Semaphorin 3F, a chemorepulsant for endothelial cells, induces a poorly vascularized, encapsulated, nonmetastatic tumor phenotype.
Melanoma is the most lethal skin cancer. Most deaths from melanoma result from metastases. Semaphorins have been shown to inhibit neuronal and endothelial cell migration, but the effects of semaphorins on tumor metastasis have not been documented. 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. Metastatic human melanoma cells were transfected with SEMA3F and implanted into mice; the resultant tumors did not metastasize. Rather, the primary tumors resembled benign nevi characterized by large areas of apoptosis, diminished vascularity, inhibition of hyperplasia in overlying epidermal cells, and encapsulated tumor borders delineated by thick layers of fibroblasts and collagen matrix. This phenotype is in stark contrast to highly invasive, vascular mock-transfected tumors. In vitro, tumor cells expressing SEMA3F had a diminished capacity to adhere and migrate on fibronectin. 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. The repulsive activity was abrogated by NRP2 RNA interference. 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.
Bielenberg
Diane R
DR
Vascular Biology Program, Children's Hospital, Harvard Medical School, 300 Longwood Avenue, New Research Building 12210, Boston, Massachusetts 02115, USA.
Hida
Yasuhiro
Y
Shimizu
Akio
A
Kaipainen
Arja
A
Kreuter
Michael
M
Kim
Caroline Choi
CC
Klagsbrun
Michael
M
D000818:Animals; D017209:Apoptosis; D015152:Blotting, Northern; D015153:Blotting, Western; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D003094:Collagen / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D004797:Enzyme-Linked Immunosorbent Assay; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D020287:In Situ Nick-End Labeling; D008168:Lung / Q000473:pathology; D008207:Lymphatic Metastasis; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D008819:Mice, Nude; D009362:Neoplasm Metastasis; D009389:Neovascularization, Pathologic; D009419:Nerve Tissue Proteins / Q000378:metabolism / Q000502:physiology*; D039943:Neuropilin-2 / Q000378:metabolism; D010641:Phenotype; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000096:biosynthesis; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D014162:Transfection
D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D039943:Neuropilin-2; D019408:Platelet Endothelial Cell Adhesion Molecule-1; C491230:SEMA3F protein, human; D003094:Collagen