Role of Platelets in Tumor Cell Metastases

Karpatkin, Simon; Pearlstein, Edward

doi:10.7326/0003-4819-95-5-636

Cited by 258 publications

(147 citation statements)

References 30 publications

(11 reference statements)

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“…Preliminary scanning electron microscopy and biochemical studies performed with our in vitro system suggest that both normal and malignant cells can recruit platelets and utilize their heparitinase activity to invade the endothelial cell layer and its underlying ECM. The possible involvement of the platelet heparitinase in the extravasation of blood-borne cells is supported by the antimetastatic effect of heparin and prostacyclin (29,32), which in the present study were also shown to inhibit the activity and release of the enzyme.…”

Section: Discussionmentioning

confidence: 50%

“…Due to their high affinity to exposed areas of the subendothelium, platelets may cause the initial damage to the integrity of the vascular intima by means of their heparitinase activity and thus produce the necessary preliminary conditions for extravasation of other cells. In fact, it has been suggested that platelets have a role in the sequestration, adherence, and penetration of tumor cells through the blood vessel endothelial cell barrier (28)(29)(30)(31). Furthermore, a correlation was found between the ability of some tumor cells to aggregate platelets in vitro and their metastatic potential in vivo (30).…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Degradation of sulfated proteoglycans in the subendothelial extracellular matrix by human platelet heparitinase.

Yahalom¹,

Eldor²,

Fuks³

et al. 1984

J. Clin. Invest.

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As bstract. Cultured vascular and corneal endothelial cells produce an underlying extracellular matrix (ECM) which induces platelet adherence, aggregation, and release reaction. Incubation of a metabolically (35S)O--labeled ECM with platelet-rich plasma or washed platelets, but not with platelet-poor plasma, resulted in degradation of its heparan sulfate-containing proteoglycans into labeled fragments four to five times smaller than intact glycosaminoglycan side chains. These fragments were sensitive to deamination with nitrous acid and were not produced in the presence of heparin, indicating that heparan sulfate in the ECM is susceptible to cleavage by the platelet heparitinase. This degradation required adhesion of platelets to the ECM rather than aggregation since it was not inhibited by aspirin, which prevented platelet aggregation but not adherence. The enzyme was not released during aggregation of platelets on the ECM but was readily liberated upon their exposure to thrombin. This liberation was inhibited in the presence of prostacyclin (PGI2). Isolated high molecular weight proteoglycans first released from the ECM by incubation with platelet poor plasma served as a substrate for further degradation by the platelet heparitinase, suggesting a cascade mechanism for degradation of heparan sulfate in the ECM. Heparitinase, although to a lower level, was also active when washed platelets were added on top of a confluent endothelial cell monolayer covering the (35S)0=-labeled ECM. It is suggested that the platelet heparitinase may be involved in the impairment of the

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Section: Discussionmentioning

confidence: 50%

Section: Discussionmentioning

confidence: 99%

Degradation of sulfated proteoglycans in the subendothelial extracellular matrix by human platelet heparitinase.

Yahalom¹,

Eldor²,

Fuks³

et al. 1984

J. Clin. Invest.

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“…18 Platelet depletion as well as their functional defect result in a significant decrease of tumor metastasis. 2 There are several steps in the cancer cell cycle that may be affected either directly by platelets or indirectly via released PMPs.…”

Section: Discussionmentioning

confidence: 99%

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

Dashevsky

Varon

Brill

2009

Intl Journal of Cancer

124

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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...

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“…5,6]. Experimentally induced thrombocytopenia (depletion of platelets) was shown to reduce the development of metastasis both in transplant and syngeneic mouse tumor models [7]. Various human and animal tumor cells were found to be capable of inducing platelet aggregation and activation [e.g.…”

Section: Introductionmentioning

confidence: 99%