A Novel Biomarker for Staging Human Prostate Adenocarcinoma: Overexpression of Matriptase with Concomitant Loss of its Inhibitor, Hepatocyte Growth Factor Activator Inhibitor-1

Saleem, Mohammad; Adhami, Vaqar M.; Zhong, Weixiong; Longley, B. Jack; Lin, Chen Yong; Dickson, Robert B.; Reagan-Shaw, Shannon; Jarrard, David F.; Mukhtar, Hasan

doi:10.1158/1055-9965.epi-05-0737

Cited by 131 publications

(107 citation statements)

References 31 publications

(49 reference statements)

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“…In the later stages therapeutic alternatives are not available, as the tumor progresses from androgen-dependence to -independence. The lack of effective therapies for advanced PCa is related to a large extent to poor understanding of the molecular mechanisms underlying the progression of disease toward invasion and metastasis (3). Therefore, the identification of new predictive biomarkers, especially those that are indicative of invasiveness of the disease, which could serve as targets for establishing effectiveness of therapeutic and chemopreventive interventions, will improve clinical management of PCa (4).…”

Section: Introductionmentioning

confidence: 99%

ADAM17 targets MMP-2 and MMP-9 via EGFR-MEK-ERK pathway activation to promote prostate cancer cell invasion

Xiao

Lin²,

Lin³

et al. 2011

Int J Oncol

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Abstract. ADAM17, also known as tumor necrosis factor-α converting enzyme (TACE), is involved in proteolytic ectodomain shedding of cell surface molecules and cytokines. Although aberrant expression of ADAM17 has been shown in various malignancies, the function of ADAM17 in prostate cancer has not been clarified. In the present study, we sought to elucidate whether ADAM17 contributes to prostate cancer cell invasion, as well as the mechanism involved in the process. The expression pattern of ADAM17 was investigated in human prostate cancer cells. The results showed that ADAM17 expression levels are correlated with the invasive ability of androgen-independent prostate cancer cell lines. Further, ADAM17 was overexpressed in cells showing high invasion characteristics, activation of the EGFR-MEK-ERK pathway, up-regulation of MMP-2, MMP-9, and an increased TGF-α release into the supernatant. However, AG1478, PD98059 and antibody against TGF-α deactivating the EGFR-MEK-ERK signaling pathway, abolished up-regulation of MMP-2, MMP-9 and prevented cell invasion. In addition, cells with knockdown of ADAM17 by siRNA exhibited low invasive ability, deactivated EGFR-MEK-ERK signaling pathway, reduced TGF-α released and down-regulation of MMP-2, MMP-9. However, these effects could be reversed by simultaneous addition of TGF-α. These data demonstrated that ADAM17 contributes to androgen-independent prostate cancer cell invasion by shedding of EGFR ligand TGF-α, which subsequently activates the EGFR-MEK-ERK signaling pathway, leading finally to overexpression of MMP-2 and MMP-9. This study suggests that the ADAM17 expression level may be a new predictive biomarker of invasion and metastasis of prostate cancer, and ADAM17 could provide a target for treating metastatic PCa. IntroductionProstate cancer (PCa) is one of the most common malignancies among Western males with an occurrence of approximately 192,280 new cases and 27,360 deaths in the US, in 2009 (1). The growth and maintenance of cancerous cells in the early stages of prostate cancer is androgen-dependent and therapy often involves androgen deprivation (2). In the later stages therapeutic alternatives are not available, as the tumor progresses from androgen-dependence to -independence. The lack of effective therapies for advanced PCa is related to a large extent to poor understanding of the molecular mechanisms underlying the progression of disease toward invasion and metastasis (3). Therefore, the identification of new predictive biomarkers, especially those that are indicative of invasiveness of the disease, which could serve as targets for establishing effectiveness of therapeutic and chemopreventive interventions, will improve clinical management of PCa (4).The ADAMs (a disintegrin and metalloproteinase) are members of the metzincin superfamily of Zn-dependent matrix metalloproteinases. They are transmembrane and secreted proteins with important roles in diverse biological functions, such as fertilization, adhesion, migration, proteolysis and signaling (5,6). Recent...

