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Molecular Oncology, Markers, Clinical Correlates |
Department of Oncology, Lombardi Cancer Center, Georgetown University Medical Center, Washington, DC 20007 [M. D. O., M. D. J., R. B. D., C-Y. L., B. S.]; Imperial Cancer Research Fund Medical Oncology Unit, Western General Hospital, Edinburgh EH4 2XU, United Kingdom [M. S., J. F. S., H. G., G. C. S.]; and Department of Pathology, University of Edinburgh Medical School, Edinburgh EH8 9AG, United Kingdom [A. W., A. a-N.]
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ABSTRACT |
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 Top ABSTRACT INTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Experimental Design: We have determined by immunohistochemistry the expression of matriptase and HAI-1 in 54 epithelial ovarian cancers. Statistical analyses of immunohistochemistry expression data with clinical outcome and clinicopathological parameters were then performed.
Results: Of 54 tumors tested, 39 (72%) and 11 (20%) were positive for matriptase and for HAI-1, respectively. All HAI-1-positive tumors were also matriptase positive. Analysis of clinicopathological parameters demonstrated a loss of matriptase associated with stage III/IV tumors as compared with stage I/II tumors (P = 0.030). There was also a loss of HAI-1 expression associated with stage III/IV tumors (P = 0.039). Of 34 stage I/II tumors, 28 (82%) stained positive for matriptase, and 10 (29%) stained positive for HAI-1; 10 (29%) tumors showed coexpression. Of 20 stage III/IV tumors, however, 11 stained positive for matriptase (55%), only 1 of which coexpressed HAI-1 (P = 0.039).
Conclusions: Advanced-stage ovarian tumors that express matriptase are more likely to do so in the absence of its inhibitor, HAI-1, indicating that an imbalance in the matriptase:HAI-1 ratio could be important in the development of advanced disease. Such an imbalance could promote the proteolytic activity of matriptase and, consequently, a more invasive phenotype.
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INTRODUCTION |
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TopABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Matriptase was first isolated as a type II transmembrane serine protease expressed in human breast milk and in breast carcinoma (1, 2, 3) and subsequently cloned (4) . Other groups have also independently identified this serine protease. The gene sequence was initially identified as ST14/SNC19 through subtractive hybridization gene expression difference analysis (5) . Reverse biochemical studies led to the isolation from the prostate cancer cell line PC-3 of the membrane-type serine protease, MT-SP1, which is identical to matriptase (6) . Matriptase has also been cloned as TADG-15, a member of a series of tumor-associated, differentially expressed genes (7) . Its mouse homologue, epithin, has been cloned from thymic stroma (8) . Matriptase is expressed in a variety of carcinomas, including ovarian carcinomas, and is overexpressed in ovarian tumors relative to normal OSE3 (7 , 9) .
Latent uPA and pro-HGF are substrates for matriptase (10 , 11) . Both substrates participate in neoplastic progression, most notably in the plasmin-mediated remodeling of the extracellular matrix surrounding tumors (uPA), the activation of latent growth factors such as HGF (uPA), and in the stimulation of cancer cell growth and motility (uPA and HGF). The binding of uPA, itself a serine protease, to its receptor increases the proliferation of human ovarian cancer cells in vitro (12) . Antisense inhibition of uPA significantly reduces the i.p. spread of ovarian cancer when grown as xenografts in mice (13) . Both uPA and its inhibitor PAI-1 predict the survival of patients with advanced ovarian cancer and are associated with the malignant progression of the disease (14, 15, 16) . HGF stimulates the in vitro motility, chemotaxis, and proliferation of ovarian carcinoma cells (17) . HGF is found in ascitic fluid of both benign and malignant ovarian tumors and stimulates the migration of ovarian carcinoma cells (18) .
The lipid metabolites LPA and S-1-P induce the activation of matriptase in immortalized breast epithelial cells.4 In ovarian carcinoma cells, LPA increases cellular proliferation and cell survival, the synthesis of proteins such as vascular endothelial growth factor, interleukin 8, and uPA, and promotes resistance to cytotoxic agents such as cisplatin (19) . Ascites from ovarian cancer patients contain LPA at concentrations that activate ovarian cancer cells and are significantly higher than that found in ascites from nonmalignant conditions (20 , 21) . LPA and S-1-P may therefore promote the progression of ovarian carcinoma through the activation of matriptase.
