Matrix Metalloproteinase-9 Expression In Cancer Cells Research Articles

Matrix Metalloproteinase 9 Induced in Esophageal Squamous Cell Carcinoma Cells via Close Contact with Tumor-Associated Macrophages Contributes to Cancer Progression and Poor Prognosis.

Tumor-associated macrophages (TAMs) contribute to disease progression in various cancers, including esophageal squamous cell carcinoma (ESCC). We have previously used an indirect co-culture system between ESCC cell lines and macrophages to analyze their interactions. Recently, we established a direct co-culture system to closely simulate actual ESCC cell-TAM contact. We found that matrix metalloproteinase 9 (MMP9) was induced in ESCC cells by direct co-culture with TAMs, not by indirect co-culture. MMP9 was associated with ESCC cell migration and invasion, and its expression was controlled by the Stat3 signaling pathway in vitro. Immunohistochemical analyses revealed that MMP9 expression in cancer cells at the invasive front ("cancer cell MMP9") was related to high infiltration of CD204 positive M2-like TAMs (p < 0.001) and was associated with worse overall and disease-free survival of patients (p = 0.036 and p = 0.038, respectively). Furthermore, cancer cell MMP9 was an independent prognostic factor for disease-free survival. Notably, MMP9 expression in cancer stroma was not associated with any clinicopathological factors or patient prognoses. Our results suggest that close interaction with TAMs infiltrating in cancer stroma or cancer nests induces MMP9 expression in ESCC cells, equipping them with more malignant features.

Gallic acid-capped gold nanoparticles inhibit EGF-induced MMP-9 expression through suppression of p300 stabilization and NFκB/c-Jun activation in breast cancer MDA-MB-231 cells

Triple-negative breast cancers (TNBCs) are highly invasive and have a higher rate of distant metastasis. Matrix metalloproteinase-9 (MMP-9) plays a crucial role in EGF/EGFR-mediated malignant progression and metastasis of TNBCs. Various studies have revealed that treatment with gallic acid down-regulates MMP-9 expression in cancer cells, and that conjugation of phytochemical compounds with gold nanoparticles (AuNPs) increases the anti-tumor activity of the phytochemical compounds. Thus, the effect of gallic acid-capped AuNPs (GA-AuNPs) on MMP-9 expression in EGF-treated TNBC MDA-MB-231 cells was analyzed in the present study. The so-called green synthesis of AuNPs by means of gallic acid was performed at pH10, and the resulting GA-AuNPs had spherical shape with an average diameter of approximately 50nm. GA-AuNPs notably suppressed migration and invasion of EGF-treated cells, and inhibited EGF-induced MMP-9 up-regulation. GA-AuNPs abrogated EGF-induced Akt/p65 and ERK/c-Jun phosphorylation, leading to down-regulation of MMP-9 mRNA and protein expression in EGF-treated cells. Meanwhile, EGF-induced p300 stabilization was found to be involved in MMP-9 expression, whereas GA-AuNPs inhibited the EGF-promoted stability of the p300 protein. Although GA-AuNPs and gallic acid suppressed EGF-induced MMP-9 up-regulation via the same signaling pathway, the effective concentration of gallic acid was approximately 100-fold higher than that of GA-AuNPs for inhibition of MMP-9 expression in EGF-treated cells to a similar extent. Collectively, our data indicate that, in comparison with gallic acid, GA-AuNPs have a superior ability to inhibit EGF/EGFR-mediated MMP-9 expression in TNBC MDA-MB-231 cells. Our findings also point to a way to improve the anti-tumor activity of gallic acid.

Bone morphogenetic protein 4 (BMP-4) and epidermal growth factor (EGF) inhibit metalloproteinase-9 (MMP-9) expression in cancer cells.

