Prostaglandin production in mouse mammary tumour cells confers invasive growth potential by inducing hepatocyte growth factor in stromal fibroblasts

Matsumoto-Taniura, N; Matsumoto, Kunio; Nakamura, Toshikazu

doi:10.1038/sj.bjc.6690677

Cited by 31 publications

(24 citation statements)

References 54 publications

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“…Simultaneously DCs undergo a process of maturation by up-regulation of costimulatory molecules while migrating to lymphoid tissues. Several studies have shown that PGE 2 promotes invasion of a variety of cancer cells, such as lung, breast, and colorectal carcinoma cells (38,40,41,53,54). Interestingly, we found that PGE 2 decreased the migratory capacity of immature DC through the ECM, thus depending on the cell type, PGE 2 can act either to promote or inhibit migration.…”

Section: Discussionmentioning

confidence: 60%

Prostaglandin E2-Dependent Enhancement of Tissue Inhibitors of Metalloproteinases-1 Production Limits Dendritic Cell Migration through Extracellular Matrix

Baratelli

Heuzé-Vourc’h

Krysan

et al. 2004

The Journal of Immunology

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Dendritic cell (DC) migration is crucial for the initiation of immune responses. The balance between metalloproteinases (MMP) and tissue inhibitors of metalloproteinases (TIMP) has been shown to modulate DC migration. PGE2, which is overproduced in a wide variety of human malignancies, has been implicated in MMP and TIMP regulation in various cells, including monocytes. In the present study, we hypothesized that tumor-derived PGE2 would affect DC migratory capacity through the extracellular matrix (ECM) by altering MMP and TIMP balance. Treatment of monocyte-derived immature DC with exogenous PGE2 induced TIMP-1 secretion but not MMP-9 production and was correlated with reduced DC migration through ECM. Because recombinant TIMP-1 replicated PGE2 inhibition of DC migration while anti-TIMP-1 neutralizing Ab reversed it, we conclude that PGE2-mediated induction of TIMP-1 was responsible for the reduced migration of PGE2-treated DC. Similarly, DC cultured for 48 h in supernatants from cyclooxygenase-2 overexpressing lung cancer cells that secrete high levels of PGE2, exhibited decreased migration through ECM. Finally, analysis of E prostanoid receptor expression and their selective inhibition revealed that the enhanced TIMP-1 secretion in PGE2-treated DC was mediated predominantly by the E prostanoid receptor 2. These findings indicate that PGE2-dependent enhancement of TIMP-1 production causes reduced migration of DC through ECM.

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Section: Discussionmentioning

confidence: 60%

Prostaglandin E2-Dependent Enhancement of Tissue Inhibitors of Metalloproteinases-1 Production Limits Dendritic Cell Migration through Extracellular Matrix

Baratelli

Heuzé-Vourc’h

Krysan

et al. 2004

The Journal of Immunology

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“…Transcription of the HGF gene is well known to be stimulated by substances that increase cyclic AMP, including PGE 2 (63). It is therefore likely that this ability of HGF to promote PGE 2 synthesis is part of a positive feedback loop that results in amplification of…”

Section: Figurementioning

confidence: 99%

The antifibrotic effects of plasminogen activation occur via prostaglandin E2 synthesis in humans and mice

Bauman¹,

Wettlaufer²,

Okunishi³

et al. 2010

J. Clin. Invest.

133

111

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Plasminogen activation to plasmin protects from lung fibrosis, but the mechanism underlying this antifibrotic effect remains unclear. We found that mice lacking plasminogen activation inhibitor-1 (PAI-1), which are protected from bleomycin-induced pulmonary fibrosis, exhibit lung overproduction of the antifibrotic lipid mediator prostaglandin E 2 (PGE 2 ). Plasminogen activation upregulated PGE 2 synthesis in alveolar epithelial cells, lung fibroblasts, and lung fibrocytes from saline-and bleomycin-treated mice, as well as in normal fetal and adult primary human lung fibroblasts. This response was exaggerated in cells from Pai1 -/-mice. Although enhanced PGE 2 formation required the generation of plasmin, it was independent of proteinase-activated receptor 1 (PAR-1) and instead reflected proteolytic activation and release of HGF with subsequent induction of COX-2. That the HGF/COX-2/PGE 2 axis mediates in vivo protection from fibrosis in Pai1 -/-mice was demonstrated by experiments showing that a selective inhibitor of the HGF receptor c-Met increased lung collagen to WT levels while reducing COX-2 protein and PGE 2 levels. Of clinical interest, fibroblasts from patients with idiopathic pulmonary fibrosis were found to be defective in their ability to induce COX-2 and, therefore, unable to upregulate PGE 2 synthesis in response to plasmin or HGF. These studies demonstrate crosstalk between plasminogen activation and PGE 2 generation in the lung and provide a mechanism for the well-known antifibrotic actions of the fibrinolytic pathway.

