Soft Tissue Sarcoma: An Insight on Biomarkers at Molecular, Metabolic and Cellular Level

Figures

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  Figure 1. Schematic illustrating the different markers of infiltration and the immune checkpoints reported for different malignancies including STSs. Reprinted with permission from reference [27]. TAM: tumor-associated macrophage. Immune cells in the tumor microenvironment might have immune-suppressive activity or exhibit anti-tumor responses. CD8+ cytotoxic T cells are activated via CD8/ MHC I/ T cell receptor (CD3 or TCR) complexes and helper T cells through the CD4/ MHC II/ TCR complex by dendritic cells. Helper T cells activate CD20+ B cells, inducing plasma cell differentiation and antibody class switching. Macrophages can be pro-inflammatory and anti-tumor CD68+ (M1), or anti-inflammatory and pro-tumor CD163+ (M2) macrophages. FOXP3+ regulatory T cells are immunosuppressive. Immune checkpoints such as PD-1, CTLA-4, TIM-3, and LAG-3 can be found on the surface of a variety of immune cells. The PD-1/PD-L1 axis and CD47/SIRPα axis are two immune checkpoint pathways that interact with tumor cells.

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  Figure 2. The workflow of metabolomics in sarcoma: both biofluids and tissue extract can be used as a whole or after metabolite extraction to reduce matrix complexity (steps 1–2); spectral data are first collected in a non-destructive way with samples by nuclear magnetic resonance followed by mass spectrometry, coupled either to gas chromatography or liquid chromatography (steps 3–4); both data from NMR and MS need extensive processing to resolve spectral overlapping and to quantify peak intensity, resulting in a table of calibrated peak intensities to be matched with metabolites with the aid of spectral databases (steps 5–6); univariate and multivariate statistics lead to candidate biomarkers being correlated with the pathologic state by pathway analysis and lab testing.

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  Figure 3. Decrease in citrulline level has been observed for many soft tissue sarcomas. Citrulline belongs to the arginine metabolic pathway: it is produced by enterocytes from glutamine and is released into the blood, where is taken up by the kidney for the synthesis of arginine or is transported to the liver where it participates in the transformation of ammonia to urea. Abbreviations: CPS, carbamoyl phosphate synthetase; ASS, argininosuccinate synthase; AL, argininosuccinate lyase; AR, arginase; OTC, ornithine transcarbamoylase.