The Myofibroblast Is the Predominant Plasminogen Activator Inhibitor-1-Expressing Cell Type in Human Breast Carcinomas

Offersen, Birgitte Vrou; Nielsen, Boye Schnack; Høyer‐Hansen, Gunilla; Rank, Fritz; Hamilton-Dutoit, Stephen; Overgaard, Jens; Andreasen, Peter A.

doi:10.1016/s0002-9440(10)63547-x

Cited by 68 publications

(82 citation statements)

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“…Immunohistochemical localization studies of proteins involved in the activation and regulation of the efficient serine protease plasminogen, including urokinase plasminogen activator (uPA) and its specific inhibitor PAI-1 show that both are mainly expressed by myofibroblasts in human breast cancer. 45,46 High levels of uPA and PAI-1 are strongly correlated with poor prognosis in breast cancer, 47,48 supporting the assumption that the myofibroblast express a promoting role in cancer invasion. We recently reported that the predominant PAI-1 expressing cell in human colorectal cancer also is the myofibroblast, 49 and earlier studies indicated that elevated levels of PAI-1 in colon cancer patients are associated with poor prognosis.…”

Section: Discussionmentioning

confidence: 94%

Localization of tissue inhibitor of metalloproteinases 1 (TIMP‐1) in human colorectal adenoma and adenocarcinoma

Holten-Andersen

Hansen

Brünner³

et al. 2004

Intl Journal of Cancer

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Tissue inhibitor of matrix metalloproteases 1 (TIMP-1) inhibits the proteolytic activity of matrix metalloproteases and hereby prevents cancer invasion. However, TIMP-1 also possesses other functions such as inhibition of apoptosis, induction of malignant transformation and stimulation of cell-growth. We have previously demonstrated that TIMP-1 is elevated in blood from colorectal cancer patients and that high TIMP-1 levels predict poor prognosis. To clarify the role of TIMP-1 in colorectal tumorigenesis, the expression pattern of TIMP-1 in benign and malignant colorectal tumors was studied. In all of 24 cases of colorectal adenocarcinoma TIMP-1 mRNA was detected by in situ hybridization. In all cases TIMP-1 expression was found in fibroblast-like cells located at the invasive front but was seen only sporadically in normal mucosa. No TIMP-1 mRNA was seen in any of the cases in benign or malignant epithelial cells, in vascular cells or smooth muscle cells. Comparison of sections processed for TIMP-1 in situ hybridization with sections immunohistochemically stained with antibodies against TIMP-1 showed good correlation between TIMP-1 mRNA and immunoreactivity. Combining TIMP-1 in situ hybridization with immunohistochemical staining for ␣-smooth muscle actin or CD68 showed TIMP-1 mRNA in myofibroblasts but not in macrophages. TIMP-1 mRNA was detected in 2 of 7 adenomatous polyps in the adenoma area: in both cases associated with focal stromal inflammation at the epithelial-stromal interface. In conclusion, TIMP-1 expression is a rare event in benign human colon tissue but is highly expressed by myofibroblasts in association with invading colon cancer cells.

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Section: Discussionmentioning

confidence: 94%

Localization of tissue inhibitor of metalloproteinases 1 (TIMP‐1) in human colorectal adenoma and adenocarcinoma

Holten-Andersen

Hansen

Brünner³

et al. 2004

Intl Journal of Cancer

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“…Intriguingly, several studies have confirmed that PAI-1 was an important factor during the transformation of fibroblasts to myofibroblasts, which amplified the inflammatory response and resulted in the progression of fibrosis [13][14][15] . Offersen et al observed that myofibroblasts were the predominant PAI-1-expressing cell in breast carcinomas based on immunohistochemistry double staining [16] . Another study showed that the crucial step was the cleavage of the uPA receptor to D2D3 after binding of PAI-1 to uPA and the uPA receptor during fibroblast-to-myofibroblast differentiation [17] .…”

Section: Discussionmentioning

confidence: 99%

siRNA against plasminogen activator inhibitor-1 ameliorates bleomycin-induced lung fibrosis in rats

Zhang

Wang

et al. 2012

Acta Pharmacol Sin

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Aim: Plasminogen activator inhibitor-1 (PAI-1) is involved in the progression of pulmonary fibrosis. The present study was undertaken to examine the effects on pulmonary fibrosis of silencing PAI-1 expression with small interfering RNA (siRNA) and to assess the possible underlying mechanisms. Methods: Male Wistar rats were subjected to intratracheal injection of bleomycin (BLM, 5 mg/kg, 0.2 mL) to induce pulmonary fibrosis. Histopathological changes of lung tissue were examined with HE or Masson's trichrome staining. The expression levels of α-smooth muscle actin (α-SMA), collagen type-I and type-III, caspase-3, as well as p-ERK1/2 and PI3K/Akt in the lung tissue were evaluated using immunohistochemistry and Western blot analysis. The fibroblasts isolated from BLM-induced fibrotic lung tissue were cultured and transfected with pcDNA-PAI-1 or PAI-1 siRNA. The expression level of PAI-1 in the fibroblasts was measured using real time RT-PCR and Western blot analysis. The fibroblast proliferation was evaluated using MTT assay. Results: Intratracheal injection of PAI-1 siRNA (7.5 nmoL/0.2 mL) significantly alleviated alveolitis and collagen deposition, reduced the expression of PAI-1, α-SMA, collagen type-I and collagen type-III, and increased the expression of caspase-3 in BLM-induced fibrotic lung tissue. In consistence with the in vivo results, the proliferation of the cultured fibroblasts from BLM-induced fibrotic lung tissue was inhibited by transfection with PAI-1 siRNA, and accelerated by overexpression of PAI-1 by transfection with pcDNA-PAI-1. The expression of caspase-3 was increased as a result of PAI-1 siRNA transfection, and decreased after transfection with pcDNA-PAI-1. In addition, the levels of p-ERK1/2 and PI3K/Akt in the fibrogenic lung tissue were reduced after treatment with PAI-1 siRNA.Conclusion: The data demonstrate that PAI-1 siRNA inhibits alveolitis and pulmonary fibrosis in BLM-treated rats via inhibiting the proliferation and promoting the apoptosis of fibroblasts. Suppression ERK and AKT signalling pathways might have at least partly contributed to this process. Targeting PAI-1 is a promising therapeutic strategy for pulmonary fibrosis.

