A translational view of cells' secretome analysis - from untargeted proteomics to potential circulating biomarkers.

The identification of circulating biomarkers capable of being used as routine for diagnosis, prognosis, risk stratification and therapeutic monitoring is still the major aim at clinical proteomics. However, the direct search in blood samples or other clinical relevant biofluids is frequently associated with technical limitations that make the biomarker discovery process extremely difficult when using these types of samples. In this sense, the use of different approaches, such as the analysis of cells' secretomes, can be an important and promising complementary method for the identification and pre-selection of potential circulating biomarkers. Therefore, the present review is focused on published works exclusively devoted to the use of cells' secretomes for the identification of new circulating biomarkers. Considering these publications, the translational workflow used to identify potential protein circulating biomarkers from untargeted cells' secretome screenings is presented and discussed in this review. This translational workflow follows a 3-phase pipeline (discovery, verification and validation phase) similar to the "triangular strategy" already applied in biomarker discovery using blood or other clinical samples. For each phase it will be indicated the type of samples, the techniques used to analyze the samples, as well as, the major outcomes and methods used to analyze the data obtained. The examples presented in this review points out the potential of this secretome-based translational pipeline for the identification of new circulating biomarker candidates, with some of the biomarkers pointed out presenting better discriminatory capacity or at least improving the discriminatory capacity of well-established biomarkers. Finally, some of the potential improvements are also identified and discussed in this review, which can increase the visibility and importance of this cells' secretome-based pipeline for the identification of new potential circulating biomarkers.