Semaphorins in cancer.
The semaphorins are the products of a large family of genes currently containing more than 30 members. These genes are divided into eight classes of which classes 1, 2 and 8 contain invertebrate and viral semaphorins, while classes 3-7 contain the vertebrate semaphorins. The semaphorins have been implicated in diverse developmental processes such as axon guidance during nervous system development and regulation of cell migration. Plexin receptors function as binding and signal transducing receptors for all semaphorins except for the class-3 semaphorins which bind to neuropilins which subsequently activate signaling through associated plexins. The class-3 semaphorins semaphorin-3B (s3b) and semaphorin-3F (s3f) function additionally as potent inhibitors of tumor development in small cell lung carcinoma. Recent evidence indicates that these semaphorins modulate the adhesive and migratory properties of responsive malignant cells. S3f as well as semaphorin-3A (s3a) were also found to function as inhibitors of angiogenesis, and it was shown that the anti-angiogenic properties of s3f contribute significantly to its anti-tumorigenic properties. In contrast with these inhibitory semaphorins, there is some evidence indicating that semaphorins such as semaphorin-3C (s3c), semaphorin-3E (s3e), semaphorin-4D (s4d), semaphorin-5C (s5c) semaphorin-6A (s6a) and semaphorin-6b (s6b) may contribute to tumorigenesis or to tumor progression. In this review we discuss the semaphorins, their receptors and their signal transduction mechanisms, and evidence linking semaphorins to the control of tumorigenesis and tumor progression.
Neufeld
Gera
G
Cancer and Vascular Biology Research Center, Rappaport Research Institute in the Medical Sciences, The Bruce Rappaport Faculty of Medicine, Technion, Israel Institute of Technology, Haifa, Israel. gera@techunix.technion.ac.il
Shraga-Heled
Niva
N
Lange
Tali
T
Guttmann-Raviv
Noga
N
Herzog
Yael
Y
Kessler
Ofra
O
D000818:Animals; D015815:Cell Adhesion Molecules / Q000737:chemistry; D045744:Cell Line, Tumor; D018450:Disease Progression; D006801:Humans; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D009389:Neovascularization, Pathologic; D009419:Nerve Tissue Proteins / Q000737:chemistry; D039921:Neuropilins / Q000737:chemistry; D039961:Semaphorins / Q000378:metabolism*; D015398:Signal Transduction
D015815:Cell Adhesion Molecules; D009419:Nerve Tissue Proteins; D039921:Neuropilins; D039961:Semaphorins; C091529:plexin