imprint:
[Erscheinungsort nicht ermittelbar]: Università degli Studi di Milano, 2014
Language:
English
Identifier:
Origination:
University thesis:
Dissertation, Università degli Studi di Milano, 2014
Footnote:
Description:
Defective apoptosis represents one of the major causative factors in the development and progression of cancer. The ability of tumour cells to evade engagement of apoptosis can play a significant role in their resistance to conventional therapeutic regimens. In the last few years, preclinical and clinical studies have indicated ceramide and the enzymes of its metabolism, in particular Acid Sphingomyelinase (A-SMase) which hydrolyzes sphingomyelin to ceramide and phosphocoline, as key players in tumour physiopathology. Different cancers have been shown to have reduced ceramide levels and, of interest, in our previous work we showed that A-SMase down-regulation was a key event in melanoma progression. This event is crucial for the tumours to become more aggressive, but the mechanisms responsible of it haven't been investigated yet. Taking into account that there is a complex crosstalk between tumour cells and its immunological microenvironment, in this work we first investigated its possible role in A-SMase downregulation in a melanoma model. To this purpose we performed in vivo and in vitro experiments which led us to identify tumour associate macrophages (TAM) as possible responsible of A-SMase downregulation through the Ap2-α transcription factor. Moreover, we demonstrated that these molecular changes in tumour cells give, in turn, pro-tumoural and immunosuppressive features to the surrounding microenvironment, with the recruitment of Myeloid-derived suppressor (MDSCs) cells and Regulatory T lymphocytes (TREGS). From these and our previous data, we clearly showed that the ability to create this immunosuppression together with the acquisition of a more aggressive phenotype, both depend on the naturally occurring A-SMase decrease in melanoma cells during tumour progression. The broad role of A-SMase in tumour pathogenesis we identified, indicates that the enzyme is at the crossroad of key pathways in tumourigenesis. This aspects has clear potential in therapeutic perspective in which A-SMase overexpression or administration might be consider as an useful adjuvant for cancer therapy. Here we demonstrated for the first time that restoring A-SMase expression in melanoma cells not only reduces tumour growth and immunosuppression, but moreover accounts for a high, unexpected recruitment of immune cells with an anti-tumoural function in the tumour microenvironment, such as Dendritic cells (DCs) and CD4+ and CD8+ T lymphocytes. In conclusion our results reveal the central role of A-SMase expressed by melanoma cells in orchestrating the cross-talk with the surrounding microenvironment. These interactions are crucial for tumour fate, lying on its rejection or progression. Our observation that A-SMase overexpression educate" tumour microenvironment against cancer cells, further encourage the use of this enzyme as an adjuvant for cancer therapy."