Disease relevance of SEMA3F

• Selective suppression of in vivo tumorigenicity by semaphorin SEMA3F in lung cancer cells [1].
• Semaphorin SEMA3F has a repulsing activity on breast cancer cells and inhibits E-cadherin-mediated cell adhesion [2].
• For example, SEMA3F, which binds specifically to NRP2, inhibits tumor angiogenesis and metastasis [3].
• Loss of heterozygosity at SEMA3B or SEMA3F was demonstrated in none of the benign tumors, 8% of borderline tumors, and 29% of carcinomas [4].
• Metastatic human melanoma cells were transfected with SEMA3F and implanted into mice; the resultant tumors did not metastasize [5].

High impact information on SEMA3F

• Consistent with semaphorin-mediated chemorepulsion of neurons, tumor cells expressing SEMA3F were chemorepulsive for vascular and lymphatic endothelial cells expressing neuropilin-2 (NRP2), a novel mechanism for a tumor angiogenesis inhibitor [5].
• We found that semaphorin 3F (SEMA3F) was markedly downregulated in highly metastatic human cell lines in vitro and in vivo, which suggested that it may be a metastasis inhibitor [5].
• Together these results indicate that SEMA3F is a potent metastasis inhibitor that targets both tumor and stromal cells and raise the possibility of SEMA3F having therapeutic potential [5].
• Semaphorins SEMA3B and its homologue SEMA3F are 3p21.3 candidate tumor suppressor genes (TSGs), the expression of which is frequently lost in lung cancers [6].
• We have identified two additional members of the human semaphorin family [human semaphorin A(V) and human semaphorin IV] in chromosome region 3p21.3, where several small cell lung cancer (SCLC) cell lines exhibit homozygous deletions indicative of a tumor suppressor gene [7].

Chemical compound and disease context of SEMA3F

• Thus, in this in vivo lung cancer model, SEMA3F has potent antitumor effects, which may impinge on activated integrin and MAPK signaling [1].

Biological context of SEMA3F

• In the present report, we investigated the attractive/repulsive effects of SEMA3F on cell migration when cells were grown in a three-dimensional system and exposed to a SEMA3F gradient [2].
• SEMA3F, isolated from a 3p21.3 deletion, has antitumor activity in transfected cells, and protein expression correlates with tumor stage and histology [8].
• By contrast, only 30-40% reduction in colony formation was seen after the transfection of SEMA3F or SEMA3B variants carrying lung cancer-associated single amino acid missense mutations [6].
• Two cDNAs corresponding to genes encoded on this P1 clone, semaphorin 3F (SEMA3F) and N23, were tested for their effects on in vitro and in vivo growth characteristics after transfection into mouse A9 cells [9].
• Moreover, SEMA3F also functioned to block apoptosis of transfected A9 cells treated with Taxol or Adriamycin [9].

Anatomical context of SEMA3F

• Using retroviral infections, we established stable SEMA3F transfectants in two NSCLC cell lines, NCI-H157 and NCI-H460 [1].
• 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 [8].
• In normal lung, SEMA3F was found in all epithelial cells at the cytoplasmic membrane and, to a lesser extent, in the cytoplasm [10].

Associations of SEMA3F with chemical compounds

• In cell lines, VEGF enhances adhesion and migration in an integrin-dependent manner, and exogenous SEMA3F causes cells to round and lose extracellular contacts [1].
• However, histone deacetylase inhibition with Trichostatin A was much more effective than 5-aza-2'-deoxycytidine in stimulating SEMA3F [11].

Physical interactions of SEMA3F

• These results suggest that VEGF and SEMA3F compete for binding to their common neuropilin receptor [2].

Other interactions of SEMA3F

• Neuropilin-2 is a receptor for semaphorin IV: insight into the structural basis of receptor function and specificity [12].
• In lung cancer patients, SEMA3F loss correlates with advanced disease and increased VEGF binding to tumor cells [1].
• Loss of the 3p21.3-encoded semaphorins, SEMA3B and SEMA3F, is implicated in lung cancer development [1].
• Following SEMA3F, Rac1 moved to the base of lamellipodia and - with their collapse - to the membrane [8].
• KLF2 attenuates cell migration by affecting multiple genes including VEGFR2 and the potent antimigratory SEMA3F [13].

Analytical, diagnostic and therapeutic context of SEMA3F

• To determine the timing of these events, we compared by immunohistochemistry VEGF, SEMA3F, NP1 and NP2 expression in 50 preneoplastic lesions and 112 lung tumours [14].
• In parallel studies, SEMA3F distribution was examined in cell cultures by confocal microscopy [10].

References