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Originally published as JCO Early Release 10.1200/JCO.2005.02.9181 on December 27 2005 © 2006 American Society of Clinical Oncology. Preoperative Serum Tissue Factor Levels Are an Independent Prognostic Factor in Patients With Ovarian CarcinomaFrom the Departments of Gynecologic Oncology, Biostatistics and Applied Mathematics, and Cancer Biology, The University of Texas M.D. Anderson Cancer Center, Houston, TX; Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Iowa Hospitals and Clinics, Iowa City, IA Address reprint requests to: Anil K. Sood, MD, Department of Gynecologic Oncology, The University of Texas M.D. Anderson Cancer Center, Unit 1362, PO Box 301439, Houston, TX 77230-1439; e-mail: asood{at}mdanderson.org
PURPOSE: Tissue factor (TF) is a procoagulant that plays an important part in tumor angiogenesis. We sought to determine the role of preoperative serum TF levels in predicting clinical outcome in patients with ovarian cancer. MATERIALS AND METHODS: TF expression was determined by reverse transcriptase polymerase chain reaction in ovarian cell lines. Using enzyme-linked immunosorbent assay, we assessed preoperative serum TF levels in 98 women with invasive epithelial ovarian carcinoma, 30 with low malignant potential (LMP) tumors, 16 with benign tumors, and a separate validation group of 39 women with adnexal masses. Clinical information was gathered from chart review.
RESULTS: TF was expressed in four of the five ovarian cancer cell lines, but absent in the nontransformed cells. Ovarian cancer patients had a median preoperative serum TF level of 85.2 pg/mL, which was significantly higher than in those with LMP tumors (12.8 pg/mL; P < .01) and benign adnexal disease (30.7 pg/mL; P < .01). TF CONCLUSION: Preoperative serum TF levels are significantly elevated in patients with ovarian carcinoma. Elevated preoperative TF level is an independent prognostic factor for death from disease.
It is known that approximately 50% of all patients with malignant disease and almost 90% of patients with metastatic lesions have abnormalities in hematologic parameters, and as a result, various coagulation factors have been evaluated.1 Furthermore, underlying factors of this intrinsic hypercoagulable state have been shown to play a role in tumor angiogenesis and metastasis.2 As the main physiologic initiator of the coagulation pathway, tissue factor (TF) is a 47-kDa transmembrane glycoprotein of the cytokine-receptor superfamily that begins the coagulation cascade in normal human physiology. However, there is increasing evidence to implicate TF in tumor angiogenesis.3 Through the clotting-dependent pathway, TF contributes to tumor angiogenesis by generating thrombin, activating platelets, and depositing fibrin, all of which produce more TF, release stored vascular endothelial growth factor (VEGF) and support new blood vessel matrix.2-4 In addition, TF triggers the clotting-independent pathways by cleaving the protease-activated receptors (PARs) and initiating the transcription of VEGF.4,5 A significant association between high TF expression and microvessel density (MVD) has been observed in colorectal, lung, breast, liver and urologic carcinomas.6-11 Furthermore, high levels of TF expression have been found to be an independent prognostic factor for poor survival in patients with solid tumors.7-10,12,13 In fact, TF expression negativity has been shown to confer a significantly better prognosis.14 Ovarian carcinoma is the most deadly of the gynecologic malignancies. Therefore, development of novel biomarkers that can sufficiently contribute to the prognosis of this disease process is paramount in identifying specific patients who may benefit from aggressive therapies. Moreover, although CA125 is useful to follow patients with established ovarian carcinoma for response to treatment and evaluation of recurrence, its diagnostic value has been limited because half of all patients with early-stage disease do not exhibit elevated CA125 level.15 Thus, additional biomarkers are needed. To the best of our knowledge, there are no data regarding the value of preoperative serum TF levels in predicting clinical outcomes in patients with ovarian carcinoma, which is the focus of our study. We also evaluated the utility of preoperative serum TF levels in predicting malignancy in patients with adnexal masses.
Study Population and Sample Collection A total of 144 patient serum specimens (98 with invasive epithelial ovarian carcinoma, 30 with low malignant potential [LMP] tumors, and 16 with benign adnexal masses) were obtained from either The University of Texas M.D. Anderson Cancer Center (Houston, TX) or the University of Iowa Hospitals and Clinics (Iowa City, IA). All specimens were collected at the preoperative visit for the evaluation of adnexal masses, and then stored in –80°C freezers in the established tumor banks of the respective institutions. Specimens used were thawed no more than twice. We complied with requirements of the institutional review boards from both centers for the protection of human subjects.
Reverse Transcriptase Polymerase Chain Reaction of Ovarian Cancer Cell Lines Total RNA was extracted from these cells with a monophasic solution of phenol and guanidine isothiocyanate (Trizol reagent, Invitrogen). Total RNA (1 µg) was reverse transcribed using an oligo (dT) primer and Moloney murine leukemia virus reverse transcriptase (Life Technologies Inc, Rockville, MD) in a final reaction volume of 20 µL (60 minutes at 42°C). The reaction was stopped by heating at 95°C for 5 minutes. The resultant cDNA was amplified by polymerase chain reaction (PCR) in GeneAMP 10x PCR buffer (Perkin-Elmer, Branchburg, NJ) with 20 pmol of gene-specific 3' and 5' primers and 2 units of Taq DNA polymerase in a total volume of 50 µL. Reactions were carried out for 35 cycles at 94°C for 1 minute, 64°C for 2.5 minutes, and 72°C for 1 minute in an Infinity Robocycler (Stratagene, La Jolla, CA).17,18 The following primers were used for TF detection: forward, 5'-ATGGAGACCCCTGCC TGGC-3'; reverse, 5'-TGAAACATTCAGTGGGGAGTTCTCCT-3'. After reverse transcriptase PCR, the reaction products were separated by electrophoresis on a 1% agarose gel. Gels were stained with ethidium bromide to visualize the PCR product size. To control for variance in loading and in PCR, samples were compared with glyceraldehyde 3-phosphate dehydrogenase (GAPDH) PCR products.
