer 26

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 ## Footnote Slide 26

Question 27

How can c-myc become oncogenic?

Answer 27

If a virus inserts proviral DNA upstream of the proto-oncogenic c-myc, it turns it oncogenic ## Footnote Slide 28

Question 28

In Burkitt's lymphoma, how does a chromosomal translocation lead to cancer?

Answer 28

Translocation places c-myc gene under influence of enhancers from immunoglobulin heavy chain genes, leading to inappropriate c-myc expression ## Footnote Slide 29

Question 29

Why is c-MYC overexpression tumorigenic?

Answer 29

* 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** ## Footnote Slide 30

Question 30

Explain how a point mutation can lead to cancer. | using c-ras as an example

Answer 30

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 ## Footnote Slide 33

Question 31

What are **tumor suppressor genes**?

Answer 31

normally act to inhibit cell proliferation and tumor development ## Footnote Slide 35

Question 32

Why does loss of retinoblastoma (RB) protein cause excessive proliferation?

Answer 32

* 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 ## Footnote Slide 37

Question 33

How does absence of the p53 Tumor Suppressor Gene lead to cancer?

Answer 33

* 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 ## Footnote Slide 38

Question 34

Tumor progression results from an accumulation of what?

Answer 34

**Mutations** ## Footnote Slide 39

Question 35

How do most anticancer drugs generally act?

Answer 35

**by inhibiting cell proliferation** ## Footnote Slide 40

Question 36

The most successful new cancer drugs interfere with what?

Answer 36

growth promoting kinases, especially tyrosine kinases ## Footnote Slide 46