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. 1998 Sep 12;317(7160):750. doi: 10.1136/bmj.317.7160.750

Association between plasma plasminogen activator inhibitor-1 and survival in colorectal cancer

Measuring C reactive protein concentrations may be more useful

Naveed Sattar 1, Donald C McMillan 1
PMCID: PMC1113880  PMID: 9732351

Editor—Nielsen et al reported an association between circulating concentrations of plasminogen activator inhibitor-1 and survival in patients with colorectal cancer.1 They suggest that this reflects the specific role of plasminogen activator inhibitor-1 in tumour progression.

It has been known for some time that disease progression in colorectal cancer is associated with an increase in the acute phase response as evidenced by the prototypical acute phase protein (C reactive protein).2 We have reported that an increase in circulating C reactive protein concentrations is associated with increased recurrence of tumour in patients who have undergone curative surgery for colorectal cancer.3 There is also evidence that an increased C reactive protein concentration is an independent predictive factor of survival in patients with gastrointestinal cancer.4 Therefore the association between increased plasminogen activator inhibitor-1 concentrations and shorter survival in patients with colorectal cancer may merely reflect the acute phase response. Indeed, there is evidence of a direct relation between the circulating concentrations of plasminogen activator inhibitor-1 and C reactive protein in patients with coronary heart disease.5

Thus a direct relation between circulating concentrations of plasminogen activator inhibitor-1 and C reactive protein might also exist in patients with colorectal cancer. Measurement of C reactive protein concentration is better standardised and more routinely available than measurement of plasminogen activator inhibitor-1. Consequently, measurement of C reactive protein concentration may have greater potential in the clinical setting to help predict recurrence of cancer or survival.

References

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BMJ. 1998 Sep 12;317(7160):750.

Authors’ reply

Hans Jørgen Nielsen 1,2,3, Ib Jarle Christensen 1,2,3, Nils Brünner 1,2,3, Steen Sørensen 1,2,3

Editor—As Sattar and McMillan suggest, disease progression in colorectal cancer may be associated with an increase in the acute phase response, as evidenced by analysis of C reactive protein concentrations. Plasminogen activator inhibitor type-1 has certainly been indicated as an acute phase reactant in some non-malignant pathological conditions. The question raised by Sattar and McMillan relates to whether the increase in plasma plasminogen activator inhibitor type-1 concentrations observed in our cohort of patients with colorectal cancer reflects an acute phase response. To our knowledge there are no reports that specifically address this question. Several points can, however, be extracted from the published literature.

Firstly, in many types of cancer the plasminogen activator inhibitor type-1 concentration in tumour tissue is higher than that in the normal tissue where the tumour arises.1-1 Secondly, in situ hybridisation and immunohistochemistry for plasminogen activator inhibitor type-1 show tumour specific expression and immunoreactivity confined to the tumour stroma—for example, endothelial cells lining the tumour vessels—while no signal is observed outside the tumour tissue.1-2 Thirdly, experiments in wild-type mice and mice in which the plasminogen activator inhibitor type-1 gene has been disrupted show that expression of plasminogen activator inhibitor type-1 permits tumour cell invasion.1-3 Finally, plasminogen activator inhibitor type-1 competes with the urokinase receptor for binding to vitronectin, and a surplus of plasminogen activator inhibitor type-1 thus facilitates migration. This effect of plasminogen activator inhibitor type-1 is clearly separated from any known function of C reactive protein.1-4

To address the question raised by Sattar and McMillan further we have applied a C reactive protein nephelometric assay (Behringwerke) on the plasma samples that we used in our study. Altogether 458 of the 597 patients had C reactive protein concentrations above the limit of detection of 25 nmol/l (figure). Patients with a C reactive protein concentration at or below the limit of detection had plasminogen activator inhibitor type-1 concentrations in a range similar to that in patients with C reactive protein concentrations above the limit of detection (figure). This means that knowledge of the C reactive protein concentration explains only part of the variability of plasminogen activator inhibitor type-1 (r2=0.096).

Figure.

Figure

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Scatter plot of plasma plasminogen activator inhibitor type-1 and plasma C reactive protein concentrations in 597 patients scheduled to undergo elective colorectal cancer surgery. Spearman rank correlation coefficient for patients with C reactive protein >25 nmol/l was 0.31; P<0.0001

The lack of a direct correlation between plasma plasminogen activator inhibitor type-1 and plasma C reactive protein suggests a more complex relation, if any, between these two molecules. Measurement of C reactive protein concentrations can therefore not be used as a direct substitute for measurement of plasminogen activator inhibitor type-1 in patients with colorectal cancer.

References

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  • 1-4.Deng G, Curriden SA, Wang SJ, Rosenberg S, Loskutoff DJ. Is plasminogen activator inhibitor-1 the molecular switch that governs urokinase receptor-mediated cell adhesion and release? J Cell Biol. 1996;134:1563–1571. doi: 10.1083/jcb.134.6.1563. [DOI] [PMC free article] [PubMed] [Google Scholar]

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