RETRACTED ARTICLE: Semaphorin 4D cooperates with VEGF to promote angiogenesis and tumor progression

Zhou, Hua; Binmadi, Nada O.; Yang, Ying-Hua; Proia, Patrizia; Basile, John R.

doi:10.1007/s10456-012-9268-y

Cited by 66 publications

(54 citation statements)

References 53 publications

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“…Studies proved SEMA4D regulate blood vessel growth and endothelial cell homing during vessel development (Carmeliet et al, 2005). Zhou et al examined the contribution of SEMA4D to tumorinduced angiogenesis when compared to VEGF and suggested that targeting these proteins might represent a complementary or parallel mode of treatment for antiangiogenic therapy of HNSCC and other solid tumors exhibiting insensitivity of anti-VEGF therapy (Zhou et al, 2012). Notably, our previous study demonstrated overexpression of SEMA4D was positively correlated with EOC angiogenesis (Chen et al, 2012).…”

Section: Discussionmentioning

confidence: 85%

Overexpression of Semaphorin4D Indicates Poor Prognosis and Prompts Monocyte Differentiation toward M2 Macrophages in Epithelial Ovarian Cancer

Chen

Zhang²,

Lv³

et al. 2013

Asian Pacific Journal of Cancer Prevention

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Previously, we demonstrated overexpression of semaphorin4D (SEMA4D, CD100) to be closely related to tumor angiogenesis in epithelial ovarian cancers (EOCs). However, the function and expression of SEMA4D in the EOC microenvironment has yet to be clarified in detail. In this study, we confirmed that overexpression of SEMA4D in primary tumors and ascites was related to low differentiation, platinum resistance and a refractory status (P<0.05), while high M2 macrophage count and percentage were evident in EOC patients with advanced FIGO stage and platinum resistance (P<0.05), using immunohistochemistry, enzyme-linked immunosorbent assay (ELISA), and fluorescence-activated cell sorting (FACS), respectively. The data showed correlations of SEMA4D expression and M2 macrophage counts in primary tumors and M2 macrophage percentage in ascites (r=0.281 and 0.355, each P<0.05). In the Cox proportional hazard mode, SEMA4D expression was an independent indicator of overall survival (OS) and progression-free survival (PFS) for EOC patients. Furthermore, higher expression of SEMA4D in ovarian cancer cell lines (SKOV3, A2780, and SW626) and their supernatants were found than that in a human primary cultured ovarian cell and its supernatant by reversed transcript PCR (RT-PCR), Western blotting and ELISA, respectively. Interestingly, peripheral blood monocytes (MOs) tended towards the M2-polarized macrophage phenotype (CD163 high ) in vitro after human recombined soluble SEMA4D protein stimulation. These findings suggest that SEMA4D might possibly serve as a reliable tool for early and accurate prediction of EOC poor prognosis and could playan important role in promoting tumor dissemination and metastasis in the EOC microenvironment. Thus SEMA4D and its role in macrophage polarization in EOC warrants further study.

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Section: Discussionmentioning

confidence: 85%

Overexpression of Semaphorin4D Indicates Poor Prognosis and Prompts Monocyte Differentiation toward M2 Macrophages in Epithelial Ovarian Cancer

Chen

Zhang²,

Lv³

et al. 2013

Asian Pacific Journal of Cancer Prevention

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“…225,226 Because sema4D activates angiogenesis using the plexin-B1 receptor and not the VEGFR-2 receptor used by VEGF, it follows that sema4D can act additively with VEGF and that inhibition of sema4D signaling can represent an alternative anti-angiogenic treatment strategy. 227 Sema4D enhances the expression of PDGF-B and angiopoietin like protein-4 in endothelial cells which in turn inhibits the association between pericytes and endothelial cells thereby influencing proliferation and differentiation of pericytes and vascular permeability, whereas VEGF lacks these effects.…”

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confidence: 99%

The role of the semaphorins in cancer

Neufeld

Mumblat

Smolkin

et al. 2016

Cell Adhesion & Migration

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The semaphorins were initially characterized as axon guidance factors, but have subsequently been implicated also in the regulation of immune responses, angiogenesis, organ formation, and a variety of additional physiological and developmental functions. The semaphorin family contains more then 20 genes divided into 7 subfamilies, all of which contain the signature sema domain. The semaphorins transduce signals by binding to receptors belonging to the neuropilin or plexin families. Additional receptors which form complexes with these primary semaphorin receptors are also frequently involved in semaphorin signaling. Recent evidence suggests that semaphorins also fulfill important roles in the etiology of multiple forms of cancer. Some semaphorins have been found to function as bona-fide tumor suppressors and to inhibit tumor progression by various mechanisms while other semaphorins function as inducers and promoters of tumor progression. The semaphorin familyThe semaphorin family members are divided into 8 subclasses of which subclasses 1 and 2 contain invertebrate semaphorins while subclasses 3-7 contain the 22 vertebrate semaphorins. The 8th subclass contains viral semaphorins. In early publications, semaphorins were assigned confusing names. This situation was rectified by the adoption of a unified nomenclature in which sema is followed by the subclass number and by alphabetic designation within the subclass.1 Semaphorins are characterized by the presence of a »500 amino-acids long sema domain located close to their N-termini which is also present in semaphorin receptors of the plexin family, and by a plexin-semaphorin-integrin (PSI) domain located downstream to the sema domain. The sema domain is essential for semaphorin activity and plays a role in the determination of the receptor binding specificity.2 The sema domains of several different semaphorins were characterized by X-ray crystallography revealing a b propeller topology.3-5 Different semaphorin subclasses are characterized by class specific structural motifs. Thus, the vertebrate semaphorins belonging to classes 3, 4 and 7 contain immunoglobulin like domains, class-5 semaphorins contain thrombospondin repeats and class-3 semaphorins contain a basic domain. Class-3 semaphorins are the only vertebrate semaphorins produced as secreted proteins while other vertebrate semaphorins are membrane anchored or trans-membrane proteins that can be further processed into soluble forms by proteolytic cleavage (Fig.

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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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RETRACTED ARTICLE: Semaphorin 4D cooperates with VEGF to promote angiogenesis and tumor progression

Cited by 66 publications

References 53 publications

Overexpression of Semaphorin4D Indicates Poor Prognosis and Prompts Monocyte Differentiation toward M2 Macrophages in Epithelial Ovarian Cancer

Overexpression of Semaphorin4D Indicates Poor Prognosis and Prompts Monocyte Differentiation toward M2 Macrophages in Epithelial Ovarian Cancer

The role of the semaphorins in cancer

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

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