Platelet Microparticles Increase Pro-Angiogenic Properties of Prostate Cancer Cell Lines

Abstract 1147

Platelets are key players in hemostasis, but are also involved in fundamental processes of vascular biology as angiogenesis, tissue regeneration and tumor metastasis. Platelet Microparticles (PMP) are vesicular membrane fragments shed from activated platelets, containing the platelet cytoplasmic content with a typical platelet membrane.

Prostate cancer is the most frequently diagnosed noncutaneous cancer in men in western countries. A major factor of the life-threatening course of this disease is the high rate of metastasis. Circulating tumor cells encounter platelets and may activate them, resulting in a production of microparticles.

We have previously reported a pro angiogenic effect of PMP, both in vitro and in vivo. We also demonstrated that prostate cancer cells that were pre-incubated with PMP acquired invasive properties. This was shown by rapid and transient increase of MMP-2 mRNA level and increased secretion of metalloproteinase-2 (MMP-2) as demonstrated by gelatin zymography.

In the present study, in vivo experiments of injection of prostate cancer cells pre-incubated with PMP to the mouse tail vain showed more rapid localization of cancer cells to the lungs, compared to untreated cancer cells. Microarray assay of prostate cancer cells pre-incubated with PMP has revealed significant differences in transcriptional regulation of genes related to cell growth, survival, tumorigenicity, invasiveness, and angiogenesis that suggested a more aggressive feature of the cells. We then investigated effect of PMP on release of the pro-angiogenic cytokine IL-8 from prostate cancer cells. RT-PCR demonstrated that protein release was accompanied by increase of IL-8mRNA and changes in regulation of related transcription factors. We have shown the involvement of the signaling molecules PI3, p38 and ERK in synthesis and expression of IL-8 from prostate cancer cells and revealed the contribution of the platelet-derived lipid mediator sphingosine 1-phosphate (S1P) and angiopoietin 1 (Ang-1) to the process.

Better understanding of the role of PMP in cancer development and identification of the mechanisms responsible for prostate cancer progression and aggression by the tumor microenvironment may lead to the development of novel effective therapies for metastatic disease.