A protective role for matrix metalloproteinase-3 in squamous cell carcinoma
A protective role for matrix metalloproteinase-3 in squamous cell carcinoma
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DOI：
10.1158/0008-5472.can-04-0910
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发表时间：
2004-10-01
期刊：
影响因子：
11.2
通讯作者：
Matrisian, LM
中科院分区：
文献类型：
--
作者：
McCawley, LJ;Crawford, HC;Matrisian, LM
基质金属蛋白酶-3（MMP-3/stromelysin-1）的高表达与多种肿瘤类型相关，尽管其在体内的功能作用尚不清楚。在人类和小鼠鳞状细胞癌（SCC）中，MMP-3在肿瘤进展的所有阶段在间质区室中表达，并且在晚期高度侵袭性肿瘤中由恶性上皮细胞表达。为了阐明MMP-3是否在SCC中起因果作用，通过局部应用完全致癌物1-甲基-3-硝基-1-亚硝基胍或用7，12-二甲基苯并[a]蒽和12-O-十四酰基佛波醇-13-乙酸酯进行两阶段引发和促进，使野生型和MMP-3缺失小鼠经历化学致癌过程。与我们的预期相反，与对照动物相比，源自MMP-3缺失小鼠的肿瘤具有增强的初始肿瘤生长速率，尽管在肿瘤发作或发病率方面没有差异。这种生长速率的提高伴随着增殖指数的升高和血管密度的降低，但对细胞凋亡没有显著影响。与对照组相比，来自MMP-3缺失小鼠的肿瘤具有未分化的梭形肿瘤的患病率，这伴随着更高百分比的MMP-3缺失小鼠证明表面肺转移。MMP-3缺失小鼠的肿瘤进展与白细胞浸润呈负相关，其中肿瘤相关巨噬细胞和中性粒细胞的总体减少是明显的。我们认为MMP-3表达为一种保护性反应，在SCC肿瘤发生过程中在宿主防御中起重要作用。
Elevated expression of matrix metalloproteinase-3 (MMP-3/stromelysin-1) is associated with a variety of tumor types, although its in vivo functional role remains unclear. In human and murine squamous cell carcinoma (SCC), MMP-3 is expressed in the stromal compartment at all of the stages of tumor progression and is expressed by the malignant epithelial cells in late-stage, highly invasive tumors. To elucidate whether MMP-3 plays a causal role during SCC, wild-type and MMP-3 null mice were subjected to chemical carcinogenesis procedures by topical application of either the complete carcinogen 1-methyl-3-nitro-1-nitroso-guanidine or two-stage initiation and promotion with 7,12-dimethylbenz[a]anthracene and 12-O-tetradecanoylphorbol-13-acetate. Contrasting with our expectations, tumors originating on MMP-3 null mice had enhanced initial tumor growth rates as compared with control animals, although there was no difference in tumor onset or incidence. This elevated rate in growth was coupled with an elevated proliferative index and a reduced vasculature density but with no significant effect on apoptosis. Tumors from MMP-3 null mice had a prevalence of undifferentiated spindle tumors as compared with controls, which was concomitant with a higher percentage of MMP-3 null mice evidencing surface lung metastases. Tumor progression in MMP-3 null mice was inversely associated with leukocyte infiltration, in which an overall reduction in tumor-associated macrophages and neutrophils was evident. We propose that MMP-3 is expressed as a protective response and plays an important role in host defense during SCC tumorigenesis.