Clinicopathologic significance of urokinase receptor- and mmp-9-positive stromal cells in human colorectal cancer: Functional multiplicity of matrix degradation on hematogenous metastasis

Saito, Kazuya; Takeha, Satoshi; Shiiba, Kenichi; Matsuno, Seiki; Sorsa, Timo; Nishimura, Hiroshi; Ohtani, Haruo

doi:10.1002/(sici)1097-0215(20000401)86:1<24::aid-ijc4>3.0.co;2-a

Cited by 34 publications

(30 citation statements)

References 23 publications

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“…The MMP-9 mRNA and immunohistochemical expression pattern observed in the primary colorectal carcinomas substantiates our previous studies on the localization MMP-9 mRNA and immunoreactivity in colorectal cancer tissue specimens done on other patient groups (15,16) and is in agreement with MMP-9 immunohistochemical and in situ hybridization studies reported by others (12,21). Our findings on colon cancer liver metastases, however, partly disagree with results reported by Zeng et al (12), who analyzed MMP-9 mRNA expression in colorectal cancer and 10 unmatched samples of colon cancer liver metastases.…”

Section: Discussionsupporting

confidence: 89%

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

Illemann¹,

Bird

Majeed

et al. 2006

Molecular Cancer Research

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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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Section: Discussionsupporting

confidence: 89%

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

Illemann¹,

Bird

Majeed

et al. 2006

Molecular Cancer Research

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“…Inflammatory cells derived from the bone marrow are a source of MMP-9 in human tumors, including lung tumors (18,19,35,36), and we observed MMP-9 immunoreactivity in stromal cells in our model. We speculated that T cells may be required for the MMP-9 effect.…”

Section: Discussionsupporting

confidence: 49%

Matrix Metalloproteinase-9 from Bone Marrow–Derived Cells Contributes to Survival but not Growth of Tumor Cells in the Lung Microenvironment

et al. 2006

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The role of specific stromal-derived matrix metalloproteinases (MMPs) was analyzed in experimental metastasis assays in wild-type and either MMP-9, MMP-7, or MMP-2 null mice. MMP-9 null mice showed an 81% reduction in Lewis lung carcinoma tumor number, whereas MMP-7 null mice showed a 42% increase in tumor number, and there was no difference in tumor number in MMP-2 null mice compared with wild-type controls. Similarly, in an orthotopic model of lung cancer, 50% fewer MMP-9 null mice were able to establish tumors in the lung compared with control mice, although the size of the tumors was not different. The effect of MMP-9 on lung tumor colonization was dependent on the expression of MMP-9 from bone marrow-derived cells and is most likely contributed by neutrophils. To examine temporal effects of stromal MMP-9, bioluminescence imaging from luciferase-expressing human lung cancer-derived A549 cells revealed that there were fewer tumor cells in the lungs of MMP-9 null mice as early as 19 hours after injection compared with control mice, with no difference in subsequent growth rates. Six hours after injection of tumor cells, MMP-9 null mice showed a 4-fold increase in the percent of tumor cells undergoing apoptosis compared with control mice. We conclude that MMP-9 from the bone marrow contributes to the early survival and establishment of tumors in the lung and has no effect on subsequent growth. These results provide insights into the failure of MMP inhibitors in clinical trials in patients with late-stage lung cancer. (Cancer Res 2006; 66(1): 259-66)

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“…An incoherence emerges with this consequence theory; that is, patients who died of cancer after curative operation, in this scenario, would be expected to have a higher number of intraepithelial CD8 þ T cells because their metastatic foci are clinically undetectable, being unable to cause systemic immunosuppression at the time of operation (cf. Saito et al, 2000). In reality, our data showed no difference in the number of T cells between the curative and noncurative groups.…”

Section: Discussionmentioning

confidence: 48%

Intraepithelial CD8+ T-cell-count becomes a prognostic factor after a longer follow-up period in human colorectal carcinoma: possible association with suppression of micrometastasis

et al. 2004

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T-cell infiltration into human cancer tissues can be a manifestation of host immune responses to cancer cells. The present study was undertaken to explore the clinicopathological significance of intraepithelial CD8 þ T cells using 371 consecutively sampled human colorectal carcinomas. By univariate analysis, we noted that the survival curves by intraepithelial CD8 þ T cells became separated only after 1 to 2 years postoperation. Multivariate analyses revealed that the beneficial effect of this factor becomes significant only after a longer (more than 2 year), but not after a shorter (less than 2 year) follow-up period. Furthermore, the number of intraepithelial CD8 þ T cells was significantly higher in patients alive for more than 5 years than in patients who either died of cancer after a curative operation or patients who underwent a noncurative operation. Patients' cancer-specific death long after a curative operation is thought to be caused by the growth of micrometastases in other organs or near the primary sites. The effects of intraepithelial CD8 þ T cells, therefore, may be mediated by suppression of micrometastasis, rather than suppression of growth in the primary tumour. In conclusion, our data support a hypothesis on the presence of systemic immunosurveillance against micrometastasis of cancer cells.

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Clinicopathologic significance of urokinase receptor- and mmp-9-positive stromal cells in human colorectal cancer: Functional multiplicity of matrix degradation on hematogenous metastasis

Cited by 34 publications

References 23 publications

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

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

Matrix Metalloproteinase-9 from Bone Marrow–Derived Cells Contributes to Survival but not Growth of Tumor Cells in the Lung Microenvironment

Intraepithelial CD8+ T-cell-count becomes a prognostic factor after a longer follow-up period in human colorectal carcinoma: possible association with suppression of micrometastasis

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