Semaphorin SEMA3F and VEGF Have Opposing Effects on Cell Attachment and Spreading

Abstract

SEMA3F, isolated from a 3p21.3 deletion, has antitumor activity in transfected cells, and protein expression correlates with tumor stage and histology. In primary tumors, SEMA3F and VEGF surface staining is inversely correlated. Coupled with SEMA3F at the leading edge of motile cells, we previously suggested that both proteins competitively regulate cell motility and adhesion. We have investigated this using the breast cancer cell line, MCF7. SEMA3F inhibited cell attachment and spreading as evidenced by loss of lamellipodia extensions, membrane ruffling, and cell-cell contacts, with cells eventually rounding-up and detaching. In contrast, VEGF had opposite effects. Although SEMA3F binds NRP2 with 10-fold greater affinity than NRP1, the effects in MCF7 were mediated by NRP1. This was determined by receptor expression and blocking of anti-NRP1 antibodies. Similar effects, but through NRP2, were observed in the C100 breast cancer cell line. Although we were unable to demonstrate changes in total GTP-bound Rac1 or RhoA, we did observe changes in the localization of Rac1-GFP using time lapse microscopy. Following SEMA3F, Rac1 moved to the base of lamellipodia and - with their collapse - to the membrane. These results support the concept that SEMA3F and VEGF have antagonistic actions affecting motility in primary tumor cell.

Effects of SEMA3G on migration and invasion of glioma cells

“…In addition, overexpression of SEMA3F in tumor cells inhibits proliferation, prevents anchorage-independent growth (18)(19)(20) and potently inhibits tumorigenesis in vivo (16). Moreover, SEMA3F inhibits cell-spreading and migration in breast carcinoma (6), melanoma cells (21) and colorectal cancer cells (22). Taken together, these findings suggest that SEMA3A, SEMA3B, and SEMA3F inhibit tumor growth.…”

“…More recently, SEMA3s have been found to act as pleiotropic signals that are able to control multiple functions in tumor cells, ranging from survival, proliferation and apoptosis to cell adhesion and migration (4)(5)(6)(7). Of the SEMA3 family members, SEMA3A, SEMA3B, and SEMA3F have the best-described roles in tumor growth and metastasis.…”

SEMA3F (sema domain, immunoglobulin domain (Ig), short basic domain, secreted, (semaphorin) 3F)

“…SEMA3F also inhibits VEGF 165 and basic-FGFinduced ERK1/2 activation and EC proliferation (Kessler et al, 2004). Similarly, SEMA3F repels breast cancer cells and has an antagonistic effect on breast cancer cell spreading by VEGF 165 (Nasarre et al, 2003). Reduced b1 integrin or b3 integrin activation was found in melanoma cells (Bielenberg et al, 2004).…”

Sémaphorines et cancers : État des lieux

“…SEMA3F réduit d'environ 30 % la capacité de cellules NCI-H1299 de carcinomes pulmonaires à former des colonies [34], et l'application de SEMA3F exogène à des lignées de carcinomes mammaires réduit leur prolifération [35]. Ces mêmes lignées, après un traitement par SEMA3F, montrent également une diminution de l'étalement ainsi qu'une réduction de l'émission de prolongements membranaires suggérant une régulation de la motilité cellulaire [35,36]. Un gradient de SEMA3F a un effet répulsif sur les cellules migrantes qui expriment NRP2 [35].…”

“…Profil d'expression SEMA4D : exprimée dans cellules B (leucémies lymphocytaires chroniques) [24] SEMA3C : expression augmentée dans les carcinomes ovariens résistants au CDDP [21] SEMA3E : expression forte dans les lignées d'adénocarcinomes mammaires métastasiques [22] SEMA6B : expression diminuée dans une lignée de glioblastome traitée par l'acide rétinoïque tout-trans [23] SEMA4D : pas d'expression dans les cellules B (lymphomes non hodgkiniens) [47] SEMA3B : expression réduite dans les tumeurs pulmonaires [55] SEMA3F : niveau d'expression inversement corrélé au degré d'agressivité des tumeurs dans le poumon [32,33], variable dans les lignées pulmonaires [55] Modèle de culture cellulaire SEMA3C : stimulation de la survie cellulaire [21] SEMA3A : induction de l'apoptose [12], inhibition de la migration cellulaire [13,20,46], répulsion cellulaire [12] SEMA3B : induction de l'apoptose [34,[41][42][43], inhibition de la prolifération cellulaire [34] SEMA3F : inhibition de la prolifération cellulaire et répulsion cellulaire [35,36] Modèle animal SEMA5C : promoteur de croissance chez la drosophile [28] SEMA3B : inhibition de la croissance tumorale [43] SEMA3F : inhibition de la croissance tumorale [37][38][39], inhibition de la néo-vascularisation des tumeurs [38][39][40], inhibition des métastases [40] Tableau I. Rôle présumé de certaines sémaphorines dans la tumorigenèse. Seul l'effet anti-tumoral des sémaphorines de classe 3 a été validé à ce jour par des modèles animaux.…”