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Section: Introductionmentioning

confidence: 99%

ADAM17 targets MMP-2 and MMP-9 via EGFR-MEK-ERK pathway activation to promote prostate cancer cell invasion

Xiao

Lin²,

Lin³

et al. 2011

Int J Oncol

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“…In normal tissue, the ratio of matriptase to HAI-1 is low, resulting in little matriptasemediated proteolysis (14). The matriptase/HAI-1 ratio increases during the progression of certain cancers, resulting in a population of active matriptase on the cell surface (15).…”

mentioning

confidence: 99%

Imaging a functional tumorigenic biomarker in the transformed epithelium

LeBeau

Lee

Murphy

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Proteases responsible for the increased peritumoral proteolysis associated with cancer represent functional biomarkers for monitoring tumorigenesis. One attractive extracellular biomarker is the transmembrane serine protease matriptase. Found on the surface of epithelial cells, the activity of matriptase is regulated by its cognate inhibitor hepatocyte growth factor activator inhibitor-1 (HAI-1). Quantitative mass spectrometry allowed us to show that, in selected cancers, HAI-1 expression decreases, leading to active matriptase. A preclinical probe specific for the measurement of emergent active matriptase was developed. Using an active-site-specific, recombinant human antibody for matriptase, we found that the selective targeting of active matriptase can be used to visualize the tumorigenic epithelium. Live-cell fluorescence imaging validated the selectivity of the antibody in vitro by showing that the probe localized only to cancer cell lines with active matriptase on the surface. Immunofluorescence with the antibody documented significant levels of active matriptase in 68% of primary and metastatic colon cancer sections from tissue microarrays. Labeling of the active form of matriptase in vivo was measured in human colon cancer xenografts and in a patient-derived xenograft model using near-infrared and single-photon emission computed tomography imaging. Tumor uptake of the radiolabeled antibody, 111 In-A11, by active matriptase was high in xenografts (28% injected dose per gram) and was blocked in vivo by the addition of a matriptase-specific variant of ecotin. These findings suggest, through a HAI-1-dependent mechanism, that emergent active matriptase is a functional biomarker of the transformed epithelium and that its proteolytic activity can be exploited to noninvasively evaluate tumorigenesis in vivo.cancer biomarker | molecular imaging

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“…Further, levels of a-2 macroglobulin, which forms complexes with KLK2 (Frenette et al, 1997;Grauer et al, 1998;Heeb and Espana, 1998;Mikolajczyk et al, 1998), KLK4 (Obiezu et al, 2006), KLK5 (Michael et al, 2005) and KLK13 (Kapadia et al, 2004), also decrease during prostate cancer progression (Kanoh et al, 2001). In addition, as noted above, increased expression of the TTSP matriptase/MT-SP1 in prostate cancer is accompanied by decreased expression of the specific inhibitor of this enzyme (Saleem et al, 2006). Interestingly, in addition to reduced levels of expression of proteinase inhibitors during prostate cancer progression there is evidence that certain trypsin-like serine proteinases also modulate inhibitor levels by inactivation.…”

Section: Dysregulated Tryptic Proteolytic Activitymentioning

confidence: 78%

“…Significantly, elevated matriptase/MT-SP1 expression is accompanied by a decrease in the expression of hepatocyte growth factor activator inhibitor-1, the specific inhibitor of this tryptic proteinase (Saleem et al, 2006). A role for matriptase/MT-SP1 in prostate cancer progression has also been indicated by application of the selective inhibitor, CVS-3983, in a prostate cancer xenograft model.…”

