Platelet‐derived microparticles promote invasiveness of prostate cancer cells via upregulation of MMP‐2 production

Abstract

Prostate cancer commonly affects men in the Western world. A major factor of the life-threatening course of this disease is the high rate of metastasis, predominantly to bones. Circulating tumor cells encounter platelets and may activate them, resulting in a production of microparticles (MPs). MPs are small platelet fragments expressing membrane receptors as well as cytoplasmic constituents. Here, we report that prostate cancer cells, Clone-1 (Cl-1), preincubated with platelet-derived MPs (PMPs), demonstrate increased invasion through a gelatin-coated (a denatured form of collagen) membrane of the Boyden chamber system. This effect was accompanied by an increased secretion of metalloproteinase-2 (MMP-2) as demonstrated by a gelatin zymography. Application of MMP-2/9 inhibitor reversed the PMP-induced tumor cell invasion. PMPs were shown to adhere to Cl-1 cells, but direct contact between them may not be mandatory for MMP secretion because PMP lysate induced MMP-2 production by Cl-1 cells to the same extent as did intact PMPs. PMP-induced MMP-2 secretion was inhibited by neutralization of either PKC or total intracellular tyrosine phosphorylation, but was not affected by blocking major intraplatelet cytokines. Actinomycin D (a transcription inhibitor) did not modify this effect, whereas cycloheximide (an inhibitor of protein translation) abolished the MMP-2 release. MMP-2 secretion was accompanied by a rapid and transient increase in MMP-2 mRNA level after a 2-hr coincubation of prostate cancer cells with PMPs. Thus, PMPs promote tumor invasiveness, at least in part by stimulation of MMP-2 production. ' 2008 Wiley-Liss, Inc.Key words: platelet-derived microparticles; prostate cancer; MMP-2 Platelet involvement in dissemination of tumor metastasis was first experimentally demonstrated several decades ago. 1 Potential mechanisms of the platelet effect on metastatic dissemination include PAR receptors, platelet-derived lysophosphatidic acid and others. 2,3 Platelets were previously shown to directly mediate tumor cell adhesion to the vascular wall thus facilitating their future egress into tissues. 4 However, functional platelet depletion several weeks after tumor inoculation also results in reduction of metastasis, 3 an effect that cannot be explained by decreased tumor cell survival or extravasation. In addition, platelets may serve as a source of numerous proangiogenic cytokines that support growth of new capillaries in the vicinity of metastasis. 5 Angiogenesis is a prerequisite for tumor growth. 6 The ability of platelets as a cellular system to induce angiogenesis in spite of numerous antiangiogenic compounds in their alpha-granules has recently been demonstrated. 7,8 Matrix metalloproteinases (MMPs) belong to a family of zinccontaining enzymes that are tightly involved in the angiogenic process as well as in tumor cell extravasation and metastasis. 9 Among this group of endopeptidases, MMP-2 and MMP-9 are considered most important for metastatic spread. Both enzymes cleave collagen that constitutes a major co...

Microparticles, Vascular Function, and Atherothrombosis

“…As detailed below (see paragraph on fibrous cap weakening), human plaque MPs harbor active proteases 116 and MPs of different cellular origin are able to induce the release of metalloproteases by different cell types. [117][118][119][120] Third, MPs regulate endothelial proliferation and capillary tube formation. Human plaque MPs isolated from endarterectomy specimens surgically obtained from patients increase endothelial cell proliferation in vitro as well as in vivo in matrigel plugs.…”

“…Platelet-derived MPs stimulate the secretion of active MMP-2 by prostate cancer cells. 117 Furthermore, T cells and monocytes MPs induce the synthesis of MMP-1, MMP-3, MMP-9, and MMP-13 in fibroblasts. 118 Finally, T-cell-derived MPs upregulate MMP-1, MMP-3, MMP-9, and MMP-13 genes in hepatic stellate cells.…”

Platelet Regulation of Angiogenesis, Tumor Growth and Metastasis

“…The mechanisms behind these effects are not fully understood and still under investigation. However, it has been suggested that platelet-derived microparticles might induce tumor secretion of various matrix-metalloproteinases, facilitating the metastatic process (Dashevsky et al, 2009) (Janowska-Wieczorek et al, 2005. A study on the role of platelet-derived microparticles for metastatic capacity in lung cancer revealed that there might as well be direct effects on both tumor cell proliferation and adhesion to fibrinogen and endothelial cells (JanowskaWieczorek et al, 2005).…”

The Application of Membrane Vesicles for Cancer Therapy

“…Many types of vesicles have been described in the literature having quite heterogeneous size, protein content, RNA content and origin. As a result there have been many names given to these different vesicle types (Table 1) (Ronquist & Brody, 1985;Ronquist & Frithz, 1986;Rooney et al, 1993;Arienti et al, 1997;Thery et al, 2006;Lehmann et al, 2008;Schiller et al, 2008;Simpson et al, 2008;Skog et al, 2008;Dashevsky et al, 2009;Di Vizio et al, 2009;Haubold et al, 2009;Jansen et al, 2009;Nilsson et al, 2009;Duijvesz et al, 2010). Unfortunately, the different names given to these vesicles lead to much confusion and it is still unclear if all of the different vesicles are unique in biological function or if they represent a sliding scale of one entity (Duijvesz et al, 2010).…”