RNA Interference Inhibition of Matrix Metalloproteinase-1 Prevents Melanoma Metastasis by Reducing Tumor Collagenase Activity and Angiogenesis

Blackburn, Jessica S.; Rhodes, C. Harker; Coon, Charles I.; Brinckerhoff, Constance E.

doi:10.1158/0008-5472.can-07-1791

Cited by 80 publications

(95 citation statements)

References 38 publications

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“…Furthermore, two MMP family members, MMP-1 and MMP-2, have been recently found to be important functional mediators in the generation of pulmonary metastases from breast carcinomas (36). Likewise, RNA interference inhibition of MMP-1 prevents melanoma metastasis by reducing tumor collagenase activity and angiogenesis (37). However, the observations reported herein for MMP-8, as well as recent findings for other MMP family members (38)(39)(40)(41)(42), clearly indicate that the cancer protective roles of MMPs may be much more relevant than anticipated.…”

Section: Discussionmentioning

confidence: 99%

Matrix Metalloproteinase-8 Functions as a Metastasis Suppressor through Modulation of Tumor Cell Adhesion and Invasion

Gutiérrez‐Fernández¹,

Fueyo

Folgueras³

et al. 2008

Cancer Research

172

153

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Collagenase-2 (matrix metalloproteinase-8, MMP-8) is an MMP mainly produced by neutrophils and associated with many inflammatory conditions. We have previously described that MMP-8 plays a protective role in cancer through its ability to regulate the inflammatory response induced by carcinogens. Moreover, it has been reported that experimental manipulation of the expression levels of this enzyme alters the metastatic behavior of human breast cancer cells. In this work, we have used mutant mice deficient in MMP-8 and syngenic melanoma and lung carcinoma tumor cells lines overexpressing this enzyme to further explore the putative antimetastatic potential of MMP-8. We report herein that MMP-8 prevents metastasis formation through the modulation of tumor cell adhesion and invasion. Thus, tumor cells overexpressing MMP-8 have an increased adhesion to extracellular matrix proteins, whereas their invasive ability through Matrigel is substantially reduced when compared with control cells. Analysis of MMP-8 in breast cancer patients revealed that the expression of this metalloproteinase by breast tumors correlates with a lower incidence of lymph node metastasis and confers good prognosis to these patients. On this basis, we propose that MMP-8 is a tumor protective factor, which also has the ability to reduce the metastatic potential of malignant cells in both mice and human.

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Section: Discussionmentioning

confidence: 99%

Matrix Metalloproteinase-8 Functions as a Metastasis Suppressor through Modulation of Tumor Cell Adhesion and Invasion

Gutiérrez‐Fernández¹,

Fueyo

Folgueras³

et al. 2008

Cancer Research

172

153

View full text Add to dashboard Cite

show abstract

“…Consequently, a tumor therapy targeting MMP-2 would be particularly efficacious in the treatment of pancreatic cancer. As a very potent tool, RNAi technology can generate a cellular knockdown of a desired gene utilizing a plasmid-based system that stably expresses siRNA molecules to target specific mRNAs for degradation [9,10] . In this study, we developed a siRNA sequence, when stably integrated into cellular DNA, which can selectively target MMP-2 expression.…”

Section: Discussionmentioning

confidence: 99%

Suppression of matrix metalloproteinase-2 via RNA interference inhibits pancreatic carcinoma cell invasiveness and adhesion

