Platelet-derived microparticles promote invasiveness of prostate cancer cells via upregulation of MMP-2 production.
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.
Dashevsky
Olga
O
Hematology Department, Coagulation Unit, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
Varon
David
D
Brill
Alexander
A
D001792:Blood Platelets / Q000378:metabolism*; D002448:Cell Adhesion; D018929:Cell Culture Techniques / Q000295:instrumentation; D003513:Cycloheximide / Q000494:pharmacology; D003593:Cytoplasm / Q000378:metabolism; D003609:Dactinomycin / Q000494:pharmacology; D005780:Gelatin / Q000737:chemistry; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000097:blood* / Q000378:metabolism / Q000473:pathology*; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D013997:Time Factors; D015854:Up-Regulation
D011500:Protein Synthesis Inhibitors; D003609:Dactinomycin; D005780:Gelatin; D003513:Cycloheximide; D020778:Matrix Metalloproteinase 2