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Galectin-1 Promotes Vasculogenic Mimicry in Gastric Cancer by Upregulating EMT Signaling.

ABSTRACT: Background: Galectin-1 (Gal-1) expression was positively associated with vasculogenic mimicry (VM) in primary gastric cancer (GC) tissue, and that both Gal-1 expression and VM in GC tissue are indicators of poor prognosis. However, whether Gal-1 promotes VM, and by what mechanismsremains unknown. Methods: To investigate the underlying mechanisms,wound healing assay, proliferation assay, invasion assay, and three-dimensional culture were used to evaluate the invasion, metastasis and promoted VM formation effects of the Gal-1. We monitored the expression level of sociated proteins in GC tissues, cell lines in vitro and nude mice tumorigenicity in vivo by immunohistochemistry and western blot. Results: Gal-1 overexpression significantly promoted the proliferation, invasion, migration, and VM formation of MGC-803 cells. Gal-1 was associated with E-cadherin and vimentin in vitro and in clinical samples. The epithelial-to-mesenchymal transition (EMT) induced in MGC-803 cells by TGF-?1 was accompanied by Gal-1 activation and promotion of VM formation, while knockdown of Gal-1 reduced the response to TGF-?1, suggesting that Gal-1 promotes VM formation by activating EMT signaling. Overexpression of Gal-1 accelerated subcutaneous xenograft growth and facilitated pulmonary metastasis in athymic mice, enhanced the expression of EMT markers, and promoted VM formation in vivo. Conclusion: Our results indicated that Gal-1 promotes VM in GC by upregulating EMT signaling; thus, Gal-1 and this pathway are potential novel targets to treat VM in GC.

SUBMITTER: You X

PROVIDER: S-EPMC6856752 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Galectin-1 Promotes Vasculogenic Mimicry in Gastric Cancer by Upregulating EMT Signaling.

You Xiaolan X Liu Qinghong Q Wu Jian J Wang Yuanjie Y Dai Jiawen J Chen Dehu D Zhou Yan Y Lian Yanjun Y

Journal of Cancer 20191017 25

<b>Background</b>: Galectin-1 (Gal-1) expression was positively associated with vasculogenic mimicry (VM) in primary gastric cancer (GC) tissue, and that both Gal-1 expression and VM in GC tissue are indicators of poor prognosis. However, whether Gal-1 promotes VM, and by what mechanismsremains unknown. <b>Methods</b>: To investigate the underlying mechanisms,wound healing assay, proliferation assay, invasion assay, and three-dimensional culture were used to evaluate the invasion, metastasis and ...[more]

PMID: 31772662

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Project description:Vasculogenic mimicry (VM), a micro vessel-like structure formed by the cancer cells, plays a pivotal role in cancer malignancy and progression. Interleukin-1 beta (IL-1β) is an active pro-inflammatory cytokine and elevated in many tumor types, including breast cancer. However, the effect of IL-1β on the VM of breast cancer has not been clearly elucidated. In this study, breast cancer cells (MCF-7 and MDA-MB-231) were used to study the effect of IL-1β on the changes that can promote VM. The evidence for VM stimulated by IL-1β was acquired by analyzing the expression of VM-associated biomarkers (VE-cadherin, VEGFR-1, MMP-9, MMP-2, c-Fos, and c-Jun) via western blot, immunofluorescent staining, and Immunohistochemistry (IHC). Additionally, morphological evidence was collected via Matrigel-based cord formation assay under normoxic/hypoxic conditions and microvessel examination through Hematoxylin and Eosin staining (H&E). Furthermore, the STRING and Gene Ontology database was also used to analyze the VM-associated interacting molecules stimulated by IL-β. The results showed that the expression of VM biomarkers was increased in both MCF-7 and MDA-MB-231 cells after IL-1β treatment. The increase in VM response was observed in IL-1β treated cells under both normoxia and hypoxia. IL-1β also increased the activation of transcription factor AP-1 complex (c-Fos/c-Jun). The bioinformatics data indicated that p38/MAPK and PI3K/Akt signaling pathways were involved in the IL-1β stimulation. It was further confirmed by the downregulated expression of VM biomarkers and reduced formation of the intersections upon the addition of the signaling pathway inhibitors. The study suggests that IL-1β stimulates the VM and its associated events in breast cancer cells via p38/MAPK and PI3K/Akt signaling pathways. Aiming the VM-associated molecular targets promoted by IL-1β may offer a novel anti-angiogenic therapeutic strategy to control the aggressiveness of breast cancer cells.

Project description:Agents that target angiogenesis have shown limited efficacy for human triple-negative breast cancer (TNBC) in clinical trials. Along with endothelium-dependent vessels, there is also vasculogenic mimicry (VM) in the microcirculation of malignant tumors. The role of VM is not completely understood regarding anti-angiogenic treatment. In this study, human TNBC MDA-MB-231 and Hs578T and non-TNBC MCF-7 and BT474 tumor-bearing mice were treated with sunitinib, an anti-angiogenic drug, using a clinically relevant schedule. The drug was administered for one week and then discontinued. Tumor growth and invasion were observed, and the microcirculation patterns were detected with PAS/endomucin staining. Moreover, hypoxia and VM-associated proteins were evaluated with Hypoxyprobe kits and immunohistochemistry, respectively. Sunitinib significantly inhibited tumor growth in the TNBC and non-TNBC tumors. However, MDA-MB-231 and Hs578T tumors regrew and were more aggressive when the treatment was stopped. The discontinuation had no significant effect on the behavior of the non-TNBC MCF-7 and BT474 tumors. The growth of endothelium-dependent vessels in the TNBC MDA-MB-231 and Hs578T tumors were blocked by sunitinib, during which the number of VM channels significantly increased and resulted in a rebound of endothelium-dependent vessels after sunitinib discontinuation. Moreover, the VM-associated proteins VE-cadherin and Twist1 upregulated in the sunitinib-treated MDA-MB-231 and Hs578T tumors. Furthermore, the clinical significance of this upregulation was validated in 174 human breast cancers. The results from human breast cancer specimens indicated that there were more VM-positive TNBC cases than those in non-TNBC cases. HIF-1α, MMP2, VE-cadherin, and Twist1 were also expressed in a higher level in human TNBC compared with non-TNBC. In aconclusion, sunitinib promoted TNBC invasion by VM. The VM status could be helpful to predict the efficacy of anti-angiogenic therapy in patients with TNBC.

Dataset Information

Galectin-1 Promotes Vasculogenic Mimicry in Gastric Cancer by Upregulating EMT Signaling.

Publications

Galectin-1 Promotes Vasculogenic Mimicry in Gastric Cancer by Upregulating EMT Signaling.

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