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“…Monoclonal anti-PAI-1 antibodies (mAbs) were described previously: mAb-1 (Nielsen et al, 1986;Bødker et al, 2003); mAb-2 (Wind et al, 2001);mAb-5 (Munch et al, 1991);mAb-6 (Wind et al, 2001);mAb-7 (Gils et al, 2003); MA33B8 (Verhamme et al, 1999;Gorlatova et al, 2003;Naessens et al, 2003); MAH4B3 (Declerck et al, 1995;Gils et al, 2003). A preparation of rabbit polyclonal anti-PAI-1 antibodies was described previously (Offersen et al, 2003). A horseradish peroxidase (HRP)-conjugated monoclonal anti-M13 phage antibody was purchased from GE Healthcare (Chalfont St. Giles, Buckinghamshire, UK).…”

Section: Methodsmentioning

confidence: 99%

A Peptide Accelerating the Conversion of Plasminogen Activator Inhibitor-1 to an Inactive Latent State

Mathiasen

Dupont²,

Christensen³

et al. 2008

Mol Pharmacol

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The serpin plasminogen activator inhibitor-1 (PAI-1) is a specific inhibitor of plasminogen activators and a potential therapeutic target in cancer and cardiovascular diseases. Accordingly, formation of a basis for development of specific PAI-1-inactivating agents is of great interest. One possible inactivation mode for PAI-1 is conversion to the inactive, so-called latent state. We have now screened a phage-displayed peptide library with PAI-1 as bait and isolated a 31-residue cysteine-rich peptide that will be referred to as paionin-4. A recombinant protein consisting of paionin-4 fused to domains 1 and 2 of the phage coat protein g3p caused a 2-to 3-fold increase in the rate of spontaneous inactivation of PAI-1. Paionin-4-D1D2 bound PAI-1 with a K D in the high nanomolar range. Using several biochemical and biophysical methods, we demonstrate that paionin-4-D1D2-stimulated inactivation consists of an acceleration of conversion to the latent state. As demonstrated by site-directed mutagenesis and competition with other PAI-1 ligands, the binding site for paionin-4 was localized in the loop between ␣-helix D and ␤-strand 2A. We also demonstrate that a latency-inducing monoclonal antibody has an overlapping, but not identical binding site, and accelerates latency transition by another mechanism. Our results show that paionin-4 inactivates PAI-1 by a mechanism clearly different from other peptides, small organochemical compounds, or antibodies, whether they cause inactivation by stimulating latency transition or by other mechanisms, and that the loop between ␣-helix D and ␤-strand 2A can be a target for PAI-1 inactivation by different types of compounds.Plasminogen activator inhibitor type-1 (PAI-1) is a fast and specific inhibitor of the urokinase-type plasminogen activator (uPA) and the tissue-type plasminogen activator. PAI-1 is therefore an important regulator of the physiological and pathophysiological functions of plasminogen activation. A high level of PAI-1 in blood is associated with an increased risk of thrombotic events (for review, see Vaughan, 1998). PAI-1 is therefore a potential target for antithrombotic therapy. A high level of PAI-1 in tumors is associated with a poor prognosis, and several studies have suggested that PAI-1 is contributory to tumor invasion and metastasis (for review, see Andreasen et al., 1997Andreasen et al., , 2000Durand et al., 2004;Andreasen, 2007). PAI-1 is therefore a potential target for anticancer therapy.PAI-1 belongs to the serpins, a protein family of which the best characterized members are known to be inhibitors of serine proteases. Serpins are globular proteins consisting of three ␤-sheets (A, B, and C) and nine ␣-helices (A-I). Of crucial importance for the inhibitory mechanism of serpins is the surface-exposed reactive center loop (RCL), tethered between ␤-strands 1C and 5A. The active site of the protease attacks the P1-P1Ј bond in the RCL as a substrate, but at the enzyme-acyl intermediate stage, where the active site serine of the protease and the P1 r...

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The Myofibroblast Is the Predominant Plasminogen Activator Inhibitor-1-Expressing Cell Type in Human Breast Carcinomas

Cited by 68 publications

References 54 publications

Localization of tissue inhibitor of metalloproteinases 1 (TIMP‐1) in human colorectal adenoma and adenocarcinoma

Localization of tissue inhibitor of metalloproteinases 1 (TIMP‐1) in human colorectal adenoma and adenocarcinoma

siRNA against plasminogen activator inhibitor-1 ameliorates bleomycin-induced lung fibrosis in rats

A Peptide Accelerating the Conversion of Plasminogen Activator Inhibitor-1 to an Inactive Latent State

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