Low molecular weight protein tyrosine phosphatase in colorectal cancer: from the bench to product generation

Abstract

Over the past decade, the groups led by Prof. Carmen Veríssima Ferreira and Prof. Maikel Peppelenbosch have explored signal transduction pathways in order to define the action mechanisms of antitumor candidates and for identifyng molecular targets related with the aggressiveness and resistance of tumor cells. In this context, we have investigated cell lines and biopsies of patients with prostate and colorectal tumors and identified the low molecular weight protein tyrosine phosphatase (LMWPTP) as one of indicators of aggressiveness/metastasis. CRC was choosen as model because we have stablished a set of CRC cell lines with low and high level of the LMWPTP expression. Besides, currently we are taking part in a Dutch National Programme for CRC screening, therefore, we have been built up a collection of stool samples (microRNAs). Therefore, the thematic project will address four main questions: 1) Could the high expression/activity of LMWPTP in colorectal cancer (CRC) cells control the exosomes biogenesis and composition (proteins and microRNAs)? 2) Could the high expression/activity of LMWPTP in colorectal cancer (CRC) cells influence their interaction with platelets (first stage of the hematogenous dissemination of the tumor)? If so, it could explain at least in part, the pro-metastasis action of this phosphatase; 3) Could this enzyme and/or microRNAs modulated by this enzyme be used as biomarkers (from liquid biopsy - stool samples) for diagnosis, prognosis and treatment monitoring?; 4) Could the pharmaceutical formulation containing the 3-bromopyruvate, effectively inhibiting the intracellular LMWPTP, decreasing the tumor cells-platelets aggregates and affecting the release of exosomes containing pro-metastatic factors? Therefore, we point out as the main contributions of the thematic project: a) the identification of new biomarkers that can be detected without the need of biopsy - the most widely used methods for early diagnosis of CRC are faecal occult blood testing and colonoscopy. Although these tests have improved survival rates across the CRC, the occult blood testing has low sensitivity and colonoscopy is expensive and invasive. In addition, certain foods and medications can lead to false-positive results of the occult blood test. Therefore, innovation in cheaper biomarkers and methods less invasive and more precise become highly relevant; b) the use of the LMWPTP as a target for inhibiting the first stage of hematogenous dissemination - the efficiency of the spread of tumor cells depends, in part, on their capacity to form mixed aggregates with blood cells, primarily platelets; c) the development of pharmaceutical formulation containing 3-bromopyruvate (3BP) encapsulated in exosomes derived from normal colon cells - despite the great potential of 3BP as antitumoral, it has failed in the clinical trials due to its toxic effect in erythrocytes. Therefore, pharmaceutical formulations that reduce or prevent this side effect are highly desirable. Finally, since this proposal is a technological cooperation between researchers from The Netherlands (Erasmus University of Rotterdam) and Brazil (Unicamp, Unifesp and UFRGS), we foreseen actions to add impact of the proposal for all institutions involved: to organize two meetings for following up the progress of the project; to provide training for the members of involved groups and to find new partners to increase the number and diversity of patient samples. (AU)