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

Chen, Ying; Zhang, Lei; Lv, Rui; Zhang, Wenqi

doi:10.7314/apjcp.2013.14.10.5883

Cited by 36 publications

(33 citation statements)

References 30 publications

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“… 1 – 11 It was reported that tumors that overexpress Sema4D are highly aggressive with poor prognosis and not easy to control during treatment. 1 , 7 , 12 , 13 Emerging evidence indicates that Sema4D might promote tumor growth and angiogenesis. 8 , 9 , 14 , 15 On the other hand, small GTPase Ras homolog (Rho) proteins, including RhoA, are highly expressed in human cancers.…”

Section: Introductionmentioning

confidence: 99%

The role of semaphorin 4D in tumor development and angiogenesis in human breast cancer

Jiang¹,

Chen²,

Sun³

et al. 2016

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BackgroundSemaphorin 4D (Sema4D) is highly expressed in certain types of tumors and functions in the regulation of tumor angiogenesis and growth. However, it is still not clear regarding the roles of Sema4D in breast cancer. This study was designed to explore the effects of Sema4D on proliferation, cell cycle progression, apoptosis, invasion, migration, tumor growth, and angiogenesis in breast cancer.Materials and methodsThe expression level of Sema4D was investigated in MCF10A, 184A1, HCC1937, MDA-MB-468, MDA-MB-231, Hs578T, BT474, MCF-7, and T47D breast cancer cell lines by Western blotting analysis. Sema4D downregulation or overexpression was established by infection with lentiviruses-encoding Sema4D short hairpin RNA (shRNA) or Sema4D. To evaluate the effects of Sema4D on cell proliferation, cell cycle progression, apoptosis, invasion, and migration of MDA-MB-231 and MDA-MB-468 cells, methods including MTT assay, flow cytometry, wound healing assay, and transwell experiments were applied. BALB/c nude mice were injected with MDA-MB-231 cells, which were respectively infected with lentiviruses-encoding Sema4D, Sema4D shRNA, and GFP, followed by tumor angiogenesis assay.ResultsSema4D was expressed at higher levels in breast cancer cell lines compared with the normal human breast epithelial cell lines, especially in MDA-MB-231 and MDA-MB-468 cells. Cell proliferation ability was remarkably inhibited in Sema4D downregulated condition, whereas the proportions of cells in the G0/G1 phase and apoptosis increased in MDA-MB-231 and MDA-MB-468 cells. In addition, the invasion and migration abilities of these cells were obviously reduced. Xenograft growth as well as angiogenesis was inhibited when infected with lentiviruses-encoding Sema4D shRNA in vivo.ConclusionDownregulation of Sema4D had notable influence on cell proliferation ability, invasion, migration, and apoptosis of both MDA-MB-231 and MDA-MB-468 cells. Furthermore, infection with lentiviruses-encoding Sema4D shRNA obviously inhibited tumor growth and angiogenesis in BALB/c nude mice. Our results showed that Sema4D may represent a novel therapeutic target for human breast cancer.

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Section: Introductionmentioning

confidence: 99%

The role of semaphorin 4D in tumor development and angiogenesis in human breast cancer

Jiang¹,

Chen²,

Sun³

et al. 2016

OTT

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“…Sema4D enhances the recruitment of monocytes and promotes the differentiation of monocytes toward the M2 phenotype of macrophages, and in ovarian cancer is a marker of poor prognosis. 231 In another study it was observed that inhibitory sema4D antibodies enhance the recruitment of activated monocytes and lymphocytes into tumors in murine Colon26 and ErbB2…”

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confidence: 98%

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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“…Activates NF-KappaB and IL-8 to promote a pro-angiogenic response in endothelial cells 77 Promotes growth and invasion in HeLa cells 164 Promotes perineural invasion in a RhoA/ROK-dependent manner 80 Overexpression is related to poor prognosis in ovarian cancer 165 Suppresses c-Met activation and migration and promotes melanocyte survival 166 Cooperates with VEGF to promote angiogenesis and tumor progression 79 Over expression as a poor prognosis marker in ovarian cancer and promotes monocyte differentiation towards M2 macrophage 167 Promotes proliferation, migration and invasion in lung cancer cells 168 Recruits pericyte and regulates vascular permeability through endothelial production of PDGF-B and ANGPLT4 71 Promotes osteosarcoma development and metastasis 72 Blocking Sema4D with monoclonal anti Sema4D antibody promotes immune infiltration into tumor and enhances response to various other immunomodulatory therapies 85 Induction of expansion of myeloid derived suppressor cells by Sema4D derived from Head and Neck Squamous Cell Carcinoma 169…”

Section: Sema4dmentioning

confidence: 98%

Transmembrane semaphorins: Multimodal signaling cues in development and cancer

Gurrapu

Tamagnone

2016

Cell Adhesion & Migration

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Semaphorins constitute a large family of membrane-bound and secreted proteins that provide guidance cues for axon pathfinding and cell migration. Although initially discovered as repelling cues for axons in nervous system, they have been found to regulate cell adhesion and motility, angiogenesis, immune function and tumor progression. Notably, semaphorins are bifunctional cues and for instance can mediate both repulsive and attractive functions in different contexts. While many studies focused so far on the function of secreted family members, class 1 semaphorins in invertebrates and class 4, 5 and 6 in vertebrate species comprise around 14 transmembrane semaphorin molecules with emerging functional relevance. These can signal in juxtacrine, paracrine and autocrine fashion, hence mediating long and short range repulsive and attractive guidance cues which have a profound impact on cellular morphology and functions. Importantly, transmembrane semaphorins are capable of bidirectional signaling, acting both in "forward" mode via plexins (sometimes in association with receptor tyrosine kinases), and in "reverse" manner through their cytoplasmic domains. In this review, we will survey known molecular mechanisms underlying the functions of transmembrane semaphorins in development and cancer.

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

Cited by 36 publications

References 30 publications

The role of semaphorin 4D in tumor development and angiogenesis in human breast cancer

The role of semaphorin 4D in tumor development and angiogenesis in human breast cancer

The role of the semaphorins in cancer

Transmembrane semaphorins: Multimodal signaling cues in development and cancer

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