Intestinal tumorigenesis is suppressed in mice lacking the metalloproteinase matrilysin
Intestinal tumorigenesis is suppressed in mice lacking the metalloproteinase matrilysin
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DOI：
10.1073/pnas.94.4.1402
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发表时间：
1997-02-18
影响因子：
11.1
通讯作者：
Matrisian, LM
中科院分区：
文献类型：
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作者：
Wilson, CL;Heppner, KJ;Matrisian, LM
基质金属蛋白酶（MMPs）与晚期肿瘤细胞侵袭和转移相关的基底膜破坏有关。然而，最近的研究表明，MMP家族成员之一，基质溶解素，在早期人类结肠直肠肿瘤中表达的比例很高。我们分析了Apc（Min）等位基因杂合小鼠（Min/+）的良性肠肿瘤中基质溶解素的表达，发现大多数（88%）腺瘤中的mRNA被诱导。在肿瘤细胞中检测到蛋白质，令人惊讶的是，它主要免疫定位于异型增生腺体的内腔表面，而不是基底膜或细胞外基质。为了解决基质溶解素在Min肠肿瘤发生中的作用，我们通过基因靶向和同源重组产生了这种MMP缺陷的Min/+小鼠。基质溶解素的缺乏导致Min/+动物中平均肿瘤多样性降低约60%，平均肿瘤直径显著减小。基于这些发现，我们得出结论，基质溶解素是Min表型的抑制剂，可能通过独立于基质降解的能力发挥作用。这些结果为MMP抑制剂在早期结肠癌的治疗和预防中的应用提供了依据。
Matrix metalloproteinases (MMPs) classically have been implicated in basement membrane destruction associated with late-stage tumor cell invasion and metastasis. However, recent studies have demonstrated that one MMP family member, matrilysin, is expressed in a high percentage of early-stage human colorectal tumors, We analyzed matrilysin expression in benign intestinal tumors from mice heterozygous for the Apc(Min) allele (Min/+) and found that the mRNA was induced in the majority (88%) of these adenomas. Protein was detected in the tumor cells, where, surprisingly, it was predominantly immunolocalized to the lumenal surface of dysplastic glands rather than the basement membrane or extracellular matrix. To address the role of matrilysin in Min intestinal tumorigenesis, we generated Min/+ mice deficient in this MMP by gene targeting and homologous recombination, The absence of matrilysin resulted in a reduction in mean tumor multiplicity in Min/+ animals of approximately 60% and a significant decrease in the average tumor diameter. Based on these findings, we conclude that matrilysin is a suppressor of the Min phenotype, possibly by functioning in a capacity independent of matrix degradation, These results argue for the use of MMP inhibitors in the treatment and prevention of early-stage colon cancer.