Thrombospondin 1 (TSP-1) is a matricellular protein involved in angiogenesis, inflammation and carcinogenesis. Colonic tumors developed in TSP-1 deficient (TSP-1-/-) mice after injections with axoxymethane (AOM) and induction of colitis by dextran sodium sulphate (DSS) showed accelerated angiogenesis and proliferation. Interestingly, fibroblasts isolated from these AOM/DSS tumors were able to develop fibrosarcomas when they were subcutaneously re-injected in TSP-1-/- mice. This study aims to reveal the metabolites and pathways promoting the malignant differentiation of these fibroblasts. These results might contribute to a better understanding of the role of fibroblasts within the tumor microenvironment.
Wild type (WT) and TSP-1-/- fibroblasts previously isolated from AOM/DSS tumors were subcutaneously injected in the flank of the mice. TSP-1-/- tumors (n = 5) and skin and subcutaneous tissues surrounding the lesions (n = 5) were collected for metabolomic analyses. As WT fibroblasts are unable to develop into tumors, the skin and subcutaneous tissues of the injection sites (n = 5) were collected as controls. Targeted analysis and absolute quantitation (3‐point calibration) was performed by using CE‐TOFMS and CE‐QqQMS. Statistical analysis reporting average, ratio and p‐value were obtained using the StatSuite software (Human Metabolome Technologies, Boston, MA)
A total of 116 metabolites were analysed and quantified. Tumors showed an increase in metabolites related with oxidative stress and differentiation of stromal cells. Intermediaries of the nitric oxide pathway and inhibitors of proliferation were depleted. Skin and subcutaneous tissue surrounding fibrosarcomas exhibited an excess of metabolites related with glycolysis and oxidation/reduction pathways; however, the same metabolites were decreased in WT skin.
This study uncovers key metabolic pathways in cancer and underlines the importance of stromal cells and matricellular proteins such as TSP-1 in carcinogenesis.
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All authors have declared no conflicts of interest.