Stromal expression of fibroblast activation protein/seprase, a cell membrane serine proteinase and gelatinase, is associated with longer survival in patients with invasive ductal carcinoma of breast

Ariga, Naohiro; Satô, Eiichi; Ohuchi, Noriaki; Nishimura, Hiroshi; Ohtani, Haruo

doi:10.1002/1097-0215(20010120)95:1<67::aid-ijc1012>3.0.co;2-u

Cited by 128 publications

(84 citation statements)

References 21 publications

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“…This is the first study, to our knowledge, to systematically examine the expression of CAF markers, FAP and αSMA, in the tumor and stromal cells of neoadjuvant EOC cases in relation to clinico-pathological characteristics. Despite evidence that FAP expression by tumor-associated stroma indicated worse prognosis in colon, pancreatic and ovarian cancers, it has been shown that FAP expression reduced tumorigenicity in mouse models of melanoma and is also associated with longer survival in patients with invasive breast carcinoma [28,29]. These conflicting observations suggest that the physiologic responses to FAP may depend not only on the in vivo tumor microenvironment but also on the different microenvironments of FAP expression and even the somatic genetic aberrations found in tumor epithelium.…”

Section: Discussionmentioning

confidence: 99%

Clinical Implications of Marker Expression of Carcinoma-Associated Fibroblasts (CAFs) in Patients with Epithelial Ovarian Carcinoma After Treatment with Neoadjuvant Chemotherapy

Mhawech‐Fauceglia

Wang

Samrao

et al. 2013

Cancer Microenvironment

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Cancer-associated fibroblasts (CAFs) play an important role in tumor initiation and progression. The aim of this study is to explore the role of 2 CAF markers, fibroblast activated protein (FAP) and α-smooth muscle actin (αSMA), in patients with epithelial ovarian cancer (EOC) post-neoadjuvant chemotherapy. Sixty-six patients with the diagnosis of EOC treated with debulking surgery after neoadjuvant therapy were retrieved from the archives. Immunohistochemistry for FAP and αSMA antibodies were performed on paraffin-embedded tissue. αSMA was expressed by tumor-associated stroma in 95 % of cases and by tumor cells in 9 % of cases. No statistical power was found for αSMA and disease status. Our data indicate that FAP plays an important role in predicting tumor aggressiveness in patients with EOC post-neoadjuvant therapy, and its frequent expression in this malignancy implicates that FAP targeted therapy could be a very attractive strategy.

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Section: Discussionmentioning

confidence: 99%

Clinical Implications of Marker Expression of Carcinoma-Associated Fibroblasts (CAFs) in Patients with Epithelial Ovarian Carcinoma After Treatment with Neoadjuvant Chemotherapy

Mhawech‐Fauceglia

Wang

Samrao

et al. 2013

Cancer Microenvironment

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“…All groups agree that seprase is induced and expressed to aberrantly high levels in human breast cancer (1,2,29). We investigated 27 cases of infiltrating ductal carcinoma of the breast and found that the carcinoma cells as well as the stromal cells express seprase (2).…”

Section: Seprase Promotes Growth Of Breast Cancer Cellsmentioning

confidence: 99%

“…The finding of carcinoma cell expression of seprase is supported by the constitutive expression of seprase in several human breast cancer cell lines and by its expression in the malignant cells of a number of other carcinomas including melanoma and gastric cancer (11,14,30). On the other hand, two other studies of human breast cancer, including one survey of 112 cases, have indicated that seprase is detected primarily in the reactive stromal fibroblasts, suggesting that reactive fibroblasts are the main source of seprase in breast cancer (21,29). Thus, there is debate about which cells express seprase in tumors of human breast cancer.…”

Section: Seprase Promotes Growth Of Breast Cancer Cellsmentioning

confidence: 99%

Seprase Promotes Rapid Tumor Growth and Increased Microvessel Density in a Mouse Model of Human Breast Cancer

Huang

Wang²,

Kelly³

2004

Cancer Research

109

113

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Seprase is a cell surface serine protease that is expressed to high levels by invading human breast carcinoma cells. To investigate the role of seprase in breast cancer, MDA MB-231 human mammary adenocarcinoma cells were engineered to express active seprase to high levels. All cells grow rapidly in cell culture. But differences are discovered when the cells are tested for tumorigenicity, growth, and microvessel density by implantation into the mammary fat pads of female severe combined immunodeficient mice. Control transfectants that do not express seprase grow slowly whereas cells that express seprase to high levels form fastgrowing tumors that are highly vascular. Microvessel density is elevated in tumors of two different lines of seprase transfectants to 146 ؎ 67.4 and 144 ؎ 33.42 vessels/mm 2 as compared with 50.5 ؎ 12.9 vessels/mm 2 for tumors of control-transfected cells that do not express seprase. Sepraseexpressing cells are better able to attract blood vessels and exhibit rapid tumor growth.

