Abstract
BackgroundDespite the association of cancer-derived circulating tissue factor (TF)-containing microvesicles and hypercoagulable state, correlations with the incidence of thrombosis remain unclear.MethodsIn this study the upregulation of TF release upon activation of various cancer cell lines, and the correlation with TF and PAR2 expression and/or activity was examined. Microvesicle release was induced by PAR2 activation in seventeen cell lines and released microvesicle density, microvesicle-associated TF activity, and phoshpatidylserine-mediated activity were measured. The time-course for TF release was monitored over 90 min in each cell line. In addition, TF mRNA expression, cellular TF protein and cell-surface TF activities were quantified. Moreover, the relative expression of PAR2 mRNA and cellular protein were analysed. Any correlations between the above parameters were examined by determining the Pearson’s correlation coefficients.ResultsTF release as microvesicles peaked between 30–60 min post-activation in the majority of cell lines tested. The magnitude of the maximal TF release positively correlated with TF mRNA (c = 0.717; p < 0.001) and PAR2 mRNA (c = 0.770; p < 0.001) expressions while the percentage increase correlated with PAR2 mRNA (c = 0.601; p = 0.011) and protein (c = 0.714; p < 0.001). There was only a weak correlation between resting TF release, and microvesicle release. However, TF release in resting cells did not significantly correlate with any of the parameters examined. Furthermore, TF mRNA expression correlated with PAR2 mRNA expression (c = 0.745; p < 0.001).Discussion and ConclusionsIn conclusion, our data suggest that TF and PAR2 mRNA, and PAR2 protein are better indicators of the ability of cancer cells to release TF and may constitute more accurate predictors of risk of thrombosis.
Highlights
Despite the association of cancer-derived circulating tissue factor (TF)-containing microvesicles and hypercoagulable state, correlations with the incidence of thrombosis remain unclear
The basal expression of TF mRNA was highest in LoVo, ASPC-1, A375 and MDA-MB-231 cell lines, with moderate amounts being expressed in LS174T, SKOV-3, WM266-4, NCI-H209, MCF-7 and BxPC-3 cells and low levels present in the remainder of the cell lines examined (Fig. 1a)
The observation for the lack correlation between TF mRNA and TF protein in some of the cell lines tested may arise from the differing rates of TF mRNA stability in these cells and may be significant in the malignant properties of these cells
Summary
Despite the association of cancer-derived circulating tissue factor (TF)-containing microvesicles and hypercoagulable state, correlations with the incidence of thrombosis remain unclear. We hypothesise that the potential of tumour cells to release TF upon activation, may be a critical criterion in the promotion of hypercoagulable state and precipitation of thrombosis. In this in vitro study, we have examined this attribute which we have termed “TF-release potential”, in seventeen different cells lines, and by correlating this potential to relevant properties including TF and PAR2 expression, attempted to identify possible marker which may prove to be indicative of the risk of thrombosis during cancer in vivo
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