Yuan¹,

Song²,

Wang³

et al. 2009

WJG

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AIM: To i n v e s t i g a t e t h e i n h i b i t o r y e f f e c t s o fRNA interference (RNAi) on expression of matrix metalloproteinase-2 (MMP-2 ) gene and invasiveness and adhesion of human pancreatic cancer cell line, BxPC-3. METHODS:RNAi was performed using the vector (pGPU6)-based small interference RNA (siRNA) plasmid gene silence system to specifically knock down MMP-2 expression in pancreatic cancer cell line, BxPC-3. Four groups of different specific target sequence in coding region of MMP-2 and one non-specific sequence were chosen to construct four experimental siRNA plasmids of pGPU6-1, pGPU6-2, pGPU6-3 and pGPU6-4, and one negative control siRNA plasmid of pGPU6 (-). MMP-2 expression was measured by reverse transcription polymerase chain reaction (RT-PCR) and Western blot. Cell proliferation and apoptosis were examined by methyl thiazolyl tetrazolium (MTT) and flow cytometry, respectively. The abilities of adhesion and invasion were detected by cell adhesion assay and cell invasion assay using Transwell chambers. RESULTS:The expression of MMP-2 was inhibited and the inhibitory effects of different sequence varied. pGPU6-1 group had the most efficient inhibitory effect, followed by pGPU6-2 and pGPU6-3 groups.Invasiveness and adhesion were more significantly reduced in pGPU6-1, pGPU6-2 and pGPU6-3 groups as compared with pGPU6 (-) and blank control groups. However, no difference concerning cell proliferation and apoptosis was observed after transfection between experiment groups and control groups. CONCLUSION:RNAi against MMP-2 successfully inhibited the mRNA and protein expression of MMP-2 in the pancreatic cancer cell line, BxPC-3, leading to a potent suppression of tumor cell adhesion and invasion without affecting cell proliferation and apoptosis. These findings suggest that the RNAi approach towards MMP-2 may be an effective therapeutic strategy for the clinical management of pancreatic tumor.

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“…Indeed, targeted inhibition of heparanase expression by antisense complementary DNA transfection showed a significant reduction in the invasive and metastatic properties of tumor cells in an animal model (Uno et al, 2001). Short hairpin RNAs that mediated the attenuation of MMP expression also prevented the progression of human tumor cells in vivo (Blackburn et al, 2007). Although there is a risk that the metastatic potential of tumor cells may be increased by heparanase expression, we found that the intrathoracic administration of 10 7 PFU of Ad-S/hep alone had no apparent effects on the growth of pleural mesothelioma, indicating that this particular dose of the virus appears to be safe (Figure 6a).…”

Section: Discussionmentioning

confidence: 85%

A novel translational approach for human malignant pleural mesothelioma: heparanase-assisted dual virotherapy

et al. 2009

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Malignant pleural mesothelioma (MPM) is a highly aggressive tumor that is related to asbestos exposure. MPM is characterized by rapid and diffuse local growth in the thoracic cavity, and it has a poor prognosis because it is often refractory to conventional therapy. Although MPM is an extraordinarily challenging disease to treat, locoregional virotherapy may be useful against this aggressive disease because of the accessibility by intrapleural virus delivery. In this study, we show that telomerasespecific, replication-selective adenovirus OBP-301 can efficiently infect and kill human mesothelioma cells by viral replication. Intrathoracic administration of virus significantly reduced the number and size of human mesothelioma tumors intrathoracically implanted into nu/nu mice. A high-definition, fluorescence optical imaging system with an ultra-thin, flexible fibered microprobe clearly detected intracellular replication of green fluorescent protein-expressing oncolytic virus in intrathoracically established mesothelioma tumors. As the extracellular matrix (ECM) may contribute to the physiological resistance of a solid tumor by preventing the penetration of therapeutic agents (including oncolytic viruses), we also examined whether the co-expression of heparanase, an endoglucuronidase capable of specifically degrading heparan sulfate, that influences the physiological barrier to macromolecule penetration, can modify the permeability of the ECM, resulting in profound therapeutic efficacy. Co-injection of OBP-301 and a replication-defective adenovirus (Ad-S/hep)-expressing heparanase resulted in more profound antitumor effects without apparent toxicity in an orthotopic pleural dissemination model. Our results suggest that intrathoracic dual virotherapy with telomerase-specific oncolytic adenovirus in combination with heparanase-expressing adenovirus may be efficacious in the prevention and treatment of pleural dissemination of human malignant mesothelioma.

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RNA Interference Inhibition of Matrix Metalloproteinase-1 Prevents Melanoma Metastasis by Reducing Tumor Collagenase Activity and Angiogenesis

Cited by 80 publications

References 38 publications

Matrix Metalloproteinase-8 Functions as a Metastasis Suppressor through Modulation of Tumor Cell Adhesion and Invasion

Matrix Metalloproteinase-8 Functions as a Metastasis Suppressor through Modulation of Tumor Cell Adhesion and Invasion

Suppression of matrix metalloproteinase-2 via RNA interference inhibits pancreatic carcinoma cell invasiveness and adhesion

A novel translational approach for human malignant pleural mesothelioma: heparanase-assisted dual virotherapy

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