|dc.description.abstract||Tumour-associated macrophages (TAMs) have been shown to play an important role
in tumour survival and progression. Thus, high numbers of macrophages in the
tumour tissue are often associated with a poor prognosis. Identification of factors
responsible for recruiting macrophages to the sites of different types of tumours
might help to develop more effective cancer treatment.
Burkitt's lymphoma (BL) is characterised by uncontrolled cell proliferation, high rate
of spontaneous apoptosis and significant macrophage infiltration. Although BL cells
undergo extensive apoptosis, in situ their corpses are cleared very effectively by
macrophages infiltrating the tumour. It is now widely believed that dying cells are
themselves able to release chemotactic molecules to ensure macrophage chemotaxis
and subsequent clearance of their site of death. Previous work carried out in this
laboratory identified fractalkine/CX3CL1 (FKN) released from dying BL cells to be
an important player in macrophage chemotaxis to BL. Yet, these results have also
indicated that FKN may not be the only chemokine involved in this process.
Following from those observations, the first part of this work focused on examination
of the potential role of monocyte chemoattractant protein-1 (MCP-1) in macrophage
recruitment to BL. Despite the initial promising results, careful analysis of the data
obtained by various techniques led to the conclusion that MCP-1 is, probably, not
expressed by BL cells.
Subsequently, effort was concentrated on understanding mechanisms regulating FKN
processing during cell death. The studies performed before in this laboratory
identified a new form of FKN to be present in apoptotic BL cells and showed that
this is the form that is, most likely, responsible for mediating macrophage migration.
Here, this apoptosis-related 60 kDa FKN was found to be a likely caspase-3 cleavage
product. Moreover, it was demonstrated that FKN and active caspase-3 are released
together in apoptotic BL cell-derived microparticles, suggesting that the proteolytic
events could take place also extracellularly. In the final results chapter the differences between BL cell lines in the way they
process FKN during cell death were revealed and a new cell death-associated 55 kDa
FKN was observed. Through several lines of evidence, this new form was identified
to be a possible product of calpain-mediated proteolysis.
To conclude, this work provides the first evidence for a possible direct participation
of the two major cell death executioner proteases – caspases and calpains, in
production of ‘find me’ signals for macrophages and thus, ensuring effective
clearance of dying cells. These results indicate that FKN cleavage and release might
be of key importance during cell death. Moreover, the studies presented here
contribute to better understanding of the process of FKN secretion.||en
|dc.publisher||The University of Edinburgh||en
|dc.relation.hasversion||Truman LA, Ford CA, Pasikowska M, Pound JD, Wilkinson SJ, Dumitriu IE, Melville L, Melrose LA, Ogden CA, Nibbs R, Graham G, Combadiere C, Gregory CD., CX3CL1/fractalkine is released from apoptotic lymphocytes to stimulate macrophage chemotaxis. Blood, 15 December 2008, Vol. 112, No. 13, pp. 5026-5036. Prepublished online as a Blood First Edition Paper on September 17, 2008; DOI 10.1182/blood-2008-06-162404. URL: http://bloodjournal.hematologylibrary.org/cgi/content/full/112/13/5026||en
|dc.title||Chemotactic signals released during Burkitt’s lymphoma cell death||en
|dc.type||Thesis or Dissertation||en
|dc.type.qualificationname||PhD Doctor of Philosophy||en