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Successful inhibition of tumor development by specific class-3 semaphorins is associated with expression of appropriate semaphorin receptors by tumor cells.

ABSTRACT: The class-3 semaphorins (sema3s) include seven family members. Six of them bind to neuropilin-1 (np1) or neuropilin-2 (np2) receptors or to both, while the seventh, sema3E, binds to the plexin-D1 receptor. Sema3B and sema3F were previously characterized as tumor suppressors and as inhibitors of tumor angiogenesis. To determine if additional class-3 semaphorins such as sema3A, sema3D, sema3E and sema3G possess anti-angiogenic and anti-tumorigenic properties, we expressed the recombinant full length semaphorins in four different tumorigenic cell lines expressing different combinations of class-3 semaphorin receptors. We show for the first time that sema3A, sema3D, sema3E and sema3G can function as potent anti-tumorigenic agents. All the semaphorins we examined were also able to reduce the concentration of tumor associated blood vessels although the potencies of the anti-angiogenic effects varied depending on the tumor cell type. Surprisingly, there was little correlation between the ability to inhibit tumor angiogenesis and their anti-tumorigenic activity. None of the semaphorins inhibited the adhesion of the tumor cells to plastic or fibronectin nor did they modulate the proliferation of tumor cells cultured in cell culture dishes. However, various semaphorins were able to inhibit the formation of soft agar colonies from tumor cells expressing appropriate semaphorin receptors, although in this case too the inhibitory effect was not always correlated with the anti-tumorigenic effect. In contrast, the anti-tumorigenic effect of each of the semaphorins correlated very well with tumor cell expression of specific signal transducing receptors for particular semaphorins. This correlation was not broken even in cases in which the tumor cells expressed significant concentrations of endogenous semaphorins. Our results suggest that combinations of different class-3 semaphorins may be more effective than single semaphorins in cases in which tumor cells express more than one type of semaphorin receptors.

SUBMITTER: Kigel B

PROVIDER: S-EPMC2538586 | biostudies-literature | 2008

REPOSITORIES: biostudies-literature

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Successful inhibition of tumor development by specific class-3 semaphorins is associated with expression of appropriate semaphorin receptors by tumor cells.

Kigel Boaz B Varshavsky Asya A Kessler Ofra O Neufeld Gera G

PloS one 20080926 9

The class-3 semaphorins (sema3s) include seven family members. Six of them bind to neuropilin-1 (np1) or neuropilin-2 (np2) receptors or to both, while the seventh, sema3E, binds to the plexin-D1 receptor. Sema3B and sema3F were previously characterized as tumor suppressors and as inhibitors of tumor angiogenesis. To determine if additional class-3 semaphorins such as sema3A, sema3D, sema3E and sema3G possess anti-angiogenic and anti-tumorigenic properties, we expressed the recombinant full leng ...[more]

PMID: 18818766

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Project description:BackgroundInitially characterized as axon guidance factors, semaphorins also have been implicated to have critical roles in multiple physiological and developmental functions, including the regulation of immune responses, angiogenesis, organ formation, and the etiology of multiple forms of cancer. Moreover, their contribution in immunity and the regulation of tumour microenvironment is becoming increasingly recognized. Here, we provide a comprehensive analysis of class-3 semaphorins, the only secreted family of genes among veterbrate semaphorins, in terms of their expression profiles and their association with patient survival. We also relate their role with immune subtypes, tumour microenvironment, and drug sensitivity using a pan-cancer study.ResultsExpression profiles of class-3 semaphorins (SEMA3s) and their association with patient survival and tumour microenvironment were studied in 31 cancer types using the TCGA pan-cancer data. The expression of SEMA3 family varies in different cancer types with striking inter- and intra- cancer heterogeneity. In general, our results show that SEMA3A, SEMA3C, and SEMA3F are primarily upregulated in cancer cells, while the rest of SEMA3s are mainly down-regulated in the tested tumours. The expression of SEMA3 family members was frequently associated with patient overall survival. However, the direction of the association varied with regards to the particular SEMA3 isoform queried and the specific cancer type tested. More specifically, SEMA3A and SEMA3E primarily associate with a poor prognosis of survival, while SEMA3G typically associates with survival advantage. The rest of SEMA3s show either survival advantage or disadvantage dependent on cancer type. In addition, all SEMA3 genes show significant association with immune infiltrate subtypes, and they also correlate with level of stromal cell infiltration and tumour cell stemness with various degrees. Finally, our study revealed that SEMA3 genes, especially SEMA3C and SEMA3F may contribute to drug induced cancer cell resistance.ConclusionsOur systematic analysis of class-3 semaphorin gene expression and their association with immune infiltrates, tumour microenvironment and cancer patient outcomes highlights the need to study each SEMA3 member as a separate entity within each specific cancer type. Also our study validated the identification of class-3 semaphorin signals as promising therapeutic targets in cancer although further laboratory validation still needed.

Project description: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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Successful inhibition of tumor development by specific class-3 semaphorins is associated with expression of appropriate semaphorin receptors by tumor cells.

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Successful inhibition of tumor development by specific class-3 semaphorins is associated with expression of appropriate semaphorin receptors by tumor cells.

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