The activity of matriptase is modulated by an inhibitor of the enzyme, termed HAI-1. HAI-1 also binds and inhibits the activity of a serine protease termed HGFA, also capable of cleaving and activating latent HGF (22 , 23) , in addition to binding and inhibiting matriptase (3) . HAI-1 is found predominantly in the columnar epithelium of many tissue types, including breast, stomach, lung, kidney, prostate, and uterus, and is up-regulated in injured or regenerative tissues (24) . HAI-1 may suppress the growth and motility of carcinoma cells by inhibiting the generation of active uPA by matriptase, active HGF by matriptase or HGFA, or by inhibiting the activity of additional unidentified serine proteases. Recently, HAI-1 immunoreactivity in human primary colorectal carcinomas was found to be decreased significantly in cells within colon carcinomas relative to adjacent normal mucosa or adenomas (25) . In contrast, the immunoreactivity of HGFA in these same tumors was comparable with that of adenomas but modestly increased relative to normal mucosa, indicating a change in the HGFA:HAI-1 ratio within these colon tumors that favors HGFA.
Taken together, these lines of evidence support a role for matriptase in the growth, invasion, and metastasis of numerous carcinomas and in particular, ovarian carcinomas. To test the hypothesis that the expression of matriptase, HAI-1, or the matriptase:HAI-1 ratio may correlate with the clinical stage, histological grade, histological type, or clinical outcome of patients with ovarian cancer, we have stained by IHC 54 epithelial ovarian tumors for matriptase and for HAI-1. We show significant associations of low matriptase and HAI-1 expression with advanced FIGO stage and of low frequency of matriptase and HAI-1 coexpression in advanced-stage tumors that favor matriptase protease activity, as compared with early-stage tumors.
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PATIENTS AND METHODS |
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TopABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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-actin [5'-ATGGCATCGTCACCAACTGG-3' (sense) and 5'-ATGACAATGCCAGTGGTGCG-3' (antisense)]. Matriptase RT-PCR amplification conditions used a touchdown protocol ranging from 67°C to 55°C: 94°C for 5 min; 94°C for 30 s, 67°C-58°C (decreasing 3°C/cycle) for 30 s, 72°C for 2 min at one cycle each; 94°C for 30 s, 55°C for 30 s, 72°C for 45 s for 30 cycles; and 72°C for 5 min. For -actin, a protocol incorporating a single annealing temperature of 55°C was used for 35 cycles. PCR products were separated on agarose gels and visualized after ethidium bromide staining.
Patients and Tissues.
Primary ovarian cancer specimens were obtained from 54 patients with ovarian cancer at the time of surgery at the Western General Hospital and Edinburgh Royal Infirmary (Edinburgh, United Kingdom) from 1988 to 1993. Optimal debulking surgery was attempted in all patients. Those with residual disease received chemotherapy according to local best practice guidelines at the time of presentation. Tumor specimens were fixed in 4% formaldehyde in PBS and rinsed in PBS before embedding in paraffin. Five-µm sections of tumor were cut from each block for immunohistochemical analysis for matriptase or HAI-1. Tumor histology was examined by two specialist gynecological histopathologists to determine their types and grades. Survival was defined as the time between histological diagnosis of ovarian cancer and ovarian cancer-specific death (30 deaths). Patients who died of other causes (2 patients) or who were still alive at the cutoff date for this study (5/29/01) were treated as censored (22 patients). The median survival time for all patients was 6 years and 1 month. The median follow-up time for censored patients was 8 years and 2 months (range, 23 months to 11 years). The histology of tumors fell into six categories: serous (18 tumors; 33%); mucinous (8 tumors; 15%); endometroid (17 tumors; 31%); clear cell (9 tumors; 17%); mixed endometrioid/clear cell (1 tumor; 2%); and unclassified carcinoma (1 tumor; 2%). Tumor stage was classified according to FIGO guidelines. Stage I tumors represented 57% of the sample; stage II, 6%; stage III, 35%; and stage IV, 2%. In this cohort of samples, the demographics are such that stage I tumors are overrepresented relative to the expected distribution of ovarian cancers (57% in this sample compared with 23% in our current clinical practice). Similarly, stage III tumors are underrepresented (35% in our sample compared with 51% in our current clinical practice). Tumor histological grade was classified as poorly differentiated (22 tumors of 49 classified; 45%), moderately differentiated (16 of 49; 33%), or well differentiated (11 of 49; 22%) according to standard histopathological grading. Histological grade was not available for 5 patients.