Matrix metalloproteinase-9 (MMP-9) plays a central role in the progression of the cancer. While a large number of studies have contributed to our understanding of the molecular mechanisms responsible for upregulating MMP-9 gene expression in normal and cancer cells, our knowledge on the signals that suppress MMP-9 expression is much more limited. Here, we report that EGF and BMP-4 cooperate to inhibit MMP-9 expression in cancer cells. Treatment with EGF reduces the expression of MMP-9 at both mRNA while augmenting BMP-4 expression. Interestingly, recombinant BMP-4 suppressed constitutive and PMA-induced MMP-9 expression in both fibrosarcoma and breast cancer cells. Addition of gremlin a natural inhibitor of BMP-4, inhibited the suppression of MMP-9 by EGF. The suppression of MMP-9 by BMP-4 likely occurs at the transcriptional level since BMP-4 suppressed MMP-9 mRNA expression and activation of a reporter vector encoding the human MMP-9 promoter. The suppressive effect of BMP-4 occurs via Smad1/5/8 and is specific since BMP-4 did not inhibit MMP-2 while BMP-2 was ineffective in suppressing MMP-9. Taken together, these results are consistent with a new paradigm for the role of EGF and BMPs in controlling MMP gene expression in cancer cells.

Anti-inflammatory macrophages activate invasion in pancreatic adenocarcinoma by increasing the MMP9 and ADAM8 expression

Patients with chronic pancreatitis with local inflammation have high risk for pancreatic cancer. The aim of this study was to examine the role of the inflammatory cells in the invasion of pancreatic cancer cells, focusing on the involvement of a disintegrin and metalloproteinase 8 (ADAM8) and matrix metalloproteinase 9 (MMP9) proteins. ADAM8 expression is associated with worse survival of pancreatic cancer patients. Monocytes from healthy donors were differentiated into macrophages. Pancreatic adenocarcinoma cells were cultured either alone or with differentiated macrophages. The cancer cell migration rate in Matrigel was measured by imaging fluorescently stained cells for 24 h. After invasion, cells were sorted into CD14 positive/negative macrophages and cancer cells with magnetic separation. The expression of ADAM8 and MMP9 was measured by the real-time PCR. Protein-level expression of ADAM8 and MMP9 was analyzed by Western blotting. In two series, siRNA technique was used to reduce either ADAM8 or MMP9 expression in the cancer cells. The coculture with macrophages increased cancer cell migration rate in Matrigel, and increased ADAM8 and MMP9 mRNA expression and protein level in the cancer cells. Reduction of ADAM8 expression with siRNA in the cancer cells decreased macrophage-induced migration rate of the cancer cells from 11.7±0.3 μm/h to 9.0±0.2 μm/h (p<0.01), and reduction of MMP9 expression decreased the migration rate to 10.1±0.2 μm/h (p<0.01). Anti-inflammatory macrophages increase pancreatic cancer cell migration rate in basement membrane matrix by inducing ADAM8 and MMP9 expression in cancer cells, thereby possibly enhancing the invasiveness of cancer.

Prognostic significance of matrix metalloproteinase-9 (MMP-9) in epithelial ovarian cancer

We investigated the expression of matrix metalloproteinase-9 (MMP-9) and its relation to clinicopathologic factors and survival and also to previously analyzed expressions of CD44 and hyaluronan in epithelial ovarian cancer. The expression of MMP-9 was analyzed immunohistochemically in 292 primary tumors and their 31 metastases. A low proportion of strong MMP-9 expression in cancer cells and high stromal MMP-9 expression correlated with advanced stage of the tumor (p=0.003, p=0.02, respectively). Stromal MMP-9 expression significantly correlated with hyaluronan positivity (p<0.0005), whereas MMP-9 did not correlate with CD44. In univariate analysis, a longer 10-year disease-related survival (DRS) was found in patients with a high proportion of MMP-9 or strong MMP-9 expression in cancer cells (p=0.02, p=0.05, respectively). However, high stromal expression of MMP-9 indicated short DRS (p=0.01). In multivariate analysis of all patients, MMP-9 expressing cancer or stromal cells were not independent prognostic factors, while in FIGO stage I patients a high percentage of MMP-9 positive cancer cells was associated with long DRS (p=0.008). These data suggest that MMP-9 has a dual role in tumor progression, acting against tumor advancement when in tumor epithelium and promoting tumor progression while in the stroma.