The Wnt agonist R-spondin1 regulates systemic graft-versus-host disease by protecting intestinal stem cells

Takashima, Shuichiro; Kadowaki, Masanori; Aoyama, Kazutoshi; Koyama, Motoko; Oshima, Takeshi; Tomizuka, Kazuma; Akashi, Koichi; Teshima, Takanori

doi:10.1084/jem.20101559

Cited by 130 publications

(147 citation statements)

References 39 publications

(110 reference statements)

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“…Similar studies have also reported the overexpression of SALL4 in various malignancies (21)(22)(23). In breast cancer, it has been demonstrated that the SALL4 mRNA level is elevated in 86.1% of tumor samples (21).…”

Section: Discussionsupporting

confidence: 68%

Expression and clinical significance of SALL4 and LGR5 in patients with lung cancer

et al. 2015

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Abstract. Lung cancer is the most frequent cancer worldwide, in terms of incidence and mortality. Due to challenges in the diagnosis of the disease, the 5-year overall survival rate is only ~16%. Previous studies have suggested that malignant transformations originate from adult stem cells, and malignant lesions may therefore express stem-cell-associated markers. The purpose of the present study is to investigate the expression and clinical significance of the stem cell-associated markers Sal-like protein 4 (SALL4) and leucine-rich repeat-containing G-protein coupled receptor 5 (LGR5) in lung cancer, and to provide novel diagnostic markers and targets for the treatment of lung cancer. The expression of the stem cell-associated markers SALL4 and LGR5 was analyzed by immunohistochemistry performed on 135 human lung cancer tissue specimens and 10 non-cancer lung tissue specimens. The clinical significance of the expression of these markers and correlation between their expression and clinical parameters was also assessed. SALL4 expression was highly upregulated in lung cancer tissues, but was not present in non-cancerous lung tissues, and the sensitivity and specificity of SALL4 reached 88% and 100%, respectively. By contrast, LGR5 demonstrated 97% sensitivity, but the specificity was poor. Therefore, SALL4 may be an extremely useful diagnostic marker for lung cancer, but LGR5 is not as useful. IntroductionLung cancer is the most common cancer worldwide, in terms of incidence and mortality, as it comprises 17% of total novel cancer cases and 23% of the total global cancer mortalities (1). In order to improve the survival rate, it is important to diagnose and surgically excise lung cancer at an early stage of disease (2). Therefore, it is necessary to identify biomarkers with the potential to facilitate tumor diagnosis, particularly in the early stages of the disease. The cancer stem cell (CSC) theory proposes that tumors contain a small subpopulation of CSCs, which are responsible for tumor growth, invasion and metastasis (2). CSCs and normal tissue stem cells share important characteristics, including self-renewal, multipotency and unlimited proliferation, and potentially possess overlapping molecular mechanisms (3,4). Currently, a considerable number of stem cell-associated markers have been identified (2,3). Numerous studies have revealed that Sal-like protein 4 (SALL4) and leucine-rich repeat-containing G-protein coupled receptor 5 (LGR5) are also involved in the tumorigenesis, development and metastasis of various tumors (5-7), and these proteins are expected to become potential diagnostic markers and therapeutic targets in cancer.SALL4, a homolog of the Drosophila homeotic gene spalt, is a zinc-finger transcription factor that is required for the proliferation and maintenance of pluripotency through interaction with OCT3/4, sex determining region Y-box 2 and NANOG (8,9). SALL4 is also highly expressed in embryonic stem cells (8)(9)(10)(11)(12). Notably, SALL4 is also overexpressed in various types of human he...

