Melanoma is notoriously resistant to immuno- and even targeted chemotherapeutic strategies despite recent advances in drug development. The overall mortality of melanoma correlates with its ability to metastasise. Breslow thickness or the depth of invasion remains the most useful prognostic indicator, thereby linking the ability of the cells to invade with their propensity to metastasise. Invasion occurs early during tumour development, but the factors driving this process remain poorly understood. There is a growing appreciation that chemotaxis plays an important role in driving the migration and invasion of melanoma cells, but the key stimuli are not known. Through the generation and validation of an improved chamber for cancer cell chemotaxis, melanoma cells are shown to create chemotactic gradients that drive or disperse themselves outwards with remarkable efficiency. This process is driven by strikingly positive chemotaxis and depends on the melanoma reaching a critical density to generate the gradient. The principal attractant is the inflammatory signal lysophosphatidic acid (LPA). Unexpectedly, it is active across all stages of melanoma evolution and LPA is both necessary and sufficient for chemotaxis in 2D & 3D assays. Growth Factors were previously considered to play essential roles in driving directed migration, but instead facilitate LPA chemotaxis. Sampling across the margins of melanomas in vivo, gradients of LPA are reliably identified, which are capable of driving accurate chemotaxis. This not only confirms the physiological importance of the results, but also is the first time a chemoattractant gradient has been measured in vivo. The corollary of these findings is that, provided with an external homogenous source of LPA, a large enough melanoma will degrade the local LPA to generate an outward gradient. Therefore it is the ability to degrade the gradient that acts as the signal to drive chemotaxis and invasion rather than the presence of LPA per se. In the chambers, cells are observed dispersing in a wave and in addition to driving efficient melanoma invasion, this may be responsible for the patterning of melanocytes across the skin during embryogenesis. Ultimately, identifying key aspects of and targeting the LPA-axis may prove a novel prognostic indicator and therapeutic target for invasion and metastasis.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:586858 |
| Date | January 2013 |
| Creators | Muinonen-Martin, Andrew James |
| Publisher | University of Glasgow |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://theses.gla.ac.uk/4836/ |
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