High-risk gastrointestinal stromal tumour (GIST) and synovial sarcoma display similar angiogenic profiles: a nude mice xenograft study

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.

Chemokine Expression Is Involved in the Vascular Neogenesis of Ewing Sarcoma: A Preliminary Analysis of the Early Stages of Angiogenesis in a Xenograft Model

“…11 Although further studies are needed to corroborate these findings, present observations show that in sarcomas, a higher aggressive behavior is associated with an early overexpression of angiogenic factors. [11][12][13] In addition to angiogenic factors, chemokines also play an important role during angiogenic induction. The co-expression of ligands and chemokine receptors in neoplastic cells suggests that autocrine and paracrine stimulation by the tumor cells results in production of angiogenic factors in response to hypoxia during the first stages of tumor growth, as reported in other neoplastic and non-neoplastic conditions.…”

“…11 Although further studies are needed to corroborate these findings, present observations show that in sarcomas, a higher aggressive behavior is associated with an early overexpression of angiogenic factors. 11–13…”

“…9,10 We recently communicated these findings in a nude mice osteosarcoma model 11 as well as in two high-grade chondrosarcomas 12 and soft tissue sarcomas. 13 The angiogenic process presents two different phases of tumor growth: an initial induction phase, in which new unstable vessels are built, followed by a remodeling phase, in which blood vessels are stabilized. 5 During the initial phase, hypoxia occurs, and the angiogenic process is activated through the well-known HIFs that induce the expression of several tumor-derived cytokines, such as VEGF or fibroblast growth factors (FGFs) and some chemokines (growth-regulated oncogene [GRO], C-X-C motif chemokine ligand 9 [CXCL9], and C-X-C motif chemokine ligand 10 [CXCL10]) with their respective receptors (C-X-C motif chemokine receptor 2 [CXCR2] and C-X-C motif chemokine receptor 3 [CXCR3]).…”

Angiogenesis in gastrointestinal stromal tumors: From bench to bedside

“…Xenograft studies in mice constitute an invaluable source of evidence about the angiogenetic mechanisms in GISTs. Our fundamental conceptualization about the orchestration of the angiogenetic process descended from Giner et al [ 18 ]. They utilized an intensely CD117, DOG1 and CD34-positive GIST with continual Ki-67 expression in about 15% of the tumor’s mass.…”

“…As regards the chemokine expression, CXCL9, CXCL10, GRO and their receptors CXCR3, CXCR2 were stained in tumor cells and stroma soon after the implantation with a slight staining predominance of the chemokine receptors. These effects are possibly orchestrated by hypoxia-inducible factor (HIF)1α and the CXCL12/CXCR4 axis, which are constantly expressed[ 18 ].…”