Semaphorin 4D expression is associated with a poor clinical outcome in cervical cancer patients

Liu, Huidong; Yang, Yanmei; Xiao, Jianbing; Yang, Shengsheng; Liu, Yan; Kang, Wenhui; Li, Xinlei; Zhang, Fengmin

doi:10.1016/j.mvr.2014.02.007

Cited by 43 publications

(34 citation statements)

References 32 publications

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“…Regulation of Rap1 or R-Ras activity by plexin-B1 normally requires stimulation with its ligand Sema4D (Oinuma et al, 2004; Wang et al, 2012), although this can be autocrine. For example, COS7 cells and cervical cancer cell lines express plexin-B1 and its ligand Sema4D (Damola et al, 2013; Liu et al, 2014), and thus Sema4D is likely to act in an autocrine manner to stimulate plexin-B1. In HeLa cells, we found that plexin-B2 induced some cell rounding in the absence of added ligand, suggesting that they secrete the plexin-B2 ligand Sema4C.…”

Section: Discussionmentioning

confidence: 99%

Rnd3-induced cell rounding requires interaction with Plexin-B2

McColl

Garg

Riou

et al. 2016

Journal of Cell Science

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Rnd proteins are atypical members of the Rho GTPase family that induce actin cytoskeletal reorganization and cell rounding. Rnd proteins have been reported to bind to the intracellular domain of several plexin receptors, but whether plexins contribute to the Rnd-induced rounding response is not known. Here we show that Rnd3 interacts preferentially with plexin-B2 of the three plexin-B proteins, whereas Rnd2 interacts with all three B-type plexins, and Rnd1 shows only very weak interaction with plexin-B proteins in immunoprecipitations. Plexin-B1 has been reported to act as a GAP for R-Ras and/or Rap1 proteins. We show that all three plexin-B proteins interact with R-Ras and Rap1, but Rnd proteins do not alter this interaction or R-Ras or Rap1 activity. We demonstrate that plexin-B2 promotes Rnd3-induced cell rounding and loss of stress fibres, and enhances the inhibition of HeLa cell invasion by Rnd3. We identify the amino acids in Rnd3 that are required for plexin-B2 interaction, and show that mutation of these amino acids prevents Rnd3-induced morphological changes. These results indicate that plexin-B2 is a downstream target for Rnd3, which contributes to its cellular function.

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Section: Discussionmentioning

confidence: 99%

Rnd3-induced cell rounding requires interaction with Plexin-B2

McColl

Garg

Riou

et al. 2016

Journal of Cell Science

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“…Plexins also participate in regulating angiogenesis. Plexins A1-A4 have been described as transducers of antiangiogenic signals conveyed by class-3 semaphorins such as sema3F, while the SEMA4D-PlexinB1 has been known as a potent inducer of angiogenesis and is associated with poor prognosis in various solid tumors (15,16). Angiogenesis and lymphangiogenesis intersect in the regulation of tumor microenvironment, and several recent studies also suggested that semaphorins may affect lymphangiogenesis (17,18).…”

Section: Introductionmentioning

confidence: 99%

Tumor-associated Lymphatic Endothelial Cells Promote Lymphatic Metastasis By Highly Expressing and Secreting SEMA4C

