Cancer

Question 1

tumour cells vs normal cells

Answer 1

• Normal cell proliferation is modulated by regulation of the cell cycle.
• Apoptosis eliminates damaged cells
• Normal cell numbers are tightly regulated
• *Cancer cells are the result of genome changes
• These range from point mutations and gene deletions and amplification to whole chromosome gain or loss.
• *Solid Tumors are complex organs composed of different cell types
• They interact with their environment to obtain a maximal growth advantage.
• *Metastatic tumor cells acquire migratory properties that enable them to invade surrounding tissues
• they spread through the body to establish secondary sites of growth. (metastases)

Question 2

6 changes in cells that cause cancer (carcinogenesis)

Answer 2

Carcinogenesis – 6 fundamental cellular properties can be altered:

1. Sustain proliferative signaling – acquire a drive to proliferate that does not require an external inducing signal
2. Evade growth suppressors – fail to sense signals that restrict cell division
3. Resist cell death – cell continues to live when it should undergo apoptosis and die
4. Activate invasion and metastasis – change attachment to surrounding cells or to the extracellular matrix, breaking loose to move away from tissue of origin
5. Enable replicative immortality – continue to proliferate past generation when normal cells senesce and die
6. Induce angiogenesis – stimulate growth of blood vessels into the tumour to supply nutrients to cells in the centre of tumour

Question 3

energy production in cancer cells

Answer 3

via ‘aerobic’ glycolysis

• Cancer cells use an unusual energy-generating mechanism in the presence of oxygen.
• Cancer cells and proliferating cells:
• Sufficient O2 – use aerobic glycolysis (Warburg effect) – convert most glucose to lactate regardless of whether sufficient oxygen is present or not (2ATP/glucose)
• Aerobic glycolysis produces low ATP output, but cancer cells use glycolysis intermediates to synthesize macromolecules and lipids.

Question 4

metastasis of cancer cells

Answer 4

a) Normal cells stop growing when they contact other cells, eventually forming a monolayer of well-ordered cells in culture.
b) Cancer cells are less adherent and can overgrow each other to form a 3D cluster of cells.

• Cancer cells escape the confines of tissues:
  o Normal cells stop growing when they contact other cells, eventually forming a monolayer of well-ordered cells in culture.
  o Cancer cells are less adherent and can overgrow each other to form a 3D cluster of cells.

Question 5

benign tumour

Answer 5

o Small and localized
o Composed of cells that may function like normal cells
o Cause serious medical problems only if sheer bulk interferes with normal functions or if they secrete excess amounts of biologically active substances such as hormones (Acromegaly – overgrowth of head, hands, and feet, can occur when a benign pituitary tumor overproduces growth hormone)

Question 6

metastatic/malignant

Answer 6

Invade other tissues and seed formation of additional tumors with cells that continue to proliferate , invade organs

Question 7

metastatic cancer cells

Answer 7

• Degrade the basement membrane
• Migrate on extracellular matrix (ECM) fibers away from the primary tumor to reach the blood vessels
• Can be attracted by signals such as epidermal growth factor (EGF), which can be secreted by macrophages
• Penetrate the blood vessel endothelial cell layer that forms the vessel walls and enter the bloodstream

Question 8

carcinoma cells

Answer 8

• penetrate the ECM and blood vessel wall:
  o Use the actin cytoskeleton to extend invadopodia
  o Produce matrix metalloproteases and other proteases that degrade basement membranes to open a path for metastasis
• Extravasation: circulating tumor cell adheres to the blood vessel lining in a new location and migrates through it to colonize a new tumor in the underlying tissue.

Question 9

origins and development of cancer

Answer 9

• Direct- and indirect-acting carcinogens mutate DNA.
• Multi-hit model – multiple mutations are required to cause cancers
• Colon cancer develops through distinct morphological stages that are commonly associated with mutations in specific tumor-suppressor genes and proto-oncogenes.
• Oncogenic genes can work synergistically to contribute to cancer development and progression.

Question 10

carcinogens/mutagens

Answer 10

• Chemical carcinogens (mutagens) cause cancer by inducing DNA damage that introduces mutational errors during DNA repair.
• Ability to transform cells and induce cancer in animal models is roughly proportional to the mutagenic effect of a carcinogen.

Question 11

direct & indirect acting carcinogens

Answer 11

Direct-acting: reactive electrophiles that react with DNA nitrogen and oxygen atoms to modify DNA bases and introduce mutations

Indirect-acting: generally unreactive, water-insoluble compounds
o can act as potent cancer inducers only after introduction of electrophilic centers
o need to be modified by cellular enzymes eg P-450

Question 12

multi-hit model

Answer 12

• Multi-hit model of cancer induction predicts increase in cancer incidence with age.
• First mutation: gives a slight growth advantage
• Second mutation: causes cells to grow more uncontrollably and form a small benign tumor
• Third mutation: allows cells to outgrow the others to form a mass of cells
• Fourth mutation: allows cells to escape into the bloodstream and metastasize.

