This image shows the proposed mechanism for Dll4-Notch1 mediated lateral inhibition of cells adjacent to those experiencing high levels of VEGF and which would be maintaining extendede filopodia.
Angiogenesis is the formation of new blood vessels from existing ones. It is stimulated and guided by environmental concentration gradients of chemicals such as VEGF and Dll4. It has a partuclar relevance to cancer research as tumours of a certain size create and rely on their own blood supply, albeit a leaky one, in order to grow. Cancer blood verssel growth is notorious for its unnormalised messy growth. However, if we could interfere with this supply network, could tumour growth be stopped? By inhibiting development of this supply it is thought tumour growth would be slowed. However, the smaller deoxygeneted tumours to result are a lot more likely to metastase, fighting back by releasing their cancerous cells to the blood stream and therefore spreding around the body.
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This image shows the proposed mechanism for Dll4-Notch1 mediated lateral inhibition of cells adjacent to those experiencing high levels of VEGF and which would be maintaining extendede filopodia. |
As a consequence, anti-angiogenesis is not as simple as it first appears as a means of treatment. In addition an efficient supply of blood may also have its advantages (especially if normalised), as it would enable an efficient supply of anti tumour drugs right to the centre of the tumour, a desirable tool. There is currently a debate over the the effectivness of the two approaches. The power of the earlier, more traditional anti-angiogenesis treatment is now being reconsidered in light of pro-angiogeneis drugs becoming an increasingly viable option.
In brief, pro-angiogenesis treatments may provide a very efficient supply of oxygen to the unstressed tumours and dramatically reduce their metastasing (spreading) ability, while giving us a means of delivering anti-tumour drugs right to the core of the tumour. Better oxygen supply may lead to faster growth of the tumour, however the potential for actual treatment, reduction and control of the cancer would be far greater.
Image of angiogenesis in vitro. Filopodia (light green) are visible on the ends of tip cells, with spaces in the network being caused by lateral inhibition. (Confocal microscopy image curtosy of H. Gerhardt) |
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It is clear a thourough unerstanding of the process of angiogenesis is needed in order to progress. In understanding the actual network formation at a mico level, we can go on to answer questions such as what causes the unnormalised vessels growth in tumours. Implications are in metastasis, drug delivery and rate of tumour growth.
Our model aims to understand the patterning of tip and stalk cells, and to explain how the characteristic salt and pepper pattern arises. Our work complements wet research done by Lars Jakobsson in the institutes Vascular Biology Lab. Aims include:
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Our model consists of 3 agent types arranged in a 3D lattice. 10 fixed EC agents make up a cylindrical 'blood vessel', representing 10 adjacent endothelial cells. The EC agents are made up of smaller memAgents which are positioned at the cylinder wall, or cell membrane. This 'wheels within wheels' approach, agents being within agents, enables us to define the cells as entities while providing a high degree of definition and local variation to the protein levels within the membrane. (Image of model to left from Bentley et al., JTB, 2008) |
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Shown are the memAgents comprising the vessel periphery. They communicate their parameters with their governing EC agent and are reallocated new levels of protein 'tokens' for each timestep.
Periphery memAgents budding off as filopodia. Agent at the end is a 'tip' cell, those comprising the length are 'stalks'. Communication limited to cells directly adjacent. Tip cell responds to VEGF. |
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MemAgents respond to fixed environmental VEGF by extending 'filopodia'. Filopodia are memAgents with a thinner shape that extend or retract depending on protein levels in relation to VEGF, and the presence of cells directly above and below them.
As enough filopodia extend from memAgents of a particular EC agent, that EC agent becomes a 'tip cell'. Tip cells are cells which in nature extend along VEGF gradients, pulling stalk cells with them and later on fusing with other tip cells to create the blood vessel network. (Later versions of the model will include this fusion of tip cells and the inevitable 'flipping of fate' of one of them as lateral inhibition occurs.)
As EC agents become tip cells the Notch1 ligand, Dll4, is released, which is recognised by adjacent EC agents and serves to inhibit those adjacent to it from also becoming tips. Despite default fate of all endothelial cells to become tip cells, two such cells can never find themselves adjacent to each other. This lateral inhibition is fundamental to tip cell selection, and the typical 'salt and pepper pattern'. EC agents have a knowledge of total protein level in all its comprising memAgents, and determines whether it becomes a filopodia extending tip, or inert inhibited cell.
MemAgents have unique levels of Notch1, Dll4 and VEGFR2 (VEGF receptors). As filopodia, memAgents are able to share grid sites, however for all other agents the smallest occupyable space is a small cubical grid space.
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©2008 Katie Bentley, David Barr, Paul Bates