Wei

Yang

Liu

et al. 2017

Clinical Cancer Research

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Purpose: Lymphatic vessels are mainly regarded as passive conduits for the dissemination of cancer cells. In this study, we investigate whether and how the tumor-associated lymphatic vessels may play an active role in tumor metastasis.Experimental Design: In situ laser capture microdissection of lymphatic vessels followed by cDNA microarray analysis was used to determine the expression profiling of lymphatic endothelial cells (LEC). Gene expression levels and activity of signaling pathways were measured by real-time RT-PCR, ELISA, or immunoblotting. Lymphangiogenesis was assessed by IHC. Lymph node metastasis was measured using fluorescence imaging. The effects of SEMA4C on lymphangiogenesis in vitro were evaluated using migration assay and tube-formation assay of LECs.Results: Tumor-associated LECs are molecularly and functionally different from their normal counterparts. In addition to expressing high levels of membrane-bound SEMA4C, tumorassociated LECs also produced soluble SEMA4C (sSEMA4C). Increased serum sSEMA4C was detected in patients with breast cancer and cervical cancer. Patients with metastasis had much higher levels of serum sSEMA4C. sSEMA4C promoted lymphangiogenesis by activating PlexinB2-ERBB2 signaling in LECs, and promoted the proliferation and migration of tumor cells by activating PlexinB2-MET signaling, thus promoting lymphatic metastasis. Although the SEMA4C signaling pathways differ between LECs and tumor cells, RHOA activation was necessary for the effects of SEMA4C in both types of cells.Conclusions: Tumor-associated LECs produce sSEMA4C to promote lymphatic metastasis of tumors. Our results suggest that SEMA4C and RHOA might be potential therapeutic targets, and that higher serum sSEMA4C could be a marker for breast cancer and cervical cancer.

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“…The role of Sema4D produced by tumor cells in inducing tumor angiogenesis, invasiveness, and progression has been demonstrated in several malignancies, both in human and animal models, and correlates with poor prognosis (32)(33)(34)(35)(36)(37)(38). Sema4D overexpression has been described in a large number of human HNSCC tumor tissue samples and in a panel of primary and metastatic cell lines (32).…”

Section: /Lowmentioning

confidence: 99%

Human Head and Neck Squamous Cell Carcinoma–Associated Semaphorin 4D Induces Expansion of Myeloid-Derived Suppressor Cells

Younis

Han

Webb

2016

The Journal of Immunology

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One of the mechanisms by which malignancies can induce immune suppression is through the production of cytokines that affect the maturation and differentiation of inflammatory cells in the tumor microenvironment. Semaphorin 4D (Sema4D) is a proangiogenic cytokine produced by several malignancies, which has been described in the regulation of the immune system. In the present study, we examined the role of human head and neck squamous cell carcinoma (HNSCC)–secreted Sema4D on myeloid cell differentiation. CD33+ cells cultured in HNSCC cell line–derived conditioned medium differentiated into myeloid derived suppressor cells (MDSC) (CD33+CD11b+HLA-DR−/low). The addition of anti-Sema4D Ab to HNSCC conditioned medium significantly reduced the expansion of the MDSC population. Similarly, knockdown of Sema4D in an HNSCC cell line resulted in a loss of MDSC function as shown by a decrease in the production of the immune-suppressive cytokines arginase-1, TGF-β, and IL-10 by MDSC, concomitant with recovery of T cell proliferation and IFN-γ production following stimulation of CD3/CD28. Importantly, CD33+ myeloid and T cells cultured in conditioned medium of HNSCC cells in which Sema4D was knocked down promoted antitumor inflammatory profile, through recovery of the effector T cells (CD4+T-bet+ and CD8+T-bet+), as well as a decrease in regulatory T cells (CD4+CD25+FOXP3+). We also showed that Sema4D was comparable to GM-CSF in its induction of MDSC. Collectively, this study describes a novel immunosuppressive role for Sema4D in HNSCC through induction of MDSC, and it highlights Sema4D as a therapeutic target for future studies to enhance the antitumorigenic inflammatory response in HNSCC and other epithelial malignancies.

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Semaphorin 4D expression is associated with a poor clinical outcome in cervical cancer patients

Cited by 43 publications

References 32 publications

Rnd3-induced cell rounding requires interaction with Plexin-B2

Rnd3-induced cell rounding requires interaction with Plexin-B2

Tumor-associated Lymphatic Endothelial Cells Promote Lymphatic Metastasis By Highly Expressing and Secreting SEMA4C

Human Head and Neck Squamous Cell Carcinoma–Associated Semaphorin 4D Induces Expansion of Myeloid-Derived Suppressor Cells

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