Tumor progression is not only due to the aggressiveness of cancer cells but also to the support given by tumour reactive stroma; reason why the study of stromal cell involvement in tumor microenvironment has become extremely important in the last decades. Tumor mass is a complex network of cancer and stromal cells, and fibroblasts are the main component. Under the influence of tumor cells, fibroblasts engage a transdifferentiation program converting them into their active form (myofibroblast), the so called cancer associated fibroblasts (CAFs), that, in turn, are able to enhance tumor cells growth, migration and invasion. This crosstalk is mediated by soluble factors, cell–cell contacts and extracellular vesicles (EVs) trafficking. Our work is focused in particular on cellular interaction based on EVs trafficking. Two types of Evs has been described, ectosomes (with a diameter from 100 nm to 1 μm) and exosomes (from 30 to 100 nm) that show differences in size, biogenesis and composition. It has been discovered by my research group that a transfer of proteins and lipids between CAFs and cancer cells mediated by ectosomes exists and that this is, essentially unidirectional from CAFs to cancer cells. We have identified about two hundreds proteins that are specifically transferred to cancer cells by this type of cargo. One of the most interesting proteins, considering its role in cancer progression is Galectin-1 We have found that Galectin-1 silencing in CAFs reduce the migration of cancer cells, revealing a novel mechanism by which tumor stroma contribute to cancer progression. These results are important because Galectin-1 has been highlighted as a good target in both cancer and fibroblast cells, increasing the possibilities to counteract cancer aggressiveness by reducing Galectin- 1 action through specific inhibitors. In the second part of my thesis the role of low molecular weight protein tyrosine phosphatase (LMW-PTP) in fibroblasts during their activation has been investigated for the first time. It is known that LMW-PTP expression in cancer increases with the staging of tumor and that it is implicated in several biological processes. Our findings show that the activation induces in CAFs an increase of LMW-PTP expression that is associated to cytoskeletal rearrangement. As a consequence CAFs show a more invasive phenotype that is reversed when LMW-PTP is silenced. Additionally our results suggest the LMW-PTP involvement in cell metabolism. The increase of LMW- PTP induces a more gycolytic metabolism and its silencing causes the induction of a more OXPHOS behaviour. We hypothesize that LMW-PTP could drive fibroblast infiltration and migration during tumor progression. These findings, taken together, contribute to highlight the role of CAFs within tumor microenvironment in sustaining tumors.
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|Titolo:||TUMOUR MICROENVIRONMENT: PROTEIN MEDIATORS OF INTERCELLULAR CROSSTALK|
|Citazione:||Toti, A. (2019). TUMOUR MICROENVIRONMENT: PROTEIN MEDIATORS OF INTERCELLULAR CROSSTALK.|
|Appare nelle tipologie:||8.1 Tesi Dottorato|