cancer

Question 1

What are the 4 stages of angiogenesis?

Answer 1

Tumour angiogenesis – 4 stages:
Four phases of angiogenesis :
proteolysis, proliferation, migration, maturation
Formation of blood vessels around tumour.
Tumour is hypoxic when small, then becomes highly vascularised after proliferation
2. Proteolysis: Release of angiogenic factors and proteases by tumour cells
1. Tumours respond to hypoxic environment- low 02 environment, grow large enough so oxygen can’t diffuse to it.
2. This triggers them to release VEGF (vascular endothelial cell growth factor) this triggers stage 2:
1. (sustaining proliferative signalling)- no longer rely on external signals.
3. Proliferation: Degradation of basement membrane and proliferation of endothelial cells
1. Degradation of basement membrane, surrounding endothelial cells and proliferation of endothelial cells along the conc gradient of VEGF.
2. VEGF degradation of basement membrane, and therefore promotes proliferation of endothelial cells of capillary
4. Migration: Migration of endothelial cells in direction of tumour
1. Endothelial cells of capillary further proliferate and migrate in direction of tumour, continually secreting VEGF.
5. Maturation: Formation of tubular structures (capillary loops) which anastomose with the existing vasculature
1. After capillary network has infiltrated the tumour, the endothelial cells will undergo a process call anastomose (joining up two ends of loop, creating vascular network)

Question 2

What are the 10 hall marks of cancer ?

Answer 2

• Sustaining Proliferative Signalling: describes the ability of cancer cells to stimulate their own growth they become self-sufficient in growth signals and no longer depend on external signals
  § (e.g. signalling through the EGFR, epidermal growth factor receptor, proliferation through these cell surface receptors depend on three pathways AKT, MAPK, mTOR).
• Mutations in egfr will mean they are always turned on, consistent growth promoting pathways activation which drives cell proliferation.
• Evading Growth Suppressors: cancer cells resist inhibitory signals that might otherwise stop their growth, major pathways involved are autophagy and apoptosis (both of these pathways ultimately lead to cell death and a reduction in tumour growth).
• Broken or damaged DNA means that the cell will either try to repair it or self destruct
• If you have a loss of mutation function in a tumour suppressor gene like P53, genes are important in these checkpoints and cells cant check their own growth or the integrity of the DNA and this damaged DNA will be passed on to subsequent cells and therefore encourage cancer development
  
  • Autophagy itself is a dynamic cellular recycling system, that results in the degradation of cytoplasmic contents and damaged organelles, these are degraded and recycled in the cell to be used for formation of other structures / proteins. Cancer can up regulate autophagy to enhance their growth and aggressiveness
     negatively regulate proliferation so it prevents cellular growth and division, tumour suppressor genes, however they become inactivated in tumour cells so they have no control in suppressing growth.
• Avoiding Immune Destruction: some cancer cells can adapt mechanisms to evade detection and destruction by the host’s immune system
  
  • one way cells can do that is by hijacking normal mechanisms of immune check point control (the built in control mechanisms of the immune system that maintain self-tolerance and help avoid collateral damage during a physiological immune response) and modulation of the innate immune response.
  • Tumour cells can secrete various factors to engineer their micro-environment in order to evade and resist immune surveillance and attack.
     tumours are usually destroyed by innate immune system, once formed, a large solid tumour is able to avoid detection

Enabling Replicative Immortality: the ability of cancer cells to revert to a pre-differentiated state (differentiation can be considered as the maturation of a cell into the phenotype it’s ultimately meant to be, cancer cells can do a reverse of this process and revert to a stem cell-like phenotype)  that allows them to have continuous cell division and other changes to survive adverse conditions
○ Allows cell to keep replication, particularly if cell is under stress.

• Tumour Promoting Inflammation: describes the ability of cancer cells to take-over inflammatory mechanisms to promote their own growth and survival
  ○ inflammation is a really important part of tumour progression, a lot of diseases that are a risk factor for cancer are associated with chronic inflammation.
  § Inflammation involves the release of various growth factors and cytokines into tissue that causes this chronic inflammatory response that can ultimately cause DNA damage and development of tissues/tumours
  ○ Here, when we have an existing tumour, tumours take over inflammatory mechanisms, tumours use the cytokines and growth factors by the inflammatory response to promote growth.
• Activating invasion & Metastasis: malignant tumour cells have this propensity to metastasise (to spread to other organs).
  
  • Metastasis involves the dissociation of the cells from the primary tumour, local tissue invasion traveling through the circulatory system to reach a second site, all this is underpinned by various changes in different types of genes (tumour suppressor genes) that allow the cells to gain these aggressive characteristics.
  • Metastasis= spreads to other organs by dissociation of the cells from the primary tumour to a second site through the circulatory system.
• Inducing Angiogenesis: closely linked to metastasis, provides the key route of dissemination and tumours in the right environment can promote angiogenesis.
  
  • In levels of low oxygen (as you would find in a rapidly growing tumour), they are able to stimulate the neovascularisation –> the creation of a new blood system to infiltrate the tumour, that not only allows the cells to access various nutrients and oxygen but it also allows the cells a route out of the tumour into the circulatory system.
    ○ New blood vessels, so get more oxygen and nutrients for growth.
• Genome Instability and Mutation: the nature of being a cancer cell, you have an unstable genome
  
  • so these cancer cells are proliferating and because they are inherently unstable, there is an increased tendency for changes at a genomic level and various mutations to occur.
  • Particularly, if you imagine a cancer cell that has a damaged DNA repair mechanism, such as P53 (the most commonly mutated gene), it is unable to repair it’s DNA effectively and so any mutations the cancer cells pick up are going to be passed on to their progeny and unrepaired essentially. So, they are inherently, genomically unstable.
• Resisting cell death: cancer cells resist signals either externally or internally, that would normally tell a cell to self-destruct, predominantly apoptotic signals can be ignored by a tumour cell
  ○ Cells ignore apoptotic signals so are able to proliferate
  ○ Eg. Evading growth factors- normally induces apoptosis.
  ○ cancer cells resist signals either externally or internally, that would normally tell a cell to self-destruct, predominantly apoptotic signals can be ignored by a tumour cell
  ○ another concept= anchorage independent growth= hallmark of anoikis resistance.
  § Path to further steps in metastasis
• Deregulating cellular energetics: cancer cells need a lot of energy to grow fast, in order to create that energy they have abnormal metabolic pathways (normal metabolic cell would use glucose as a fuel source,
  
  • glucose is metabolised by glycolysis, resulting in creation of pyruvate, which will enter mitochondria where it undergoes Kreb’s cycle to generate ATP).
  • However, in cancer cells, much of this pyruvate that is created by glycolysis is directed away from the mitochondria to create lactate.
  • In contrast to normal cells that have mitochondrial glycolysis, lactate production in tumour cells is termed anaerobic glycolysis or the Warburg effect.
    Mechanisms in which tumour cells create a large amount of energy.

Question 3

What are the 3 stages of the Multistage model of carcinogenesis – how do tumours arise and develop these hallmarks?

Answer 3

• Initiation –irreversible genetic alterations occur in a target cell.
• Event that’s occurred that has caused DNA damage. (loss of gene (or partial) mutation of 1 DNA base)  could give rise to a diff amino acid, codon change= difference in functioning protein.
• Promotion – exposure to stimulatory agents (e.g. growth factors) allows clonal expansion of altered cell
• Expands rapidly
• Progression – further genetic alterations support further growth and gain of aggressive features
• At some point the alterations will start affecting genes that contribute to hallmarks.
  Stepwise progress takes a long period of time to give rise to tumours.