Neuronal Repellent Slit2 Inhibits Dendritic Cell Migration and the Development of Immune Responses

Guan, Hongbing; Zu, Guorui; Xie, Yi; Tang, Hao; Johnson, Martin R.; Xu, Xiaochun; Kevil, Christopher G.; Xiong, Wen Cheng; Elmets, Craig A.; Rao, Yi; Wu, Jane Y.; Xu, Hui

doi:10.4049/jimmunol.171.12.6519

Cited by 85 publications

(88 citation statements)

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“…Two examples are slit2 and Sema3A that in addition to their role in angiogenesis and neuronal development are very potent inhibitors of dendritic cell activation and of the immune response. 167,168 However, it is not because tumor cells express some axon guidance proteins that their function in these cells is identical and it would probably be a mistake to directly apply models based on neurons to tumor cell biology. For instance, the semaphorin receptors appear to be distinct in the immune system and nervous system.…”

Section: Discussionmentioning

confidence: 99%

The brain within the tumor: new roles for axon guidance molecules in cancers

2005

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Slits, semaphorins and netrins are three families of proteins that can attract or repel growing axons and migrating neurons in the developing nervous system of vertebrates and invertebrates. Recent studies have shown that they are widely expressed outside the nervous system and that they may play important roles in cancers. Several of the genes encoding these proteins are localized on chromosomal region associated with frequent loss-of-heterozygosity in tumors and cancer cell lines and there is also significant hypermethylation of their promoter suggesting that they may act as tumor suppressors. In addition, proteins in all these families and their receptors appear to control the vascularization of the tumors. Last, many axon guidance molecules also regulate cell migration and apoptosis in normal and tumorigenic tissues. Overall, this suggests that molecules that could mimick or block the activity of axon guidance molecules may be used as therapeutic agents for the treatment of malignancy.

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Section: Discussionmentioning

confidence: 99%

The brain within the tumor: new roles for axon guidance molecules in cancers

2005

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“…The SLIT molecules (SLIT1, SLIT2 and SLIT3) bind with members of the roundabout, axon guidance receptor (ROBO) family of receptors and interact with heparan sulphate chains [16]. In retinal axons in vivo, SDF-1 has been shown to modulate SLIT and ROBO signalling [17], while in leucocytes SLIT2 may modulate SDF-1-mediated chemotaxis [14,18,19], transendothelial migration and adhesion of T cells [13], and migration of dendritic cells [15].…”

Section: Introductionmentioning

confidence: 99%

“…Members of the SLIT protein family are large glycoproteins that are important for nervous system development, but can be expressed by epithelial [14] and endothelial cells [15]. The SLIT molecules (SLIT1, SLIT2 and SLIT3) bind with members of the roundabout, axon guidance receptor (ROBO) family of receptors and interact with heparan sulphate chains [16].…”

Section: Introductionmentioning

confidence: 99%

SDF-1–CXCR4 differentially regulates autoimmune diabetogenic T cell adhesion through ROBO1–SLIT2 interactions in mice

et al. 2013

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Aims/hypothesis We had previously reported that stromal cellderived factor 1 (SDF-1) mediates chemorepulsion of diabetogenic T cell adhesion to islet microvascular endothelium through unknown mechanisms in NOD mice. Here we report that SDF-1-mediated chemorepulsion occurs through slit homologue (SLIT)2-roundabout, axon guidance receptor, homologue 1 (Drosophila) (ROBO1) interactions. Methods C-X-C receptor (CXCR)4 and ROBO1 protein expression was measured in mouse and human T cells. Parallel plate flow chamber adhesion and detachment studies were performed to examine the molecular importance of ROBO1 and SLIT2 for SDF-1-mediated T cell chemorepulsion. Diabetogenic splenocyte transfer was performed in NOD/LtSz Rag1 −/− mice to examine the effect of the SDF-1 mimetic CTCE-0214 on adoptive transfer of diabetes. Results CXCR4 and ROBO1 protein expression was elevated in diabetic NOD/ShiLtJ T cells over time and coincided with the onset of hyperglycaemia. CXCR4 and ROBO1 expression was also increased in human type 1 diabetic T cells, with ROBO1 expression maximal at less than 1 year post diagnosis. Cell detachment studies revealed that immunoneutralisation of ROBO1 prevented SDF-1-mediated chemorepulsion of NOD T cell firm adhesion to TNFα-stimulated islet endothelial cells. SDF-1 increased NOD T cell adhesion to recombinant adhesion molecules, a phenomenon that was reversed by recombinant SLIT2. Finally, we found that an SDF-1 peptide mimetic prevented NOD T cell adhesion in vitro and significantly delayed adoptive transfer of autoimmune diabetes in vivo. Conclusions/interpretation These data reveal a novel molecular pathway, which regulates diabetogenic T cell recruitment and may be useful in modulating autoimmune diabetes.

