Prognostic significance of matrix metalloproteinases‐1, ‐2, ‐7 and ‐13 and tissue inhibitors of metalloproteinases‐1, ‐2, ‐3 and ‐4 in colorectal cancer

Hilska, Marja; Roberts, Peter; Collan, Yrjö; Laine, V.; Kössi, Jyrki; Hirsimäki, Pirkko; Rahkonen, Otto; Laato, Matti

doi:10.1002/ijc.22747

Cited by 133 publications

(114 citation statements)

References 52 publications

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“…These results are consistent with previous reports that show stroma-restricted expression of the MMPs in human liver metastases of colorectal cancer (21,22). Abundant expression of MMP2 or MMP9 is associated with poor prognosis and high mortality of colon cancer patients (23)(24)(25)(26)(27). Although selective inhibitors of MMP2/9 significantly block mouse liver metastasis of colon cancer and prolong the survival of tumor-bearing mice (28), clinical trials for MMP inhibitors have failed because of severe side effects such as musculoskeletal pain and inflammation (29)(30)(31).…”

Section: Discussionsupporting

confidence: 93%

Inactivation of chemokine (C-C motif) receptor 1 (CCR1) suppresses colon cancer liver metastasis by blocking accumulation of immature myeloid cells in a mouse model

Kitamura

Fujishita

Loetscher

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

153

139

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Recent reports have suggested critical roles of myeloid cells in tumor invasion and metastasis, although these findings have not led to therapeutics. Using a mouse model for liver dissemination, we show that mouse and human colon cancer cells secrete CCchemokine ligands CCL9 and CCL15, respectively, and recruit CD34 + Gr-1 − immature myeloid cells (iMCs). They express CCL9/15 receptor CCR1 and produce matrix metalloproteinases MMP2 and MMP9. Lack of the Ccr1, Mmp2, or Mmp9 gene in the host dramatically suppresses outgrowths of disseminated tumors in the liver. Importantly, CCR1 antagonist BL5923 blocks the iMC accumulation and metastatic colonization and significantly prolongs the survival of tumor-bearing mice. These results suggest that CCR1 antagonists can provide antimetastatic therapies for patients with disseminated colon cancer in the liver.C olon cancer is one of the leading causes of cancer-related deaths (1). Although most primary tumors can be resected surgically, colorectal cancer frequently spreads to the liver, which is responsible for the high mortality of the disease (2). For successful metastasis, cancer cells need to invade surrounding tissues, penetrate microvessels, survive in circulation, disseminate to distant organs, form micrometastases, and expand into macrometastases. To progress through these steps, tumor cells often acquire the capability of survival and invasion by activating metastatic signaling pathways or inactivating metastasis suppressor genes (2, 3). In addition to these cell autonomous changes, tumor stromal cells, especially bone marrow-derived myeloid cells, actively participate in early steps of the metastatic cascade in some mouse models (4). For example, tumor-associated macrophages (TAMs) promote migration and intravasation of mammary tumor cells (5, 6). Bone marrow-derived cells that express myeloid cell marker CD11b and granulocyte marker Gr-1 (CD11b + Gr-1 + ) also promote metastasis of breast cancer cells, likely through promotion of intravasation and suppression of immune responses (7). Furthermore, CD11b + myeloid cells that express vascular endothelial growth factor receptor 1 (VEGFR1) accumulate at the metastatic sites before the arrival of lung cancer and melanoma cells and foster the dissemination of the cancer cells (8). These reports suggest that bone marrow-derived myeloid cells can help cancer epithelium in early steps of metastasis. It remains to be determined whether therapeutics targeting such myeloid cells can prevent cancer metastasis (9).As a model for invasive colon cancer, we previously constructed cis-Apc +/Δ716 Smad4 +/− (Apc/Smad4) mice that develop intestinal adenocarcinomas with marked invasions by loss of Apc and Smad4 tumor suppressor genes in the intestinal epithelium (10, 11). In the Apc/Smad4 tumors, we reported that the invading cancer epithelium is associated with immature myeloid cells (iMCs) that express myeloid progenitor cell marker CD34 and CD11b (12). Because these iMCs do not express Gr-1 or VEGFR1, they belong to a different subc...

