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THEME 1 – Molecular regulation of energy and nutrient metabolismIntroduction (1.1)
Cancer = class of diseases which a group of cells display uncontrolled growth, but also
invasion that intrudes upon and destroys adjacent tissues, and sometimes metastasis, or
spreading to other locations in the body via lymph or blood (=malignant/kwaadaardig). LET
OP! Benign (=goedaardig) tumours do not invade or metastasize.
▪ A tumour is a neoplasm → cancer is a malignant neoplasm.
Proliferation induces problems in cellular metabolisms; each passage through the cell cycle
yields two daughter cells and requires a doubling of total biomass → take up nutrients in
excess of bioenergetic needs and shunt metabolites into biosynthetic pathways.
Cell transformation = the process of cell change, in which a cell loses its ability to control its
rate of division, and thus becomes a tumour cell
Metastasis = cancer spreads to a different body part from where it started
Cancer cells differ from their counterparts in several respects:
✓ Cancer cells are immortal, they grow indefinitely (usually accompanied with
increased loss of functions)
✓ Cancer cells display sufficiency in growth signals → have a lower growth factor
requirements than normal cells
✓ Cancer cells are invasive and support invasion and metastasis:
o Loss of contact inhibition → do not stop growing when they come in contact
with another cell
o Reduced cellular adhesion → cells of the same origin do nót stick together
o Loss of anchorage dependence → do not have to be attached to a substrate
to grow
o Have less organized, more mobile surface proteins
o Altered secreted protein profile → increased secretion of proteolytic
enzymes, which facilitates cell migration and invasiveness
✓ Cancer cells are resistant to programmed cell death (=apoptosis)
✓ Cancer cells have an altered nutrient and energy metabolism
✓ Cancer cells show an increased rate of glycolysis
✓ Cancer cells have a more negative surface charge of the cell membrane and
sustained angiogenesis → negative cell surface facilitates uptake of nutrients
o Angiogenesis = the growth of blood vessels from the existing vasculature
LET OP! Cancer cells are not fundamentally different from normal cells → cancer cells are re-
programmed such that optimal growth of the individual cell is facilitated, but at the expense
of the organism to which the cancer belongs.
1
,“Hallmarks of Cancer” by Hanahan and Weinberg:
1. Sustaining proliferative signalling
2. Evading growth suppressors
3. Resisting cell death
4. Enabling replicative immortality
5. Inducing angiogenesis
6. Activating invasion and metastasis
7. Evading immune destruction
8. Reprogramming of energy metabolism
Mitochondria (1.2)
Mitochondria are organelles that reside in eukaryotic cells:
▪ Mitochondria have a double membrane → mitochondrial outer membrane (MOM)
and the mitochondrial inner membrane (MIM)
▪ Mitochondria have their own circular DNA
o Mitochondrial DNA encodes for 13 proteins, while mitochondria contain 1250
proteins
o Most of the mitochondrial proteins are encoded by nuclear DNA and
imported into the mitochondria via TOM (translocator of outer membrane)
and TIM (translocator of inner membrane) complexes
Mitochondrial functions, takes care of:
1) Produce ATP =main function
2) Respond to cellular energy
requirements
3) Balanced use of energy substrates
(lipids, sugars, amino acids)
4) Urea cycle
5) Calcium homeostasis
6) Amino acid metabolism
7) Heme and iron-sulphur cluster
biosynthesis
8) Apoptosis
9) Immune defence
10) Oxidative signalling, mediated by reactive oxygen species (ROS)
LET OP! These functions are altered in cancer cells.
Sugars are metabolized in glycolysis → anaerobic, 2 molecules of ATP and 2 molecules of
pyruvate per molecule glucose.
Pyruvate goes into the TCA cycle → breaks down acetyl CoA - derived from pyruvate, fatty
acid and amino breakdown – to generate CO2 → reduced NAD+ to NADH and FAD to FADH2.
