Goss K J, Brown P D, Matrisian L M
Department of Cell Biology, Vanderbilt University, Nashville, TN 37232, USA.
Int J Cancer. 1998 Nov 23;78(5):629-35. doi: 10.1002/(sici)1097-0215(19981123)78:5<629::aid-ijc17>3.0.co;2-8.
Matrix metalloproteinase (MMP) activity has been associated with tumor invasion and metastasis in many different tumor types, but recent studies also support a role for these enzymes in earlier stages of the tumor progression continuum. Specifically, the expression pattern of MMPs in benign human and mouse gastrointestinal tumors suggests that they may function in the development or growth of non-invasive tumors. To address the contribution of MMP activity to the development of intestinal adenomas, we administered the synthetic MMP inhibitor batimastat and expressed the tissue inhibitor of metalloproteinases-1 (TIMP-1) in the gastrointestinal tract of Min mice, which spontaneously develop pre-malignant small and large intestinal tumors. Batimastat administration resulted in a 48% decrease in the number of Min tumors. This reduction in tumor number is similar to that observed in mice lacking the metalloproteinase matrilysin, and demonstrates the therapeutic and chemopreventive potential of MMP inhibitors for pre-malignant intestinal tumors. In contrast, forced TIMP-1 expression in transgenic mice had no effect or, in one line, unexpectedly augmented Min tumor multiplicity by 32%. This observation supports an in vivo tumor-promoting activity of TIMP-1 that could be related to the growth stimulatory effects of TIMP that have been documented in vitro. Taken together, these 2 approaches of modulating MMP activity in Min mice support a critical function of MMPs in Min tumorigenesis, underscore the importance of an MMP/inhibitor balance in maintaining tissue homeostasis and demonstrate that endogenous MMP inhibitors can have complex effects in particular cellular contexts.
基质金属蛋白酶（MMP）的活性与多种不同肿瘤类型的侵袭和转移相关，但最近的研究也支持这些酶在肿瘤进展连续过程的早期阶段发挥作用。具体而言，MMPs在人类和小鼠良性胃肠道肿瘤中的表达模式表明，它们可能在非侵袭性肿瘤的发生或生长中起作用。为了研究MMP活性对肠腺瘤发生的作用，我们给Min小鼠（可自发发生恶性前的小肠和大肠肿瘤）的胃肠道施用了合成MMP抑制剂batimastat并表达了金属蛋白酶组织抑制剂-1（TIMP-1）。施用batimastat导致Min肿瘤数量减少48%。肿瘤数量的这种减少与在缺乏金属蛋白酶matrilysin的小鼠中观察到的情况相似，证明了MMP抑制剂对恶性前肠肿瘤的治疗和化学预防潜力。相比之下，在转基因小鼠中强制表达TIMP-1没有效果，或者在一个品系中意外地使Min肿瘤的多发性增加了32%。这一观察结果支持了TIMP-1在体内具有促进肿瘤的活性，这可能与体外已记录的TIMP的生长刺激作用有关。综上所述，在Min小鼠中调节MMP活性的这两种方法支持了MMPs在Min肿瘤发生中的关键作用，强调了MMP/抑制剂平衡在维持组织稳态中的重要性，并证明内源性MMP抑制剂在特定细胞环境中可能具有复杂的作用。