Immunohistochemistry for Matriptase and HAI-1.
Immunohistochemistry was performed using the Vectastain ABC kit (Vector Laboratories, Burlingame, CA) with minor modifications to the manufacturer’s protocol. Briefly, 5-µm tumor sections were heated in an oven to 56°C for 1 h and then dewaxed in xylene. Slides were then rehydrated by immersion in a decreasing gradient of ethanol in water. Endogenous peroxidase activity was quenched by immersion in 1.5% H2O2/methanol for 20 min, followed by washed in PBS. Sections were blocked for 30 min in blocking buffer (2% rabbit serum, 0.1% BSA in PBS) before incubation with the primary antibody. Sections were incubated in the presence of the matriptase-specific monoclonal antibody clone S5 (IgG1; Ref. 9
) at a concentration of 1 µg/ml or the HAI-1-specific monoclonal antibody clone M58 (IgG1; Ref. 3
) at a concentration of 5 µg/ml for 1 h at room temperature. Ovarian cancer sections known to show positive staining for matriptase and HAI-1 were used as positive controls, and mouse IgG at a concentration of 5 µg/ml was used with a duplicate of these same sections as a negative control. After incubation in the primary antibody, sections were washed in PBS to remove unbound antibody and then were incubated with a biotinylated rabbit antimouse secondary antibody. After washes in PBS, the staining was completed by incubation with streptavidin-horseradish peroxidase and 3,3'-diaminobenzidine colorimetric reagents from the Vectastain kit according to the manufacturer’s protocol. The colorimetric reaction for the negative control slides was developed for the same amount of time as the experimental slides and did not show any development of the color reagent. After verification of positive staining of the positive control slides, all experimental slides were scored independently for matriptase (S5) or HAI-1 (M58) staining by two specialist gynecological histopathologists.
In Situ Hybridization.
Probes for use in ISH were prepared by generating digoxigenin-labeled sense and antisense RNA riboprobes using the Dig-RNA labeling kit (Boehringer-Mannheim, Mannheim, Germany) according to a modified manufacturer’s protocol. Briefly, a 650-bp BamHI-SacII fragment of the matriptase sequence corresponding to the 5' end of the matriptase cDNA was cloned into the pBluescript SK- vector (Stratagene, La Jolla, CA). This vector was subsequently linearized with SacII or BamHI and used as a template for the synthesis of sense and antisense digoxigenin-labeled riboprobes, respectively, with T7 or T3 RNA polymerase (Life Technologies, Inc., Rockville, MD), according to the manufacturer’s protocol, using digoxigenin-11-UTP. Synthesized probes were purified by G50 column chromatography to remove unincorporated nucleotides, including unincorporated digoxigenin-11-UTP. The concentration of the labeled riboprobes was determined spectrophotometrically. The accuracy of the concentration assignment was confirmed by analysis of the riboprobes by 1% agarose/2.2 M formaldehyde gel electrophoresis, followed by ethidium bromide staining. The equal efficiency of digoxigenin incorporation into sense and antisense probes was confirmed by dot blotting of equal amounts of probe onto Hybond-N nylon membranes (Amersham Pharmacia Biotech, Buckinghamshire, United Kingdom), followed by detection of labeled riboprobe with an alkaline phosphatase-conjugated anti-digoxigenin antibody and colorimetric substrate (data not shown). In addition, the efficiency of digoxigenin incorporation was confirmed by dot blotting equal amounts of denatured double-stranded vector containing the full-length sequence of matriptase and probing these blots with digoxigenin-labeled sense or antisense probes for matriptase. Equal signals were observed for equal amounts of sense or antisense probe used in the hybridization to membrane-bound plasmid (data not shown). For detection of matriptase mRNA in paraffin-embedded ovarian tumor sections, 20 ng of labeled sense or antisense riboprobe were used in a standard protocol provided by Boehringer-Mannheim (Mannheim, Germany). Briefly, 5-µm paraffin-embedded ovarian tumor sections were deparaffinized, rehydrated, treated with 0.2 M HCl, permeabilized with proteinase K, and postfixed with 4% paraformaldehyde before prehybridization in 50% foramide/1x SSC at 65°C and hybridization at 65°C in hybridization buffer for 12 h in a humidified chamber. After hybridization, unbound probe was removed by two washes in 2x SSC, two washes in 1x SSC, and two washes in 0.1x SSC at 42°C. Bound probe was detected by use of an alkaline phosphatase-conjugated anti-digoxigenin antibody that produces an insoluble blue precipitate in the presence of a nitrotetrazolium blue/X-phosphate color solution. Sense and antisense probes were hybridized and washed under identical conditions, and the colorimetric reactions were stopped at the same time for sense and antisense hybridized sections.