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Section: Discussionsupporting

confidence: 68%

Expression and clinical significance of SALL4 and LGR5 in patients with lung cancer

et al. 2015

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“…19,20 We recently demonstrated that Paneth cells are targeted by GVHD, resulting in a subsequent alteration in the intestinal flora. 21,22 Other groups have also demonstrated a dramatic alteration in intestinal microbiota in GVHD, both in mice and in humans. [23][24][25] Metaplastic Paneth cells can express a-defensins, 17,26 and therefore Paneth cell metaplasia may be a compensatory mechanism for reduced number of Paneth cells in the small intestine and subsequent alteration of the intestinal microbiota.…”

Section: Resultsmentioning

confidence: 99%

Evaluating the association between histological manifestations of cord colitis syndrome with GVHD

Shimoji

Kato

Eriguchi

et al. 2013

Bone Marrow Transplant

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Cord colitis syndrome (CCS) is a recently proposed clinical entity characterized by a persistent diarrheal illness after cord blood transplantation (CBT), which is not caused by GVHD or CMV colitis. CCS is histologically characterized by chronic active colitis with granulomatous inflammation and Paneth cell metaplasia suggesting chronicity. However, the specificity of these pathological features to CCS remains to be validated. We conducted a retrospective study of 49 patients who had diarrhea and underwent diagnostic colonoscopy with biopsy following allogeneic hematopoietic SCT. None of the patients met the clinical criteria for CCS. Chronic active colitis with granulomatous inflammation and Paneth cell metaplasia was present in 12/33 (36%) patients with biopsy-proven GVHD, 4/6 (67%) patients with CMV colitis and 2/15 (13%) patients with nonspecific colitis. In patients with GVHD and/or CMV colitis, these pathological features were present in 4/8 (50%) patients after CBT and in 11/26 (42%) patients undergoing BMT or PBSCT. These results demonstrate that chronic active colitis with granuloma and Paneth cell metaplasia is not only a specific feature of CCS but also is present in GVHD and CMV colitis, irrespective of stem cell source.

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“…New studies also highlight the role of Wnt and its homolog partners R-spondins in autoimmune and inflammatory disease models including hepatic I/R injury (13,14). R-spo1 ameliorates inflammation-associated tissue damage in murine models of experimental colitis (14), graftversus-host disease (15), and arthritis (16) and may have clinical value. Considering the growing number of studies that implicate the beneficial role of R-spondins, we asked if these proteins could also prevent inflammation-associated tissue damage in ischemic disorders.…”

mentioning

confidence: 99%

R-spondin3 prevents mesenteric ischemia/reperfusion-induced tissue damage by tightening endothelium and preventing vascular leakage

Kannan

Kis-Tóth

Yoshiya

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Inflammation and vascular injury triggered by ischemia/reperfusion (I/R) represent a leading cause of morbidity and mortality in a number of clinical settings. Wnt and its homolog partners R-spondins, in addition to regulating embryonic development have recently been demonstrated to serve as wound-healing agents in inflammation-associated conditions. Here we ask whether R-spondins could prevent inflammation-associated tissue damage in ischemic disorders and thus investigate the role of R-spondin3 (R-spo3) in a mouse model of mesenteric I/R. We demonstrate that R-spo3 ameliorates mesenteric I/R-induced local intestinal as well as remote lung damage by suppressing local and systemic cytokine response and deposition of IgM and complement in intestinal tissues. We also show that decreased inflammatory response is accompanied by tightening of endothelial cell junctions and reduction in vascular leakage. We conclude that R-spo3 stabilizes endothelial junctions and inhibits vascular leakage during I/R and thereby mitigates the inflammatory events and associated tissue damage. Our findings uniquely demonstrate a protective effect of R-spo3 in I/R-related tissue injury and suggest a mechanism by which it may have these effects. permeability | tissue repair | organ damage | junctional integrity

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The Wnt agonist R-spondin1 regulates systemic graft-versus-host disease by protecting intestinal stem cells

Abstract: R-spondin1 stimulates the proliferation of intestinal stem cells through the Wnt signaling pathway and protects against graft-versus-host disease.

Cited by 130 publications

References 39 publications

Expression and clinical significance of SALL4 and LGR5 in patients with lung cancer

Expression and clinical significance of SALL4 and LGR5 in patients with lung cancer

Evaluating the association between histological manifestations of cord colitis syndrome with GVHD

R-spondin3 prevents mesenteric ischemia/reperfusion-induced tissue damage by tightening endothelium and preventing vascular leakage

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