Enhanced Ovarian Cancer Tumorigenesis and Metastasis by the Macrophage Colony-Stimulating Factor

Abstract

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.

Comparative secretome of ovarian serous carcinoma: Gelsolin in the spotlight

“…These proteins have previously been studied in ovarian cancer cells (19)(20)(21)(22)(23). CSF-1 may serve an important role in ovarian carcinogenesis, as it has the capacity to increase the invasive ability of ovarian cancer cells (24) and to promote metastasis (25). Furthermore, high expression levels of CSF-1 are associated with poor patient outcome, suggesting that this protein may be a potential biomarker and prognostic factor (20,21).…”

Posttranscriptional Suppression of Proto-Oncogene c-fms Expression by Vigilin in Breast Cancer

“…The Membrane Invasion Culture System (MICS) chamber was used to quantitate the degree of invasion of MDA-MB-231 and BT20 transiently transfected vigilin or HuR overexpressing or silenced clones. Assay details were similar to those described previously (43) except that breast cancer cells were cultured in the presence of 100 nM Dex and remained under starved conditions for transfection duration prior to the invasion and motility assays. Parent or transfected cells, 1 ϫ 10 5 per well in a 6-well plate, were seeded onto 10-m-pore filters coated with a human defined matrix containing 50 g/ml human laminin, 50 g/ml human collagen IV, and 2 mg/ml gelatin in 10 mM acetic acid.…”

Colony-stimulating factor 1 potentiates lung cancer bone metastasis

“…In rodents with ovarian or breast cancer, overexpression of CSF1 accelerated tumor progression and 1 metastasis. 8,9 Patients with lung cancer show increased circulating CSF1 and high levels correlate with tumor progression and poor prognosis. 10 Lung cancer cells including the human A549 lung adenocarcinoma cell line express CSF1R, CSF1 mRNA, and protein, and, in vitro, CSF1 increases A549 proliferation and invasion.…”