Abstract
Semaphorin 4D (Sema4D; CD100) is a transmembrane homodimer 150-kDa glycoprotein member of the Semaphorin family. Semaphorins were first identified as chemorepellants that guide neural axon growth. Sema4D also possesses immune regulatory activity. Recent data suggest other Sema4D functions: inactivation of platelets, stimulation of angiogenesis, and regulation of bone formation. Sema4D is a coupling factor expressed on osteoclasts that inhibits osteoblast differentiation. Blocking Sema4D may, therefore, be anabolic for bone. Sema4D and its receptor Plexin-B1 are commonly dysregulated in cancers, suggesting roles in cancer progression, invasion, tumor angiogenesis, and skeletal metastasis. This review focuses on Sema4D in bone and cancer biology and the molecular pathways involved, particularly Sema4D–Plexin-B1 signaling crosstalk between cancer cells and the bone marrow microenvironment—pertinent areas since a humanized Sema4D-neutralizing antibody is now in early phase clinical trials in cancers and neurological disorders.
Highlights
Semaphorin 4D (Sema4D; known as CD100), is a member of class IV of the Semaphorin protein family, with established functions as an immune regulator
We summarize the role of Sema4D/Plexin-B1 in cancers based on overexpression of Sema4D or Plexin-B1 by the cancer cells or by other cells in the tumor microenvironment including immune cells, and the role of Sema4D/Plexin-B1 in distant metastasis
Targeting Sema4D in the clinic has become practical with the development of a specific neutralizing antibody, which has low toxicity and an impressive response rate in early clinical trials of patients with refractory cancers
Summary
Semaphorin 4D (Sema4D; known as CD100), is a member of class IV of the Semaphorin protein family, with established functions as an immune regulator. (4) Yang et al [3] found that shRNA knockdown of Sema4D in MDA-MB-231 breast cancer cells decreased bone metastases in a standard xenograft model. Whether Sema4D/Plexin-B1 complexes activate or inhibit downstream GTPases depends on their interactions with specific receptor tyrosine kinases: ErbB-2 or c-Met [23].
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