Abstract
BackgroundGastrointestinal stromal tumour (GIST) is the most common primary mesenchymal tumour of the gastrointestinal tract. Spindle cell monophasic synovial sarcoma (SS) can be morphologically similar. Angiogenesis is a major factor for tumour growth and metastasis. Our aim was to compare the angiogenic expression profiles of high-risk GIST and spindle cell monophasic SS by histological, immunohistochemical and molecular characterisation of the neovascularisation established between xenotransplanted tumours and the host during the initial phases of growth in nude mice.MethodsThe angiogenic profile of two xenotransplanted human soft-tissue tumours were evaluated in 15 passages in nude mice using tissue microarrays (TMA). Tumour pieces were also implanted subcutaneously on the backs of 14 athymic Balb-c nude mice. The animals were sacrificed at 24, 48, and 96 h; and 7, 14, 21, and 28 days after implantation to perform histological, immunohistochemical, and molecular studies (neovascularisation experiments).ResultsMorphological similarities were apparent in the early stages of neoplastic growth of these two soft-tissue tumours throughout the passages in nude mice and in the two neovascularisation experiments. Immunohistochemistry demonstrated overexpression of pro-angiogenic factors between 24 h and 96 h after xenotransplantation in both tumours. Additionally, neoplastic cells coexpressed chemokines (CXCL9, CXCL10, GRO, and CXCL12) and their receptors in both tumours. Molecular studies showed two expression profiles, revealing an early and a late phase in the angiogenic process.ConclusionThis model could provide information on the early stages of the angiogenic process in monophasic spindle cell SS and high-risk GIST and offers an excellent way to study possible tumour response to antiangiogenic drugs.
Highlights
High-grade sarcomas can be implanted into immunodeficient mice, where they grow as xenografts supported by the murine stroma blood supply [1]
Hypoxia occurs and the angiogenic process is activated through the well-known hypoxia-inducible transcription factors (HIF) that induce the expression of several tumour-derived cytokines, such as vascular endothelial growth factors (VEGF) or fibroblast growth factors (FGF) [6] and some chemokines (GRO, CXCL9, and CXCL10) with their respective receptors (CXCR2 and CXCR3) [8, 13, 14]
The importance of vascularisation in the context of Gastrointestinal stromal tumour (GIST) is the action mechanism of the second-generation drug sunitinib, which is based on the blockade of VEGF activity along with tyrosine kinase receptor blockade that has been used with success in some GIST patients [37, 38]
Summary
High-grade sarcomas can be implanted into immunodeficient mice, where they grow as xenografts supported by the murine stroma blood supply [1]. In which new unstable vessels are built, followed by a remodelling phase, in which blood vessels are stabilised [12] At this point, hypoxia occurs and the angiogenic process is activated through the well-known hypoxia-inducible transcription factors (HIF) that induce the expression of several tumour-derived cytokines, such as vascular endothelial growth factors (VEGF) or fibroblast growth factors (FGF) [6] and some chemokines (GRO, CXCL9, and CXCL10) with their respective receptors (CXCR2 and CXCR3) [8, 13, 14]. Our aim was to compare the angiogenic expression profiles of high-risk GIST and spindle cell monophasic SS by histological, immunohistochemical and molecular characterisation of the neovascularisation established between xenotransplanted tumours and the host during the initial phases of growth in nude mice
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