Tumour Biology part 3 Flashcards
What are the types of treatments ?
Personalized cocktail chemotherapies are required to eliminate all tumour subpopulations
How do cancer cells divide constantly?
By bypassing cell cycle checkpoints
Sustain proliferation signal
Cancer cells deregulate growth-promoting signals and become self-governing.
Growth factors, hormones and cytokines bind to cell-surface receptors with intracellular tyrosine kinase domains.
These receptors control by phosphorylation different intracellular signalling pathways that regulate the cell cycle and metabolism.
How do cancer cells sustain proliferative signalling by: -?
- Producing growth factor ligands themselves (autocrine proliferative stimulation).
- Sending signals to stimulate normal cells within the supporting tumourassociated stroma, which reciprocate by supplying the cancer cells with various growth factors.
Sustain proliferation signals
Cancer cells may also activate constitutively molecular factors involved in the signalling pathways acting downstream of the signal receptors. Then, the stimulation of these pathways by a ligand-mediated receptor activation is no longer needed.
Evading growth suppressors
Cancer cells must bypass programs that limit cell growth and cell proliferation. These programs depend on tumour suppressor genes.
The two prototypical tumour suppressors genes encode the RB (retinoblastomaassociated) and p53 proteins.
These two proteins are central control nodes of complementary cellular regulatory circuits.
They direct cells towards either cell proliferation or cellular senescence and apoptosis.
Evading growth suppressors
RB or pRb transduces growthinhibitory signals that originate outside of the cell to determine whether it should proceed through the cell cycle or not.
Thus, in absence of the RB pathway, cancer cells are able of persistent cell proliferation
Evading Growth suppressors
p53 receives inputs from stress and abnormality sensors in response to genome damage, or if the levels of nucleotide pools, growth-promoting signals, glucose, or oxygenation are suboptimal.
p53 stops cell-cycle progression until these conditions have been normalized. If damage is irreversible, p53 can trigger apoptosis.
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Evading growth suppressors
Contact inhibition (cell-to-cell contact proliferative suppression) is abolished in various types of cancer cells.
NF2 orchestrates contact inhibition by modulating cell-surface adhesion molecules and sequestering growth factor receptors.
LKB1 overrules the mitogenic effects of the powerful Myc oncogene. When LKB1 expression is suppressed, epithelial integrity is destabilized.
Resisting cell death
The apoptotic machinery is divided into two major circuits: extrinsic apoptosis (sensing extracellular death-inducing signals), and intrinsic apoptosis (sensing intracellular signals).
Each culminates in activation of a normally latent protease (caspases 8 and 9, respectively).
These caspases initiate a cascade of proteolysis to disassemble the cell, which is then consumed by phagocytosis.
To circumvent apoptosis cancer cells: -eliminate p53 -upregulate antiapoptotic proteins (Bcl-2, Bcl-xL) -downregulate proapoptotic factors (Bax, Bim, Puma) -bypass the extrinsic ligandinduced death pathway
Enabling replicative immortality
Cancer cells require unlimited replicative potential.
Normal cells are able to pass only a limited cell growth-and-division cycles. This could en up in senescence, an irreversible non-proliferative but viable state, and crisis, which involves cell death.
Telomerase is a specialized DNA polymerase that adds telomere repeat segments to the ends of telomeric DNA.
It is almost absent in non-immortalized cells but over-expressed in the vast majority (90%) of immortalized cells.
By extending telomeric DNA, telomerase is able to counter the progressive telomere erosion, which is correlated with a resistance to induction of both senescence and crisis/apoptosis
Inducing angiogenesis
Tumours require nutrients and oxygen as well as an ability to evacuate metabolic wastes and carbon dioxide. This is addressed by a tumourassociated neo-vasculature generated by the process of angiogenesis.
Cancer blood vessels are typically aberrant: -precocious capillary sprouting
-convoluted and excessive vessel branching -distorted and enlarged vessels -erratic blood flow -micro-hemorrhaging -leakiness -abnormal levels of endothelial cell proliferation and apoptosis
Activating Invasion and Metastasis
Malignant cancer cells spread using different strategies.
Cancer cells develop alterations in their shape and in their attachment to other cells and to the extracellular matrix (ECM).
In general, genes encoding cell-to-cell and cell-toECM adhesion molecules that favour cytostasis are down-regulated in cancer cells.
Conversely, adhesion molecules normally associated with the cell migrations that occur during embryogenesis and inflammation are upregulated.
Activating Invasion and Metastasis
Metastasis requires a permissive tumour microenvironment.
Most disseminated cancer cells are likely to be poorly adapted to the microenvironment of the tissue in which they have landed.
Certain tissue micro-environments may be intrinsically hospitable to disseminated cancer cells, some cancers have tissue-specific colonizing abilities (i.e. metastatic tropism).
Reprogramming Energy Metabolism
Cancer cells reprogram their glucose metabolism to glycolysis. They compensate for the ∼18-fold lower efficiency of ATP production by up-regulating glucose transporters
Increased uptake and utilization of glucose have been documented in many human tumour types
Increased glycolytic intermediates facilitate generating nucleosides and amino acids, and in turn, the synthesis of macromolecules and organelles required for assembling new cells.