Statistical Analysis.
The expression profiles of matriptase and HAI-1 were each analyzed in relation to the patient clinicopathological data using the 
2 test or Fisher’s exact test as appropriate. Survival curves were constructed by the method of Kaplan-Meier, and the impact of matriptase and HAI-1 on survival was assessed using the log-rank test and Cox proportional hazards regression. All analyses were performed with the STATA (version 6.0) software package.
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RESULTS |
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TopABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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The histological type, histological grade, clinical staging (classified according to FIGO guidelines), size of residual disease after initial surgery, survival status at the time of the writing of this report, and matriptase and HAI-1 immunohistochemical staining for the tumors are presented in Table 1
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. An example of positive matriptase (Fig. 1G)
and positive HAI-1 (Fig. 1H)
immunohistochemical staining of normal OSE is also presented. The OSE in Fig. 1G
is lined by active Mullerian epithelium. In addition, we have demonstrated matriptase expression in normal OSE by ISH and by RT-PCR (data not shown).
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. It should be noted that with only 30 deaths in this cohort of patients, there is little power to detect any potential survival differences. The high proportion of stage I patients may have compounded this limitation in the analysis.
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. From a total of 54 ovarian tumors tested, 28 of 34 stages I and II tumors (82%), and 11 of 20 stages III and IV tumors (55%) scored positive for matriptase. For HAI-1, 10 of 34 stages I and II tumors (29%), and 1 of 20 stages III and IV tumors scored positive (5%). Therefore, stage I/II ovarian tumors are statistically more likely to express matriptase than are the more advanced disease stage III/IV tumors. Correspondingly, loss of HAI-1 expression is statistically significantly more likely to be associated with stage III/IV tumors than stage I/II tumors. Taken together, these data indicate that early-stage tumors are more likely to coexpress matriptase and HAI-1 (P = 0.039), whereas advanced-stage tumors that express matriptase are significantly more likely to do so in the absence of HAI-1. Such an imbalance could promote the proteolytic activity of matriptase and, consequently, a more invasive phenotype in the advanced tumors.
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DISCUSSION |
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TopABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Despite the frequent LOH in the region of the matriptase gene and the original cloning of the gene as a putative tumor suppressor gene (ST14, alias SNC19) by subtractive hybridization methods using normal and cancerous colon tissue (5) , little biochemical evidence exists that matriptase may be a tumor suppressor or negative modifier of tumor aggressiveness. In fact, because of its ability to cleave and activate growth factors and other serine proteases thought to be involved in cancer progression, matriptase has been implicated as a potential pro-invasion and metastasis factor. In support of this hypothesis, matriptase (TADG-15) mRNA expression was found by RT-PCR and by IHC using a rabbit polyclonal anti-matriptase antibody to be present in ovarian tumors but absent in the normal OSE (7) . In this study, we have demonstrated by IHC and by ISH that matriptase is indeed expressed in normal OSE. This difference may reflect methodological differences or differences in the antibody reagents used. In addition, we have detected matriptase expression in cultured human OSE cells by RT-PCR (data not shown).
To further elucidate the potential role of matriptase in neoplasia, we examined the levels of matriptase immunoreactivity and also those of its inhibitor HAI-1 in a cohort of 54 primary ovarian tumor samples using immunohistochemistry. In a correlative study, we have also examined by mRNA ISH the expression of matriptase in a subset of these ovarian tumors (data not shown). We have shown by IHC that expression of matriptase is statistically more likely to be associated with ovarian tumors of stages I/II, as compared with tumors of stages III/IV. Correspondingly, the expression of its inhibitor, HAI-1, is also more likely to be associated with stage I/II tumors rather than stage III/IV tumors. Significantly, however, stage III/IV tumors that do express matriptase are more likely to do so in the absence of HAI-1, a ratio that favors matriptase proteolytic activity. Furthermore, expression of matriptase mRNA was shown by ISH to correlate with immunohistochemical detection of the protein.
