title: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Institute of Medical Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Kunming, People's Republic of China; Molecular Epidemiology Joint Laboratory, Yunnan Key Laboratory of Vaccine Research & Development on Severe Infectious Diseases, Kunming, People's Republic of China.
authors.forename: Xiaojie
authors.initials: X
authors.lastname: Ding
authors.affiliation: Institute of Medical Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Kunming, People's Republic of China; Molecular Epidemiology Joint Laboratory, Yunnan Key Laboratory of Vaccine Research & Development on Severe Infectious Diseases, Kunming, People's Republic of China.
authors.forename: Lijuan
authors.initials: L
authors.lastname: Qiu
authors.affiliation: Department of Pathology, The Third Affiliated Hospital of Kunming Medical University (Yunnan Provincial Tumor Hospital), Kunming, People's Republic of China.
authors.forename: Lijuan
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Institute of Medical Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Kunming, People's Republic of China; Molecular Epidemiology Joint Laboratory, Yunnan Key Laboratory of Vaccine Research & Development on Severe Infectious Diseases, Kunming, People's Republic of China.
authors.forename: Juemin
authors.initials: J
authors.lastname: Xi
authors.affiliation: Institute of Medical Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Kunming, People's Republic of China; Molecular Epidemiology Joint Laboratory, Yunnan Key Laboratory of Vaccine Research & Development on Severe Infectious Diseases, Kunming, People's Republic of China.
authors.forename: Duo
authors.initials: D
authors.lastname: Li
authors.affiliation: Institute of Medical Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Kunming, People's Republic of China; Molecular Epidemiology Joint Laboratory, Yunnan Key Laboratory of Vaccine Research & Development on Severe Infectious Diseases, Kunming, People's Republic of China.
authors.forename: Xinwei
authors.initials: X
authors.lastname: Huang
authors.affiliation: Institute of Medical Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Kunming, People's Republic of China; Molecular Epidemiology Joint Laboratory, Yunnan Key Laboratory of Vaccine Research & Development on Severe Infectious Diseases, Kunming, People's Republic of China.
authors.forename: Yujiao
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Institute of Medical Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Kunming, People's Republic of China; Molecular Epidemiology Joint Laboratory, Yunnan Key Laboratory of Vaccine Research & Development on Severe Infectious Diseases, Kunming, People's Republic of China.
authors.forename: Xiaodang
authors.initials: X
authors.lastname: Wang
authors.affiliation: Institute of Medical Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Kunming, People's Republic of China; Molecular Epidemiology Joint Laboratory, Yunnan Key Laboratory of Vaccine Research & Development on Severe Infectious Diseases, Kunming, People's Republic of China.
authors.forename: Qiangming
authors.initials: Q
authors.lastname: Sun
keywords: VEGF; angiogenesis; colorectal cancer; migration; semaphorin 4D; xenografts