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“…Seprase has also been shown to be one of a number of serine proteases required for microvascular endothelial cell reorganization and capillary morphogenesis in vitro (Aimes et al 2003). It is overexpressed by invasive tumour cells (Pineiro-Sanchez et al 1997;Monsky et al 1994) in particular it has been shown to be expressed by activated fibroblasts in the stroma of various epithelial cancers, mesenchymal tumours and breast-cancer cells (Ariga et al 2001). Clinicopathologic analysis has revealed increased Seprase expression in cases of invasive ductal carcinoma is associated with longer overall and disease-free survival (Ariga et al 2001;Kelly et al 1998).…”

Section: Introductionmentioning

confidence: 99%

“…It is overexpressed by invasive tumour cells (Pineiro-Sanchez et al 1997;Monsky et al 1994) in particular it has been shown to be expressed by activated fibroblasts in the stroma of various epithelial cancers, mesenchymal tumours and breast-cancer cells (Ariga et al 2001). Clinicopathologic analysis has revealed increased Seprase expression in cases of invasive ductal carcinoma is associated with longer overall and disease-free survival (Ariga et al 2001;Kelly et al 1998). Seprase activity is most often assessed by zymography, which is not a quantitative assay, but can be assessed qualitatively by measuring the release of gelatin fragments from radiolabelled gelatin (Kelly, 1999).…”

Section: Introductionmentioning

confidence: 99%

Purification, identification and characterisation of seprase from bovine serum

Collins

McMahon

O’Brien

et al. 2004

The International Journal of Biochemistry & Cell Biology

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ABBREVIATIONSAMC, 7-amino-4-methylcoumarin; BCA, bicinchoninic acid; CPC, calcium phosphate cellulose; DFP, diisopropylfluorophosphate; FPLC, fast protein liquid chromatography; HIC, hydrophobic interaction chromatography; PO, prolyl oligopeptidase; TFA, trifluoroacetic acid; Z, N-benzyloxycarbonyl; ZIP, Z-Pro-prolinal-insensitive Z-Gly-Pro-AMC-hydrolysing peptidase. ABSTRACTThe study and identification for the first time of a soluble form of a Seprase activity from bovine serum is presented. To date, this activity has only been reported to be an integral membrane protease but has been known to shed from its membrane. The activity was purified 30,197-fold to homogeneity, using a combination of column chromatographies, from bovine serum. Inhibition by DFP, resulting in an IC 50 of 100nM confirms classification as a serine protease. The protease after separation and visualisation by native PAGE was subjected to tryptic digestion and the subsequent peptides sequenced. Each peptide sequenced was found to be present in the primary structure of Seprase/Fibroblast Activation Protein (FAP), a serine gelatinase specific for proline-containing peptides and macromolecules. Substrate specificity studies using kinetic, RP-HPLC and LC-MS analysis of synthetic peptides suggest that this peptidase has an extended substrate-binding region in addition to the primary specificity site S 1 . This analysis revealed at least five subsites to be involved in enzyme-substrate binding, 2 with the smallest peptide cleaved being a tetrapeptide. A proline residue in position P 1 was absolutely necessary therefore showing high primary substrate specificity for the Pro-X bond, while a preference for a hydrophobic residue at the C-terminal end of the scissile bond (P 1 ʹ′) was evident. The enzyme also showed complete insensitivity to the prolyl oligopeptidase specific inhibitors, JTP-4819, Fmoc-Ala-pyrrCN and Z-Phe-Pro-BT. To date, no physiological substrate has clearly been defined for this protease but its ability to effectively degrade gelatin suggests a candidate protein substrate in vivo and a possible role in extracellular matrix protein degradation.

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Stromal expression of fibroblast activation protein/seprase, a cell membrane serine proteinase and gelatinase, is associated with longer survival in patients with invasive ductal carcinoma of breast

Cited by 128 publications

References 21 publications

Clinical Implications of Marker Expression of Carcinoma-Associated Fibroblasts (CAFs) in Patients with Epithelial Ovarian Carcinoma After Treatment with Neoadjuvant Chemotherapy

Clinical Implications of Marker Expression of Carcinoma-Associated Fibroblasts (CAFs) in Patients with Epithelial Ovarian Carcinoma After Treatment with Neoadjuvant Chemotherapy

Seprase Promotes Rapid Tumor Growth and Increased Microvessel Density in a Mouse Model of Human Breast Cancer

Purification, identification and characterisation of seprase from bovine serum

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