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“…[9][10][11][12] The interaction of Slits with Robo has a significant effect on axon guidance and neuronal migration. [13][14][15] …”

mentioning

confidence: 99%

“…[9][10][11][12] The interaction of Slits with Robo has a significant effect on axon guidance and neuronal migration. [13][14][15] Recently, Slit2 has been reported to play a significant role in carcinogenesis. Some studies have indicated that in human cancers, the Slit2 gene is frequently inactivated by hypermethylation in the promoter region or by allele loss in lung, breast, ovarian, 16 and colorectal cancers as well as malignant gliomas, [17][18][19] suggesting a tumor-suppressive role for Slit2.…”

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confidence: 99%

Slit2 promotes tumor growth and invasion in chemically induced skin carcinogenesis

Lan

et al. 2014

Laboratory Investigation

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Slit, a neuronal guidance cue, binds to Roundabout (Robo) receptors to modulate neuronal, leukocytic, and endothelial migration. Slit has been reported to have an important effect on tumor growth and metastasis. In the current study, we evaluated the role of Slit2 in skin tumor growth and invasion in mice using a two-step chemical carcinogenesis protocol. We found that Slit2 expression correlated with the loss of basement membrane in the samples of human skin squamous cell carcinoma at different stages of disease progression. Slit2-Tg mice developed significantly more skin tumors than wild-type mice. Furthermore, the skin tumors that occurred in Slit2-Tg mice were significantly larger than those in the wild-type mice 10 weeks after 7,12-dimethylbenz[a]anthracene initiation until the end of the experiment. We also found that pathological development of the wild-type mice was delayed compared with that of Slit2-Tg mice. To further investigate the mechanism of increasing tumors in Slit2-Tg mice, we analyzed the expression of 5-bromo-2 0 -deoxyuridine (BrdU) in mouse skin lesions and found that the number of BrdU-positive cells and microvessel density in skin lesions were significantly higher in Slit2-Tg mice than in wild-type mice. Histological staining of PAS and type IV collagen and the colocalization of Slit2 and type IV collagen demonstrated varying degrees of loss of the basement membrane in the skin lesions from Slit2-Tg mice that were at the stage of carcinoma in situ. However, the basement membrane was well defined in the wild-type mice. In addition, MMP2, but not MMP9, was upregulated in the skin tissue of Slit2-Tg mice. Interruption of Slit2-Robo1 signaling by the antibody R5 significantly repressed the invasive capability of the squamous cell carcinoma cell line A431. Taken together, our findings reveal that Slit2 promotes DMBA/TPA-induced skin tumorigenesis by increasing cell proliferation, microvessel density, and invasive behavior of cutaneous squamous cell carcinoma, along with loss of basement membrane, by upregulation of MMP2 expression. Skin cancer is one of the most common malignant tumors. Approximately 2 to 3 million cases of nonmelanoma skin cancer occur annually worldwide, and its incidence has been rising rapidly over the past several decades. 1 Skin cancer develops through a multistage process that includes initiation, promotion, and progression, as shown in experimental animal models. 2 The two-stage murine skin carcinogenesis model, which comprises two distinctly separate stages (initiation and promotion), is one of the most well-established in vivo models of experimental carcinogenesis. After 7, anthracene (DMBA) initiation, repeated applications of the tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) promote papillomas and eventually carcinomas. 3 Slit, a member of neuronal guidance cues, has been implicated to play an important role in tumor progression. 4 The Slit family consists of three members (Slit1, Slit2, and Slit3) that are expressed in the nervous system, whereas Slit...

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Neuronal Repellent Slit2 Inhibits Dendritic Cell Migration and the Development of Immune Responses

Cited by 85 publications

References 50 publications

The brain within the tumor: new roles for axon guidance molecules in cancers

The brain within the tumor: new roles for axon guidance molecules in cancers

SDF-1–CXCR4 differentially regulates autoimmune diabetogenic T cell adhesion through ROBO1–SLIT2 interactions in mice

Slit2 promotes tumor growth and invasion in chemically induced skin carcinogenesis

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