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Tumor VEGF modulates host proteolytic activity during<br />
ovarian cancer progression<br />
D. Belotti 1 , C. Calcagno 1 , A. Garofalo 1 , L. Manenti 1 , M. Broggini 2 ,<br />
G. Taraboletti 1 and R. Giavazzi 1<br />
1<br />
Laboratory of Biology and Treatment of Metastasis, and 2 Laboratory of Molecular<br />
Pharmacology, Department of Oncology, Mario Negri Institute for Pharmacological<br />
Research, 24125 Bergamo, Italy<br />
A mutual regulation between VEGF and MMPs has been recently reported. VEGF<br />
stimulates MMP production, and, in turn, MMPs regulate the bioavailability of VEGF.<br />
We have previously reported that MMPs are involved in the release of VEGF and<br />
in ascites formation in ovarian carcinoma. To further investigate the functional<br />
interplay between VEGF and MMPs in ovarian carcinoma progression, we have<br />
established a model of human ovarian carcinoma cells overexpressing VEGF and<br />
disseminating in the peritoneal cavity of nude mice. Xenograft variants derived<br />
from the A2780 human ovarian carcinoma (1A9), stably expressing VEGF 121<br />
in sense<br />
(1A9-VS-1) and antisense orientation (1A9-VAS-3) were generated and the invasive<br />
and metastatic potential of tumor cells producing different levels of VEGF was<br />
evaluated. 1A9-VS-1 and 1A9-VAS-3 disseminated in the peritoneal cavity of nude<br />
mice, but only 1A9-VS-1, the VEGF 121<br />
overexpressing tumor variant, produced ascites.<br />
Significant levels of soluble VEGF were detected in plasma of mice bearing 1A9-VS-<br />
1.<br />
p2<br />
Supported by the European Union FP6, LSHC-CT-2003-503297.<br />
An augmentation in murine MMP9 expression was observed in tumors of mice<br />
transplanted with 1A9-VS-1 compared to mice bearing 1A9-VAS-3 tumors, indicating<br />
that VEGF produced by tumor cells stimulates host expression of the matrixdegrading<br />
enzyme. Moreover, we found that tumor VEGF modulated the proteolytic<br />
activity of stromal cells not only within the tumor but also in distant organs of<br />
tumor-bearing-mice. In particular the organs could be ordered into three typologies<br />
in relation to their proteolytic activity: 1) organs that presented a general increase<br />
in gelatinases in tumor-bearing mice compared to healthy mice, but independently<br />
from VEGF production (spleen, lung, liver, and uterus); 2) organs that showed no<br />
alteration in the levels of gelatinases (kidney and pancreas); and 3) organs that<br />
presented a VEGF-dependent increase in murine MMP-9 (ovaries). Notably, the<br />
levels of proMMP-9 in ovaries correlated with the plasma levels of VEGF.<br />
In vitro VEGF did not induce autocrine changes in tumor cell migration and<br />
invasiveness. On the contrary, tumor derived VEGF modulated invasion and MMP2<br />
and MMP9 expression in endothelial cells. The use of specific inhibitors of VEGF<br />
receptor demonstrated the specificity of the effects.<br />
Altogether these findings point to a complex cross-talk between VEGF and MMPs in<br />
determining ovarian tumor progression.<br />
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