Our data are consistent with the hypothesis that the matriptase:HAI-1 ratio is important in the development or progression of ovarian cancer. Matriptase is present as a latent, one-chain enzyme that is cleaved to an active, two-chain enzyme held together by disulfide bonds. The activated enzyme binds the inhibitor HAI-1, which effectively eliminates the proteolytic activity of matriptase (36) . In a previous study, we observed the loss of HAI-1 protein expression in some tumors of OSE origin that maintain matriptase protein expression as determined by Western blot analysis (9) . Our present study suggests that the matriptase:HAI-1 ratio is increased in tumors of more advanced stage, thereby favoring matriptase expression with unopposed proteolytic activity. Matriptase proteolytic activity may therefore activate pro-invasive/metastatic factors such as uPA and HGF, or other as yet uncharacterized substrates. Active HGF may then promote tumor growth and motility, and uPA may promote the proteolytic degradation of the basement membrane and extracellular matrix and the activation of latent growth factors, consequently leading to an invasive phenotype. This cascade of events could be promoted by activators of matriptase (S-1-P and LPA) that have been found to be elevated in ovarian cancer.
This study suggests that larger scale studies of matriptase, HAI-1, and the matriptase:HAI-1 ratio, perhaps by IHC or ISH using microtissue arrays or tumor cytosols in an ELISA-based format are indicated to determine the full potential of these proteins as predictors of response to therapy or as prognostic markers in ovarian cancer. Furthermore, the determination of matriptase activity, in addition to its expression, may be important in this regard. Monoclonal antibodies that recognize only the activated form of the enzyme and not both the latent and active forms as in this study (S5) may be useful in this regard once they have been optimized for use in IHC or in ELISA-based methods (36) . In the future, identification of a high matriptase:HAI-1 ratio or matriptase activity in an advanced-stage ovarian cancer may indicate the use of an anti-matriptase-based therapy for the individualization of patient treatment. The definition of tumors as positive for matriptase, or more importantly the activated form of matriptase, opens up potential avenues for therapeutics based on small molecule inhibitors. Indeed, a structure-based database screening approach identified a novel analogue of hexamidine as a potent inhibitor of matriptase activity, while showing only weak inhibitory effects toward thrombin or uPA (37) . Studies of this nature may pave the way to the identification of even more potent and selective matriptase inhibitors for testing in clinical trials as new ovarian cancer therapeutics.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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1 Supported by Grant DRA99-003037 from the Susan G. Komen Breast Cancer Foundation (to M. D. O. and M. D. J.); NIH Specialized Program of Research Excellence Grant 1P50CA58158 in breast cancer and NIH Grant R21CA80897 (to R. B. D. and C. Y-L.); Imperial Cancer Research Fund (to M. S., J. F. S., H. G., and G. C. S.); and University of Edinburgh (to A. W., A. a-N.). 
2 To whom requests for reprints should be addressed, at Cancer Research UK Edinburgh Oncology Unit, Western General Hospital, Crewe Road, Edinburgh EH4 2XR, United Kingdom. Phone: 44-(0)131-777-3500; Fax: 44-(0)131-777-3520; E-mail: grant.sellar{at}cancer.org.uk
3 The abbreviations used are: OSE, ovarian surface epithelium; uPA, urokinase plasminogen activator; HGF, hepatocyte growth factor; HGFA, HGF activator; LPA, lysophosphatidic acid; S-1-P, sphingosine-1-phosphate; HAI-1, hepatocyte growth factor activator inhibitor-1; FIGO, Fédération Internationale des Gynaecologistes et Obstetristes; IHC, immunohistochemistry; ISH, in situ hybridization; LOH, loss of heterozygosity; RT-PCR, reverse transcription-PCR.
4 R. B. Dickson and C-Y. Lin, unpublished data.
Received 9/ 7/01; revised 1/ 2/02; accepted 1/28/02.
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