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Angiogenesis, Metastatis, and the Cellular Microenvironment

MMP-9 Is Differentially Expressed in Primary Human Colorectal Adenocarcinomas and Their Metastases

¹ The Finsen Laboratory; ² Department of Pathology, Rigshospitalet, Copenhagen, Denmark; ³ Academic Surgical Unit, University of Sheffield, Sheffield, England; and ⁴ The Gade Institute, Section of Pathology, Haukeland University Hospital, Bergen, Norway

Requests for reprints: Boye Schnack Nielsen, The Finsen Laboratory, Strandboulevarden 49, 7.2, DK-2100 Copenhagen Ø, Denmark. Phone: 45-3545-5727; Fax: 45-3538-5450. E-mail: schnack{at}finsenlab.dk

Matrix metalloproteinase-9 (MMP-9) is up-regulated in macrophages in various human cancer types. In human colon cancer, MMP-9 is expressed in a macrophage subpopulation located at the tumor edge, indicating a specific induction of MMP-9 in macrophages in direct association with cancer invasion. To test whether MMP-9 is also induced in tumor edge macrophages in metastases from colorectal adenocarcinomas, we have compared the expression pattern of MMP-9 in primary colorectal adenocarcinomas (n = 15) with that in liver metastases (n = 15) and local lymph node metastases (n = 7) from the same patients by in situ hybridization and immunohistochemistry. In all the colorectal adenocarcinomas, the expression of MMP-9 mRNA and immunoreactivity in macrophages was located at the invasive front. In contrast, only 3 of the 15 liver metastases had MMP-9 mRNA and immunoreactivity at the periphery, and this expression was confined to small foci of macrophages located either among lymphocytes or in a dense desmoplastic stroma. Expression of MMP-9 mRNA and immunoreactivity was in all liver metastases seen in macrophages located in the lumen of malignant glandular structures and in central necrotic tissue. In all the 7 lymph node metastases, MMP-9 mRNA and immunoreactivity was seen in macrophages located in the stromal tissue surrounding the metastases. We conclude that MMP-9 is not up-regulated in tumor edge macrophages in liver metastases like in their primary tumor and local lymph node metastases, suggesting that disseminating colorectal cancer cells can adopt alternative proteolytic mechanisms for invasion depending on the local microenvironment. (Mol Cancer Res 2006;4(5):293–302)

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