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“…43 Finally, tumor-derived PG can also have a paracrine effect in stimulating the production of hepatocyte growth factor by stromal cells which may in turn stimulate uPA activity in tumor cells. 44 …”

Section: Prostaglandins and Cellular Invasivenessmentioning

confidence: 99%

Cyclooxygenase inhibitors retard murine mammary tumor progression by reducing tumor cell migration, invasiveness and angiogenesis

2001

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Tumor-derived prostaglandins (PGs) have been implicated in the progression of murine and human breast cancer. Chronic treatment with a non-selective PG inhibitor indomethacin was shown in this laboratory to retard the development and metastasis of spontaneous mammary tumors in C3H/HeJ female retired breeder mice. The present study examined the role of endogenous prostaglandins in the proliferation/survival, the migratory and invasive behavior and angiogenic ability of a highly metastatic murine mammary tumor cell line, C3L5, originally derived from a C3H/HeJ spontaneous mammary tumor. This cell line was shown to express high levels of cyclooxygenase (COX) -2 mRNA and protein as detected by Northern and Western blotting as well as immunostaining. PGE 2 production by C3L5 cells was primarily owing to COX-2, since this was blocked similarly with non-selective COX inhibitor indomethacin and selective COX-2 inhibitor NS-398, but unaffected with the selective COX-1 inhibitor valeryl salicylate. C3L5 cell proliferation/survival in vitro was not influenced by PGs, since their cellularity remained unaffected in the presence of PGE 2 or NS-398 or PG-receptor (EP1/EP2) antagonist AH6809; a marginal decline was noted only at high doses of indomethacin, which was not abrogated by addition of exogenous PGE 2 . Migratory and invasive abilities of C3L5 cells, as quantitated with in vitro transwell migration/invasion assays, were inhibited with indomethacin or NS-398 or AH6809 in a dose-dependent manner; the indomethacin and NS-398-mediated inhibition was partially reversed upon addition of exogenous PGE 2 . An in vivo angiogenesis assay that used subcutaneous implants of growth factor-reduced matrigel inclusive of tumor cells showed a significant inhibition of blood vessel formation in these implants in animals treated with indomethacin compared with animals receiving vehicle alone. These studies show that selective and nonselective COX-2 inhibitors retarded tumor progression in this COX-2-expressing murine mammary tumor model by inhibiting tumor cell migration, invasiveness and tumor-induced angiogenesis. The inhibitory effects were not entirely PG dependent; some PG-independent effects were also noted. Prostaglandins (PGs) produced by tumor cells or tumor-associated host cells (macrophages, endothelial cells and stromal cells) have long been considered to play a stimulating role in the progression and metastases of a variety of animal and human tumors including mammary tumors. Malignant breast tumors produce more PGs than normal breast tissue, and tumors with greater PG production were shown to have greater association with metastasis. 1,2 Also, patients with higher PG levels in breast tumor showed lower rates of survival after surgery. 3 The cyclooxygenase enzymes, COX -1 and -2, synthesize PGs from arachidonic acid, an unsaturated fatty acid found in cell membrane lipids. COX-1 is constitutively expressed in most tissues leading to relatively low levels of PG production. COX-2 expression is induced in a variety of cells, e....

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Prostaglandin production in mouse mammary tumour cells confers invasive growth potential by inducing hepatocyte growth factor in stromal fibroblasts

Cited by 31 publications

References 54 publications

Prostaglandin E2-Dependent Enhancement of Tissue Inhibitors of Metalloproteinases-1 Production Limits Dendritic Cell Migration through Extracellular Matrix

Prostaglandin E2-Dependent Enhancement of Tissue Inhibitors of Metalloproteinases-1 Production Limits Dendritic Cell Migration through Extracellular Matrix

The antifibrotic effects of plasminogen activation occur via prostaglandin E2 synthesis in humans and mice

Cyclooxygenase inhibitors retard murine mammary tumor progression by reducing tumor cell migration, invasiveness and angiogenesis

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