2
,These intermediates provide electrons to the electron transport complexes (ETC). Complex
I, II, III and IV transfer energy between the intermediates in the chain.
1) Electrons are transferred from NADH to Complex I or from TCA derived FADH 2 to
Complex II
2) Shuttled to Complex III
3) In Complex IV, the electrons are transferred to oxygen (O2) to form H2O → use of
oxygen = respiration
Transport of electrons is accompanied by transfer of protons from the matrix to the inter-
membrane space = proton-motive force.
In Complex V (F1F0-ATP synthase), moves the protons inward which results in
phosphorylation of ADP to ATP → energy!
The ECT together with complex V is called oxidative phosphorylation → generates 32-34
(OXPHOS) + 2 (glycolysis) ATP per molecule of glucose. LET OP! Aerobic, however, very active
process; uses a lot of oxygen (80%-90% of our body oxygen)
Mitochondria are major sources of generation of free radicals → reactive oxygen species
(ROS). Interaction of unpaired electrons with O2 results in generation of superoxide ions O2-.
These are highly reactive and are converted to other radical species, such as OH- (hydroxyl
ions) and H2O2 (hydrogen peroxide). These are very harmful; lipid peroxidation and damage
to cell membranes and DNA.
Anti-oxidant defence: Superoxide dismutase convert superoxide to hydrogen peroxide and
glutathione peroxidase or catalase can convert peroxide to water.
ROS production is increased with, increased pyruvate influx, decreased ATP demand and
increased membrane potential, while uncoupling (=uncoupling the proton gradient from ATP
production, so in fact by passing complex V) will decrease ROS formation.
LET OP! An imbalance between
the generation of ROS and the
cell’s ability to clear oxidants can
lead to pathogenic levels of ROS
leading to increased damage of
proteins, lipids and DNA. By
causing DNA damage, high levels
of ROS can be carcinogenic.
3
, Apoptosis
Cancer cells are resistant to apoptosis. In vertebrates, apoptosis occurs through 2 main
pathways:
• Extrinsic pathway / Receptor mediated pathway → death receptors from TNF on
surface of cell membranes → activation by death ligand leads to recruitment of
proteins into a death-inducing signalling complex (DISC) → activated caspase 8 (or
10) triggers execution of apoptosis
• Intrinsic pathway / Mitochondrial pathway of cell death → activated by cellular
stresses above treshold (radiation, damage, infections) → results in mitochondrial
outer membrane permeabilization (MOMP) → release of pro-apoptotic proteins and
loss of mitochondrial membrane potential → proteins released:
o Activating caspase dependent pathway
o Release of death proteins (apoptosis inducing factor AIF & endonuclease G,
endo G)
Programmed necrosis is a fully mitochondrial dependent process.
Mechanisms that result in MOMP:
✓ Prolonged opening of the permeability transition pore (PTP) → formed by Complex V
o Under normal conditions, PTP allows a regulated exchange of ions and small
metabolites between the cytosol and the mitochondrial matrix
o Prolonged opening of PTP results in free influx of ions into the mitochondrial
matrix = mitochondrial permeability transition (MPT) → loss of mitochondrial
membrane and swelling of the matrix
✓ Channel formation by pro-apoptotic proteins BAX and BAK1 → promote PMP
opening
✓ Direct MOMP effects of pro-apoptotic stimuli
Cancer cells are resistant to apoptosis → caused by deregulation of HIF1, c-Myc and TP53,
which results in:
1) Upregulation of anti-apoptotic proteins (BCL-2)
2) Suppression of pro-apoptotic proteins (BAX en BAK)
3) Silencing death receptors
4) Hexokinase II binds more tightly to voltage dependent anion channel; increased
resistance of mitochondrial permeability transition (MPT)
Reprogramming of metabolism (1.3)
Growth-factor signalling regulates the uptake and metabolism of extracellular nutrients in
normal cells → facilitates growth and replication. Cancer cells are growth factor
4
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