Shattuck-Brandt R L, Lamps L W, Heppner Goss K J, DuBois R N, Matrisian L M
Department of Cell Biology, Vanderbilt School of Medicine, Nashville, Tennessee 37232, USA.
Mol Carcinog. 1999 Mar;24(3):177-87.
Both the matrix metalloproteinase matrilysin and the prostaglandin H synthase cyclooxygenase-2 (Cox-2), are thought to play key roles in colorectal carcinogenesis. These enzymes are overexpressed in 85-90% of human colorectal cancers. Furthermore, mice carrying an adenomatous polyposis coli germline mutation that are also nullizygous for either matrilysin or Cox-2 display a significant reduction in tumor multiplicity. To determine if there is a direct link between matrilysin and Cox-2, their expression was characterized in two mouse models of intestinal carcinogenesis and in human colorectal tumor samples. Both matrilysin and Cox-2 expression was increased in the mouse models and in the human colorectal cancers; however, immunohistochemistry and in situ hybridization indicated that their localization within the tumors was different. In the mouse models, Cox-2 was expressed in the superficial stroma, whereas matrilysin expression was localized exclusively to the neoplastic epithelium. In contrast, in human colorectal cancers, both Cox-2 and matrilysin were expressed in the neoplastic epithelium. Although over 80% of the specimens expressed both matrilysin and Cox-2, the levels and localization of matrilysin and Cox-2 expression were distinct. Cox-2 expression was strongest in well-differentiated areas, and matrilysin immunostaining was strongest in the more dysplastic and invasive regions of the tumor. These results indicate that these two important modulators of colorectal tumorigenesis are differentially expressed and imply that the therapeutic benefit may be improved by combination therapy utilizing selective Cox-2 and matrilysin inhibitors.
基质金属蛋白酶matrilysin和前列腺素H合成酶环氧化酶-2（Cox-2）被认为在结直肠癌发生过程中起关键作用。这些酶在85%至90%的人类结直肠癌中过度表达。此外，携带腺瘤性息肉病基因种系突变且matrilysin或Cox-2纯合缺失的小鼠，其肿瘤多发性显著降低。为了确定matrilysin和Cox-2之间是否存在直接联系，在两种肠道癌发生小鼠模型和人类结直肠肿瘤样本中对它们的表达进行了特征分析。在小鼠模型和人类结直肠癌中，matrilysin和Cox-2的表达均增加；然而，免疫组织化学和原位杂交表明它们在肿瘤内的定位不同。在小鼠模型中，Cox-2在浅表基质中表达，而matrilysin表达仅局限于肿瘤上皮。相反，在人类结直肠癌中，Cox-2和matrilysin均在肿瘤上皮中表达。尽管超过80%的标本同时表达matrilysin和Cox-2，但matrilysin和Cox-2表达的水平和定位是不同的。Cox-2在高分化区域表达最强，而matrilysin免疫染色在肿瘤发育异常和侵袭性更强的区域最强。这些结果表明，这两种结直肠癌发生的重要调节因子表达存在差异，意味着利用选择性Cox-2和matrilysin抑制剂的联合治疗可能会提高治疗效果。
