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Published on: August 14, 2017
Platelet-activating factor inactivation by local expression of platelet-activating factor acetyl-hydrolase modifies
Luigi Biancone1, Vincenzo Cantaluppi, Lorenzo Del Sorbo
1Department of Internal Medicine, University of Turin, Corso Dogliotti 14, 10126 Turin, Italy.
Purpose:
Platelet-activating factor (PAF), a phospholipid mediator of inflammation, has been recently detected on tumor cells but its effect in tumor development is largely undefined.
Experimental Design:
To address its potential role in tumor biology, we inhibited intratumor PAF activity by engineering tumor cell lines to express plasma PAF-acetylhydrolase (PAF-AH), the major PAF-inactivating enzyme, and studied their behavior in vitro and in vivo.
Results:
When transfected with PAF-AH, KS-Imm human Kaposi's sarcoma cells implanted in SCID mice and B16F10 mouse melanoma cells implanted in syngenic C57Bl/6J mice showed significantly reduced vascularization and growth allowing longer survival compared with control tumors. The amounts of bioactive PAF extracted from PAF-AH-transfected tumors were significantly reduced. In vitro, expression of PAF-AH did not influence cell proliferation, whereas it inhibited PAF-dependent cell motility in Kaposi's sarcoma cells that express PAF-receptor but not in melanoma cells that did not express it. On the other hand, PAF-induced endothelial tubulogenesis in Matrigel was inhibited by incubation with supernatant from PAF-AH-transfected melanoma cells, indicating that PAF-AH inhibits in vitro neoangiogenesis.
Conclusions:
We demonstrated that in situ PAF inactivation affects tumor vascularization and growth through inhibition of neoangiogenesis and, in the case of cells expressing PAF receptor, also tumor cell motility.
Insights
Inhibiting platelet-activating factor (PAF) in tumors reduced vascularization and growth. This demonstrates PAF inactivation
Area of Science:
- Oncology
- Immunology
- Biochemistry
Background:
- Platelet-activating factor (PAF) is a phospholipid mediator involved in inflammation.
- PAF has been detected on tumor cells, but its role in tumor development is not well understood.
Purpose of the Study:
- To investigate the role of PAF in tumor biology.
- To determine the effect of inhibiting intratumor PAF activity on tumor growth and vascularization.
Main Methods:
- Engineered tumor cell lines to express plasma PAF-acetylhydrolase (PAF-AH), a PAF-inactivating enzyme.
- Studied the in vitro and in vivo behavior of these engineered tumor cells.
- Quantified bioactive PAF levels in tumors and assessed tumor vascularization, growth, and cell motility.
Main Results:
- Tumors engineered with PAF-AH showed significantly reduced vascularization and growth, leading to longer survival in mouse models.
- In vitro, PAF-AH expression inhibited PAF-dependent cell motility in Kaposi's sarcoma cells but not melanoma cells.
- PAF-induced endothelial tubulogenesis was inhibited by PAF-AH, indicating its role in neoangiogenesis.
Conclusions:
- In situ inactivation of PAF significantly impacts tumor vascularization and growth.
- Inhibition of neoangiogenesis is a key mechanism by which PAF inactivation affects tumors.
- PAF receptor expression influences the effect of PAF inactivation on tumor cell motility.
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