Reply

We thank our colleagues for their complementing data and their addition to our conclusions. The quantitative data that they show correlate well with those obtained in our study (1).

Gerhards et al. (2) state that they found fewer patients with noninvasive tumors (stages Ta and T1) having elevated levels of urinary MMP-2¹ and MMP-9 as compared with our study. Gerhards et al. show(see Fig. 1 in Ref. 2) that about 28% (12 of 43) of the patients with stage pTa-pT1 have elevated MMP-2 activity and about 30%(13 of 43) have elevated MMP-9 levels. However, a detailed look at the data published by Sier et al. (see Table 2 in Ref. 1) shows that for both total MMP-2 and total MMP-9 31% of the patients have elevated activity levels when pTa-pT1 data were combined. This fits quite well with the data of Gerhards et al. (2). For active MMP-9 (only measured by Sier et al., Ref. 1), 41% of the patients with early stage bladder cancer (pTa and pT1 combined) was found to have elevated levels. On the basis of these results, we suggested that active MMP-9 might be a more sensitive marker than total MMP-9 or MMP-2. However, we also indicated in the discussion that because of the transcriptional regulation of MMP-9 by various cytokines, inflammatory cells might contribute to the increase of urinary MMP-9 either by direct production or by stimulation of production by the tumor cells. We discussed that our qualitative data about the inflammatory cells did not allow us to investigate this issue, and we hoped that future studies would clarify this. Therefore, we are happy with the data shown by Gerhards et al. (2), who convincingly show that indeed elevated urinary MMP-9 levels may be related to inflammation. On the other hand, both MMP-2 and MMP-9 levels in bladder tumor biopsies showed a statistically significant increase with tumor grade and invasiveness (Papathoma et al., Ref. 3).

We started this investigation with bladder cancer because we assumed that the urinary MMP activity would derive directly from the tumor. Interestingly, a recent study (Hanemaaijer et al., Ref. 4) shows that the MMP-9 activity in urine from patients with various other solid tumors are similarly enhanced, which indicates that the matter is probably more complex.