Role of Class 3 Semaphorins and Their Receptors in Tumor Growth and Angiogenesis

Abstract

Class 3 semaphorins (SEMA3) were first identified as glycoproteins that negatively mediate neuronal guidance by binding to neuropilin and repelling neurons away from the source of SEMA3. However, studies have shown that SEMA3s are also secreted by other cell types, including tumor cells, where they play an inhibitory role in tumor growth and angiogenesis (specifically SEMA3B and SEMA3F). SEMA3s primarily inhibit the cell motility and migration of tumor and endothelial cells by inducing collapse of the actin cytoskeleton via neuropilins and plexins. Besides binding to SEMA3s, neuropilin also binds the protumorigenic and proangiogenic ligand vascular endothelial growth factor (VEGF). Although some studies attribute the antitumorigenic and antiangiogenic properties of SEMA3s to competition between SEMA3s and VEGF for binding to neuropilin receptors, several others have shown that SEMA3s display growthinhibitory activity independent of competition with VEGF. A better understanding of these molecular interactions and the role and signaling of SEMA3s in tumor biology will help determine whether SEMA3s represent potential therapeutic agents. Herein, we briefly review (a) the role of SEMA3s in mediating tumor growth, (b) the SEMA3 receptors neuropilins and plexins, and (c) the potential competition between SEMA3s and VEGF family members for neuropilin binding. (Clin Cancer Res 2009;15(22):6763-70)

Effects of SEMA3G on migration and invasion of glioma cells

“…Taken together, these findings suggest that SEMA3A, SEMA3B, and SEMA3F inhibit tumor growth. Although most members of the SEMA3s have been shown to be inhibitory, some promote tumor growth and metastasis (23). For instance, SEMA 3C promotes glomerular endothelial cell proliferation, adhesion, directional migration, and tube formation in vitro (24).…”

“…Although it is reported that overexpression of SEMA3G can inhibit breast cancer and melanoma growth and angiogenesis (8,25), its role in the inhibition of invasion and migration has not been reported. Because SEMA3s exert its function by interacting with its receptors neuropilins (NRP) and plexins (23) and SEMA3G receptor NRP2 participates in human glioma progression (26), we designed this study to determine the role of SEMA3G in glioma cell migration and invasion ability. In this study, we generated the SEMA3G stable expressing human glioblastoma U251 (U251MG) cell line and then examined the migratory and invasive behavior.…”

Progesterone and 1,25-Dihydroxyvitamin D3 Inhibit Endometrial Cancer Cell Growth by Upregulating Semaphorin 3B and Semaphorin 3F

“…SEMAs are glycoproteins that were originally described as mediators of neuronal guidance (10,11). Class 3 SEMAs (SEMA3) serve as key regulators of cellular processes, such as cell survival, proliferation, apoptosis, and migration (11,12).…”

“…Class 3 SEMAs (SEMA3) serve as key regulators of cellular processes, such as cell survival, proliferation, apoptosis, and migration (11,12). Both SEMA3F and SEMA3B are mapped to chromosome 3p21.3, a region of frequent loss in lung, breast, and endometrial cancers (13)(14)(15).…”

Frequent deletion of 3p21.1 region carrying semaphorin 3G and aberrant expression of the genes participating in semaphorin signaling in the epithelioid type of malignant mesothelioma cells

“…NRP1 can enhance the affinity of some VEGF isoforms to bind to VEGF-R2 (23,24). SEMA3s include seven family members; six of them bind to NRP1, NRP2, or to both receptors (25,26). SEMA3s play a dual inhibitory role on tumor angiogenesis and tumor growth.…”