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Section: Discussionsupporting

confidence: 93%

Inactivation of chemokine (C-C motif) receptor 1 (CCR1) suppresses colon cancer liver metastasis by blocking accumulation of immature myeloid cells in a mouse model

Kitamura

Fujishita

Loetscher

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

153

139

View full text Add to dashboard Cite

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“…The cutoff point analysis showed a broad range of MMP-2 levels with a significant and unidirectional relation with survival outcome: high tumour MMP-2 levels are unfavourable for the patients' prognosis. Our ELISA-derived MMP-2 data correspond very well with a recent immunohistochemical study in a group of 351 colorectal cancer patients, showing that high expression of MMP-2 in malignant epithelium as well as in the surrounding stroma was associated with reduced survival (Hilska et al, 2007). Similar analysis on our tumour MMP-9 data revealed that not only patients with the highest, but also those with the lowest levels had a worse survival than patients with intermediate levels.…”

Section: Discussionsupporting

confidence: 89%

MMP-2 geno-phenotype is prognostic for colorectal cancer survival, whereas MMP-9 is not

et al. 2008

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The prognostic significance of single-nucleotide polymorphisms (SNPs) and tumour protein levels of MMP-2 and MMP-9 was evaluated in 215 colorectal cancer patients. Single-nucleotide polymorphism MMP-2 À1306T and high MMP-2 levels were significantly associated with worse survival. Extreme tumour MMP-9 levels were associated with poor prognosis but SNP MMP-9 À1562C4T was not. Tumour MMP levels were not determined by their SNP genotypes.

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“…The involvement of different molecular pathways in colorectal carcinogenesis is exemplified by the fact that cancers of "mutator" phenotypes preferentially occur in the proximal (right side) colon, whereas the adenomacarcinoma sequence phenotype is characteristic of carcinomas in the distal (left side) colon and rectum [22,23] . Corresponding differences have also been shown in association with other potential prognosticators [24] . Interestingly, a marginally significant relation was observed between the NI and MI and response to treatment.…”

Section: Discussionmentioning

confidence: 53%

Nuclear β-catenin expression as a prognostic factor in advanced colorectal carcinoma

Elzagheid

Buhmeida²,

Korkeila³

et al. 2008

WJG

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AIM:To investigate the changing pattern of β-catenin expression and its prognostic value in advanced colorectal cancer (CRC). METHODS: Archival tumor samples were analyzed for β-catenin using immunohistochemistry (IHC) in 95 patients with advanced CRC. RESULTS: Membranous β-catenin expression was found in the normal colorectal epithelium. Almost 1 0 0 % o f C R C c a s e s s h o w e d m e m b ra n o u s a n d cytoplasmic expression, and 55 (58%) cases showed nuclear expression. In univariate (Kaplan-Meier) survival analysis, only the nuclear index (NI) was a significant predictor of disease-free survival (DFS) (P = 0.023; n = 35), with a NI above the median associated with longer DFS (34.2 mo) than those with a NI below the median (15.5 mo) (P = 0.045, ANOVA). The other indices were not significant predictors of DFS, and none of the three tested indices (for membranous, cytoplasmic, or nuclear expression) predicted diseasespecific survival (DSS). However, when dichotomized as positive or negative nuclear expression, the former was a significant predictor of more favorable DFS (P = 0.041) and DSS (P = 0.046). CONCLUSION: Nuclear β-catenin expression provides additional information in predicting patient outcome in advanced CRC.

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Prognostic significance of matrix metalloproteinases‐1, ‐2, ‐7 and ‐13 and tissue inhibitors of metalloproteinases‐1, ‐2, ‐3 and ‐4 in colorectal cancer

Cited by 133 publications

References 52 publications

Inactivation of chemokine (C-C motif) receptor 1 (CCR1) suppresses colon cancer liver metastasis by blocking accumulation of immature myeloid cells in a mouse model

Inactivation of chemokine (C-C motif) receptor 1 (CCR1) suppresses colon cancer liver metastasis by blocking accumulation of immature myeloid cells in a mouse model

MMP-2 geno-phenotype is prognostic for colorectal cancer survival, whereas MMP-9 is not

Nuclear β-catenin expression as a prognostic factor in advanced colorectal carcinoma

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