Abstract
About 15-20% of colorectal cancer cases progress to metastasis in other organs reducing the efficiency of current therapy regimens and reducing patient survival. In recent years, research groups have focused on the study of the contribution of Extracellular Vesicles (EVs) in the tumor process. EVs are no longer understood as reservoirs for unwanted proteins and have now been considered as important carrier structures of several biomolecules such as lipids, proteins and oncogenic factors, as well as being a proven cell-to-cell communication. Based on that, in the master project (FAPESP process 2016/02770-6), we verified that Low Molecular Weight Protein Tyrosine Phosphatase (LMWPTP) positively modulates the biogenesis of EVs and their production also has a positive correlation with aggressiveness of Colorectal Cancer Cells (CRC). Other interesting findings were the identification of both mRNA and LMWPTP protein in EVs by our group and the group of Professor Yong Song Gho, respectively. More recently, data obtained in the thematic project (Process FAPESP n° 2015/20412-7) have shown that CRC cells with greater amount of LMWPTP present greater efficiency for the formation of mixed thrombus (platelet-tumor cells). Considering these findings and considering that this phosphatase has a critical participation in the metastasis and resistance process of different types of tumors, both solid and hematopoietic, the following question was raised: Could LMWPTP present in the EVs derived from CRC tumor cells educate the platelets, even before the beginning of the metastatic process, and consequently to promote the release of pro-metastatic and prothrombogenic factors? It must be mentioned that despite the importance of the interaction of platelets with tumor cells for metastasis has already known, the molecular aspects of this process, as well as the mechanisms by which the tumor affects platelet function, still need to be clarified. Thus, the general objectives of this research project are to: a) find out if EVs derived from CRC cells containing high and low level of LMWPTP and bioengineered EVs containing LMWPTP-GFP are able to modulate platelet function, from the point of view of aggregation and metabolism (platelet signaling pathways); b) investigate whether EVs carrying LMWPTP lead to phenotypic and morphological alteration of cells from the tumor microenvironment (fibroblasts and endothelial cells); c) assess whether chemical inhibition of LMWPTP reduces the efficiency of production of the EVs by CRC cells; d) evaluate whether the chemical inhibition of LMWPTP affects platelet function/reactivity. The data obtained may demonstrate a new molecular aspect that supports the importance of LMWPTP as one of the key mediators of the hematogenous spread of CRC cells. In addition, it will be possible to show if this enzyme, besides acting intra-tumor cell promoting greater capacity of migration and resistance, is also able to "educate" platelets and cells of the microenvironment in favor of the tumor. Therefore, we expect to prove the hypothesis that tumor cells release LMWPTP to prepare the environment for the initiation and development of metastasis in CRC. Another relevant aspect will be the investigation if the LMWPTP could contribute to the thromboembolism process, once in cancer patients this condition is responsible for high rates of morbidity and mortality. (AU)
|