Owen Jennifer L, Iragavarapu-Charyulu Vijaya, Gunja-Smith Zeenat, Herbert Lynn M, Grosso Joseph F, Lopez Diana M
Department of Microbiology, University of Miami School of Medicine, Miami, FL 33101, USA.
J Immunol. 2003 Oct 15;171(8):4340-51. doi: 10.4049/jimmunol.171.8.4340.
Matrix metalloproteinase-9 (MMP-9), a matrix-degrading enzyme, is crucial in tumor invasion and metastasis and is implicated in leukocyte extravasation. In this report, we demonstrate that during growth of the D1-7,12-dimethylbenzanthracene-3 mammary tumor in BALB/c mice, there is progressive up-regulation of MMP-9 in splenic T cells at both the transcriptional and translational levels. Our previous work has identified several factors produced by this tumor, including PGE(2), GM-CSF, and phosphatidyl serine; however, none of these agents induces increased production of MMP-9 by normal splenic T cells. Although not produced by the tumor, TNF-alpha and IL-6 are up-regulated in both macrophages and B cells in tumor-bearing mice. Exposure of normal T cells to these two cytokines, however, also fails to up-regulate MMP-9 production. Vascular endothelial growth factor (VEGF) is produced by many tumors, and we determined that the mammary tumor used in our studies expresses high levels of this angiogenic growth factor. Importantly, splenic T cells from tumor bearers constitutively produce increased amounts of VEGF, and treatment of normal T cells with VEGF results in up-regulated MMP-9 production. Of crucial importance is the finding that tumor-infiltrating T cells also produce high levels of VEGF and MMP-9. Our studies indicate that VEGF can act directly on T lymphocytes and that elevated VEGF levels may contribute to the aberrant MMP-9 secretion by mammary tumor bearers' T cells.
基质金属蛋白酶-9（MMP-9）是一种基质降解酶，在肿瘤侵袭和转移中起关键作用，并与白细胞外渗有关。在本报告中，我们证明，在BALB/c小鼠的7,12-二甲基苯并蒽-3乳腺肿瘤（D1）生长过程中，脾T细胞中MMP-9在转录和翻译水平上均呈渐进性上调。我们之前的研究已经鉴定出该肿瘤产生的几种因子，包括前列腺素E2（PGE2）、粒细胞-巨噬细胞集落刺激因子（GM-CSF）和磷脂酰丝氨酸；然而，这些因子均不能诱导正常脾T细胞增加MMP-9的产生。虽然肿瘤不产生肿瘤坏死因子-α（TNF-α）和白细胞介素-6（IL-6），但在荷瘤小鼠的巨噬细胞和B细胞中，这两种因子均上调。然而，正常T细胞暴露于这两种细胞因子也不能上调MMP-9的产生。血管内皮生长因子（VEGF）由许多肿瘤产生，我们确定我们研究中使用的乳腺肿瘤表达高水平的这种血管生成生长因子。重要的是，荷瘤小鼠的脾T细胞组成性地产生增加量的VEGF，用VEGF处理正常T细胞会导致MMP-9产生上调。至关重要的发现是肿瘤浸润T细胞也产生高水平的VEGF和MMP-9。我们的研究表明，VEGF可直接作用于T淋巴细胞，VEGF水平升高可能导致乳腺肿瘤荷瘤小鼠T细胞异常分泌MMP-9。
