Abstract: . . .  was a significant inhibition in the tumor burden detected after Prinomastat treatment (decrease by 73.8%, 95% CI 40.9–100, P 0.03) compared with untreated mice, after adjusting for the survival time. Furthermore, there was a slower rate of increase of EGFP detection with time in Prinomastat treated mice compared with the control group ( P 0.022 for the interaction term; Fig. 4 A ). In the liver, Prinomastat had no effect on tumor burden ( P 0.52; Fig. 4 B ). Immunohistochemistry of TH in these organs consistently indicated an inhibitory effect of Prinomastat treatment on the presence of neoplastic cells in the lung but not in the liver (Fig. 4, C and D , P 0.001 for the lung, P 0.10 for the liver). As previously observed, tumor cells were confined to the inside of blood vessels in the lungs, whereas in the liver, they were present in the parenchyma (Fig. 4 E–H ). To confirm the absence of effect of Prinomastat treat- ment on liver colonization, we tested its effect on the formation of macroscopic experimental metastases in the liver after i.v. injection of tumor cells. For this experiment, three groups of 15 mice each, injected i.v. with SK-N-BE(2).10 cells, were examined 28 days after injection for the presence of macroscopic metastatic tumor nodules on the surface of the liver. Treatment with Prinomastat was initiated either 48 h before tumor cell injection (early treatment) or 48 h after tumor cell injection (late treatment), and control mice were treated with the vehicle solution. . . .
. . .  obtained at days 23 and 31 after implantation, a significant network of fluorescent microvessels was detected in tumors from control mice, whereas in tumors from MMP-9 ko/ko mice, only a few blood vessels were observed, and there was little evidence of vascular organization. To obtain additional insight into the role of MMP-9 on the tumor vasculature and, in particular, to evaluate the ability of newly formed microvessels to recruit pericytes, sections of primary or- thotopic tumors derived from MMP-9 ko/ko mice and control mice were immunostained for the presence of SMA. This analysis re- vealed a significant difference between MMP-9 ko/ko and control. In tumors from control mice, SMA-positive pericytes formed a uni- form layer around vascular structures containing RBCs. In con- trast, in tumors derived from MMP-9 ko/ko , the layer of SMA- positive cells was discontinuous, suggesting a lack of pericyte recruitment along blood vessels in MMP-9 ko/ko mice (Fig. 10, A and B ). This observation was confirmed by transmission electron microscopy analysis of these tumor samples. In tumors derived from control mice, a uniform and continuous layer of pericytes was detected around the endothelial cells. In tumors derived from MMP-9 ko/ko mice, few pericytes were detected, and they only partially surrounded the endothelial layer (Fig. 10, C and D ). To quantify this lack of pericyte recruitment, tumor sections were then double stained for the presence of endothelial cells using an anti-PECAM/CD31 . . .
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