Section: Par Cleavage By Other Prostatic Trypsin-like Serine Proteinasesmentioning

confidence: 99%

“…These include secreted enzymes, such as trypsin I, II (Paju et al, 2000;Bjartell et al, 2005) and IV (Takeuchi et al, 1999;Cottrell et al, 2004); other more complex secreted serine proteinases, containing modular nonproteolytic domains, such as factor XIIa (Takeuchi et al, 1999), plasma kallikrein (Neth et al, 2001;Fink et al, 2007), urokinase (also known as urinary plasminogen activator, uPA; Gavrilov et al, 2001;Riddick et al, 2005;Usher et al, 2005) and protein C (He et al, 1995;Takeuchi et al, 1999); the multi-serine proteinase domain containing enzymes polyserase-2 and -3 (Cal et al, 2005(Cal et al, , 2006; the glycosyl-phosphatidylinositol membraneanchored serine proteinase prostasin (Chen et al, 2001); as well as nine members of the type II transmembrane serine proteinase (TTSP) sub-family (Hooper et al, 2001;Netzel-Arnett et al, 2003) including hepsin, enteropeptidase (Cottrell et al, 2004), matriptase/MT-SP1 (Saleem et al, 2006), TMPRSS2 (Lin et al, 1999), TMPRSS3 (Scott et al, 2001), TMPRSS13 (Kim et al, 2001), human airway trypsin-like proteinase (HAT) (Hahner et al, 2005), DESC1 (Lang and Schuller, 2001) and the multi-catalytic domain TTSP polyserase-1 (Okumura et al, 2006). It is also interesting to note the co-expression in prostatederived cell lines of trypsinogen I, II and IV and the in vivo Brought to you by | University of Queensland -UQ Library Authenticated Download Date | 9/14/15 3:38 AM activator of these enzymes, the TTSP enteropeptidase (Light and Janska, 1989;Kitamoto et al, 1994).…”

Section: Par Cleavage By Other Prostatic Trypsin-like Serine Proteinasesmentioning

confidence: 99%

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Prostatic trypsin-like kallikrein-related peptidases (KLKs) and other prostate-expressed tryptic proteinases as regulators of signalling via proteinase-activated receptors (PARs)

Ramsay

Reid

Adams

et al. 2008

BCHM

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The prostate is a site of high expression of serine proteinases including members of the kallikrein-related peptidase (KLK) family, as well as other secreted and membrane-anchored serine proteinases. It has been known for some time that members of this enzyme family elicit cellular responses by acting directly on cells. More recently, it has been recognised that for serine proteinases with specificity for cleavage after arginine and lysine residues (trypsin-like or tryptic enzymes) these cellular responses are often mediated by cleavage of members of the proteinase-activated receptor (PAR) family -a four member sub-family of G protein-coupled receptors. Here, we review the expression of PARs in prostate, the ability of prostatic trypsin-like KLKs and other prostateexpressed tryptic enzymes to cleave PARs, as well as the prostate cancer-associated consequences of PAR activation. In addition, we explore the dysregulation of trypsin-like serine proteinase activity through the loss of normal inhibitory mechanisms and potential interactions between these dysregulated enzymes leading to aberrant PAR activation, intracellular signalling and cancer-promoting cellular changes.

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A Novel Biomarker for Staging Human Prostate Adenocarcinoma: Overexpression of Matriptase with Concomitant Loss of its Inhibitor, Hepatocyte Growth Factor Activator Inhibitor-1

Cited by 131 publications

References 31 publications

ADAM17 targets MMP-2 and MMP-9 via EGFR-MEK-ERK pathway activation to promote prostate cancer cell invasion

ADAM17 targets MMP-2 and MMP-9 via EGFR-MEK-ERK pathway activation to promote prostate cancer cell invasion

Imaging a functional tumorigenic biomarker in the transformed epithelium

Prostatic trypsin-like kallikrein-related peptidases (KLKs) and other prostate-expressed tryptic proteinases as regulators of signalling via proteinase-activated receptors (PARs)

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