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The role of semaphorin 4D as a potential biomarker for antiangiogenic therapy in colorectal cancer.

ABSTRACT: BACKGROUND:Semaphorin 4D (Sema4D) belongs to the class IV semaphorins, and accumulating evidence has indicated that its elevated level may be one strategy by which tumors evade current anti-angiogenic therapies. The biological roles of Sema4D in colorectal cancer (CRC), however, remain largely undefined. This study was designed to investigate the effects of Sema4D on tumor angiogenesis and growth in CRC, especially in different vascular endothelial growth factor (VEGF) backgrounds. METHODS:The expression of Sema4D in human CRC was evaluated by immunohistochemical analysis of tumors and their matching normal control tissues. The expression level of Sema4D and VEGF was investigated in different CRC cell lines. To evaluate the contributions of Sema4D to tumor-induced angiogenesis, two CRC cell lines with opposite VEGF backgrounds were infected with lentiviruses expressing Sema4D or Sema4D short hairpin RNA, followed by in vitro migration and in vivo tumor angiogenic assays. RESULTS:Immunohistochemical analysis of human CRC revealed high levels of Sema4D in a cell surface pattern. In all, 84.85% of CRC samples analyzed exhibited moderate to strong Sema4D expression. The positive ratios of Sema4D staining for well, moderately, and poorly differentiated cancers were 71.43%, 96.67%, and 77.27%, respectively. Sema4D is highly expressed in five different CRC cell lines, while VEGF expression level varies among these cell lines. HCT-116 showed the lowest VEGF level, while Caco-2 showed the maximum VEGF level. In vitro migration results show that regardless of cell type and VEGF background, Sema4D showed an enhanced in vitro proangiogenic effect to induce the migration of human umbilical vein endothelial cells. Finally, in vivo tumor angiogenic assays demonstrated that Sema4D alone can elicit a significant angiogenic response to promote tumor growth independently of VEGF. CONCLUSION:Targeting Sema4D might serve as a parallel option for antiangiogenic therapy for CRC, particularly when traditional anti-VEGF therapies fail or tumors develop resistance to strategies targeting a single angiogenic signaling pathway.

SUBMITTER: Ding X

PROVIDER: S-EPMC4789851 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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The role of semaphorin 4D as a potential biomarker for antiangiogenic therapy in colorectal cancer.

Ding Xiaojie X Qiu Lijuan L Zhang Lijuan L Xi Juemin J Li Duo D Huang Xinwei X Zhao Yujiao Y Wang Xiaodang X Sun Qiangming Q

OncoTargets and therapy 20160308

<h4>Background</h4>Semaphorin 4D (Sema4D) belongs to the class IV semaphorins, and accumulating evidence has indicated that its elevated level may be one strategy by which tumors evade current anti-angiogenic therapies. The biological roles of Sema4D in colorectal cancer (CRC), however, remain largely undefined. This study was designed to investigate the effects of Sema4D on tumor angiogenesis and growth in CRC, especially in different vascular endothelial growth factor (VEGF) backgrounds.<h4>Me ...[more]

PMID: 27022279

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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.

Dataset Information

The role of semaphorin 4D as a potential biomarker for antiangiogenic therapy in colorectal cancer.

Publications

The role of semaphorin 4D as a potential biomarker for antiangiogenic therapy in colorectal cancer.

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