Enhanced ovarian cancer tumorigenesis and metastasis by the macrophage colony-stimulating factor.
Coexpression of the macrophage colony-stimulating factor (CSF-1) and its receptor (CSF-1R) in metastatic ovarian cancer specimens is a predictor of poor outcome in epithelial ovarian cancer. This suggests that an autocrine loop is produced by which ovarian tumors can secrete CSF-1 stimulating the CSF-1R resulting in a more aggressive phenotype. Our current work sought to validate this autocrine stimulation model using stable transfection of a 4-kb CSF-1 construct into otherwise nonvirulent Bix3 ovarian cancer cells. A representative clone, Bix3T8.2, produced a 72-fold increase in CSF-1 gene transcription rate (by nuclear run-off assays) and a 57-fold increase in secreted CSF-1 protein (by sandwich ELISA), compared to parent cells. Comparison of Bix3T8.2 invasion, adhesion, and motility in vitro and metastasis in vivo were made to parental and transfectant controls. Up to 12-fold higher invasiveness was seen with Bix3T8.2 and 2- and 6-fold higher adhesion and motility, respectively, over controls in vitro. In nude mice, i.p. injection of Bix3T8.2 produced a wide array of visceral, nodal, and distant metastasis with a degree of enhanced tumor burden not seen in any of the 10 mice inoculated with transfectant control cells. Complete absence of tumor take distinguished 40% of mice implanted with transfectant control cells. Disruption of this autocrine loop using antisense oligomer therapy against CSF-1R and 3' untranslated region knockdown of CSF-1 protein resulted in reversal of in vitro and in vivo tumor phenotypes. This CSF-1 feedback loop offers a model by which novel biologic therapies can potentially target multiple levels of this pathway.
Toy
Eugene P
EP
Department of Obstetrics and Gynecology, University of Rochester, Rochester, NY, USA.
Azodi
Masoud
M
Folk
Nancy L
NL
Zito
Christina M
CM
Zeiss
Caroline J
CJ
Chambers
Setsuko K
SK
D000818:Animals; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D002448:Cell Adhesion; D002465:Cell Movement; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D005260:Female; D006801:Humans; D016173:Macrophage Colony-Stimulating Factor / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis / Q000473:pathology*; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000473:pathology; D016376:Oligonucleotides, Antisense / Q000627:therapeutic use; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000473:pathology*; D010641:Phenotype; D016186:Receptor, Macrophage Colony-Stimulating Factor / Q000187:drug effects / Q000235:genetics; D014407:Tumor Cells, Cultured
D014408:Biomarkers, Tumor; D016376:Oligonucleotides, Antisense; D016173:Macrophage Colony-Stimulating Factor; D016186:Receptor, Macrophage Colony-Stimulating Factor