Question 13

genetic basis of cancer

Answer 13

Cancer promoting mutations:
o Increase ability of cell to proliferate
o Decrease susceptibility of cell to apoptosis
o Increase general mutation rate in cell or its longevity
o Increase in cell longevity

1. Dominant gain-of-function mutations in proto-oncogenes
   - Proto-oncogenes encode growth-promoting signaling proteins and their receptors, signal-transducing proteins, transcription factors, and anti- apoptotic proteins.
2. Recessive loss-of-function mutations in tumor-suppressor genes contribute to cancer.
   - Tumor-suppressor genes encode proteins that directly or indirectly control cell-cycle progression.

Question 14

mutations in 7 protein types –> cancer

Answer 14

1. Oncogenes; Proteins that normally promote cell growth:
I. Extracellular signaling molecules
II. Signal receptors 
III. Signal-transducing proteins
IV. Transcription factors 

2. Tumor-suppressor gene mutations:
   I. Cell-cycle control proteins, which function to restrain cell proliferation
   II. DNA-repair proteins
3. Both oncogenes and tumor-suppressor genes:
   I. Apoptotic proteins

Question 15

mutations in cancer cells

Answer 15

1. Oncogene mutations (dominant)
   - Mutation only required in one allele for tumour formation
   - The gene in its normal un-mutated form = proto-oncogene
   - usually for proteins that promote growth or proliferation, only need to have one allele over-expressing this for it to cause a problem
2. Tumour Suppressor gene mutations (recessive)
   - For cancer to occur, both alleles of gene must be mutated & have no activity
   - concept ‘loss of heterozygosity’
   - genes code for proteins that induce apoptosis or halt the cell cycle. So if there is still one functional allele the cell can still be protected.

Question 16

dys-regulation of cell growth and death pathways in cancer

Answer 16

Most tumor cells produce constitutively active forms of one or more intracellular signal-transducing proteins.
o Inappropriate production of gene transcription factors (TFs) can induce cell transformation.
o Loss of growth regulators or apoptotic proteins can contribute to cancer.

Question 17

effects of oncogenic mutations in proto-oncogenes that encode cell surface receptor

Answer 17

(breast cancer)

• Mutations that result in overproduction or unregulated, constitutive activity of certain proteins promote cell proliferation and transformation.
• Mutations that result in overproduction or unregulated, constitutive activity of certain proteins promote cell proliferation and transformation.
• Different mechanism but both now constitutively active

Question 18

RTK/RAS/MAP kinase pathway

Answer 18

• Components frequently mutated in cancer
• Many oncogenes encode constitutively active signal-transducing proteins.
• RTK/RAS/MAP kinase pathway components:
  o Oncogenic mutations in human cancers (green)
  o Inactivating mutations found in cancer cells (red)
• Ras activity mutations:
  o G12 mutation to any other amino acid inhibits RAS GTPase activity, maintaining RAS in the on state.
  o Recessive loss-of-function mutation in a GTPase-activating protein (GAP) leaves Ras in GTP on state

Question 19

dys-regulation of cell cycle and DNA maintenance pathways in cancer

Answer 19

• Over-expression of cell-cycle proto-oncogenes or loss-of-function mutations in tumor-suppressor genes contribute to 80% of human tumors.
• Loss-of-function mutations in the p53 DNA-damage checkpoint gene found in >50% of human cancers.
• Mutations in genome-maintenance genes lead to a high rate of mutagenesis of the genome that can cause accumulation of additional mutations and uncontrolled cell proliferation.

Question 20

p53 - guardian of the genome

Answer 20

p53 is a DNA damage sensor
- DNA is damaged by: 	
o UV-radiation e.g skin cells
o g-irradiation e.g. thymocytes 
ochemotherapeutics e.g. cisplatin
o telomere shortening upon cell division

When DNA is damaged (e.g. UV-induced thymine-thymine dimers or double strand breaks) p53 protein (activity) is induced
- Loss of p53 abolishes the DNA damage checkpoint
o unphosphorylated MDM2 E3 ubiquitin ligase activity ubiquitinates p53, targeting it for proteasomal degradation

Question 21

p53 stabilisation and inactivation

Answer 21

p53 stabilization
o MDM2 phosphorylation inhibits p53 binding, preventing degradation
o p14ARF sequesters MDM2 in the nucleolus, where it cannot access p53 and cause its degradation.

P53 inactivated in most human tumors through
o Mutation
o Down-regulation/mutation of positive regualtions of p53
o Up-regulation of negative regualtors of p53