Inhibition of solid tumor growth by Fas ligand-expressing myoblasts.
A major problem with standard treatments of solid tumors such as chemotherapy is that the effects are not localized to the tumor. As a result, normal tissue function is often severely impaired. Here we show that myoblasts from skeletal muscle that have been engineered with retroviral vectors to express Fas ligand (FasL) have potential as site-specific anti-tumor agents. FasL-expression by myoblasts was previously shown to lead to neutrophil-mediated immunodestruction, both of the cells and the surrounding tissue. Moreover, myoblasts expressing FasL induced apoptosis in Fas-expressing human tumor cells in vitro. These findings led us to investigate the possibility that myoblasts expressing FasL could serve as anti-tumor agents acting by both apoptotic and immunological mechanisms. The C57BL/6 lpr/lpr mouse primary myoblasts either expressing or not expressing murine FasL were co-injected with Fas-positive or Fas-negative human rhabdomyosarcoma cells into the tibialis anterior of immunodeficient mice. After 19-31 days, FasL-expressing myoblasts resulted in a marked accumulation of neutrophils and inhibited tumor growth in every case. By contrast, control myoblasts did not prevent significant tumor growth. The status of Fas expression by the tumor tissue in vivo was confirmed by immunostaining tumor sections with antibodies against Fas. Tumor inhibition was observed regardless of the presence or absence of Fas on the tumor cells, suggesting that in vivo, the induction of a neutrophil response is remarkably potent and sufficient to inhibit tumors.
Springer
M L
ML
Department of Molecular Pharmacology, Stanford University School of Medicine, California 94305-5332, USA.
Kraft
P E
PE
Blau
H M
HM
D000818:Animals; D017209:Apoptosis / Q000235:genetics; D002460:Cell Line; D053222:Fas Ligand Protein; D015972:Gene Expression Regulation, Neoplastic; D006131:Growth Inhibitors / Q000096:biosynthesis* / Q000502:physiology*; D006801:Humans; D008024:Ligands; D008562:Membrane Glycoproteins / Q000096:biosynthesis* / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D019463:Mice, Inbred MRL lpr; D008819:Mice, Nude; D016513:Mice, SCID; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000473:pathology* / Q000637:transplantation; D009368:Neoplasm Transplantation; D012208:Rhabdomyosarcoma / Q000737:chemistry / Q000378:metabolism* / Q000473:pathology*; D014162:Transfection; D014407:Tumor Cells, Cultured
C505661:FASLG protein, human; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D006131:Growth Inhibitors; D008024:Ligands; D008562:Membrane Glycoproteins