TF Enzyme-Linked Immunosorbent Assay
TF Immunohistochemistry Negative controls were carried out using normal mouse immunoglobulin G instead of the primary antibody. The scoring system was based on staining intensity and percentage of positive cells, both of which contributed to an overall score. The staining intensity was classified as weak, moderate, or strong by subjective observer evaluation. The percentage of positively stained cells was defined as follows: negative for less than 10% staining; moderate for 10% to 50%; and strong for > 50%. Two independent observers, who were blinded to the serum TF and clinical data, evaluated and confirmed the findings. In cases with discordant scoring, the observers conferred to reach an agreement.
Clinicopathologic Data
Validation Set
Statistical Analysis
Next, we confirmed the results of our initial exploratory data by conducting an independent validation test. The significance of high serum TF ( All of the statistical analyses were performed using SAS, version 8.02 (SAS Institute, Cary, NC) and S-Plus, version 6.1 (Insightful Corp, Seattle, WA).
To determine whether TF is directly expressed by ovarian cells, we characterized TF expression in a panel of cell lines using RT-PCR (Fig 1). TF expression was absent in the A2780-PAR cells and the nontransformed ovarian cell line, HIO-180. However, TF was expressed at varying levels in the OVCAR3, SKOV3, EG, and 222 ovarian cancer cell lines.
Next, we examined the clinical relevance of serum TF levels. Overall, our study included 144 patients with a mean age of 58.6 years. The mean age for women with benign disease was 56 years (range, 11 to 80 years), 59.9 years (range, 35 to 90 years) for women with LMP tumors, and 60.5 years (range, 44 to 88 years) for individuals with invasive ovarian carcinomas. We evaluated serum TF levels in the 98 patients with invasive epithelial ovarian carcinoma, 30 with LMP tumors, and 16 with benign disease of the ovaries. There was an overall significant difference in TF levels among all three groups (Fig 2). TF levels were significantly higher in patients with invasive cancer (median, 85.2 pg/mL) when compared with those with LMP tumors (median, 12.8 pg/mL; P < .01) and those with benign disease (median 30.7 pg/mL; P < .01). In addition, there was a significant difference in TF levels between patients with LMP tumors and those with benign disease (P < .01); however, the number of samples in these two groups was relatively small.
We then examined the association of TF with patient characteristics such as stage, grade, histology, presence of ascites and level of cytoreduction in women with invasive ovarian cancer. Of the 98 patients with invasive epithelial ovarian carcinoma, 30.6% (30 of 98) and 22.4% (22 of 98) had low grade and early stages, respectively (Table 1). The majority, 77.6% (76 of 98) underwent optimal cytoreduction. Sixty-eight percent of the tumors were of serous histology. The median TF levels were not significantly different on the basis of tumor stage, grade and level of cytoreduction. Elevated median TF levels approached significance in individuals with serous histology, presence of ascites, and positive lymph nodes (Table 1).
Using exploratory statistical analysis, patients with ovarian carcinoma were dichotomized into two groups, high TF and low TF, based on a cutoff value of 190 pg/mL, which yielded the highest hazard ratio. This level was selected for all subsequent analyses. The effects of traditional prognostic factors and preoperative TF levels on survival with death as outcome were examined using univariate analysis (Table 2). Age, high stage, serous histology, suboptimal cytoreduction, presence of ascites, and preoperative TF value  190 pg/mL were all significantly associated with decreased survival. A Kaplan-Meier survival curve, based on TF dichotomization (low, <190 pg/mL v high, 190 pg/mL) is depicted in Figure 3. Using log-rank test, we found a significant difference in survival based on this dichotomization with P < .01. Median survival time for patients with high TF levels was 1.64 years, whereas that of patients with low TF levels was 5.13 years.
After adjusting for age, grade, stage, histology, cytoreduction, ascites, and preoperative CA125 levels in a multivariate Cox regression model, high TF remained significantly associated with poor survival (P < .01). Age and stage were the only other factors associated with poor survival in this multivariate model (P = .02; Table 3). In addition, we substituted TF as a continuous variable into the same multivariate Cox regression model and found that it remained a significant prognostic factor (P = .01).
From a receiver operating characteristics curve, we determined the diagnostic value of TF as a biomarker for ovarian malignancy by calculating the sensitivity and specificity to detect cancer. On the basis of our patient population, the maximum sensitivity and specificity achieved were 89% and 83%, respectively, when a TF cutoff of 35 pg/mL was applied. Preoperative CA125 levels were available for 129 out of a total of 144 patients. The sensitivity and specificity of predicting malignancy in our patient population using a CA125 cutoff value of 35 u/mL were 93.5% and 62.2%, respectively. Furthermore, we have previously assessed the role of preoperative serum VEGF levels as a diagnostic marker, and arrived at a cutoff level of 246 pg/mL.19 In the current study, preoperative VEGF levels were available in 78 of the 144 patients. On the basis of the known association of TF with VEGF,2-5 we examined their correlation. The spearman correlation coefficient between TF and VEGF was 0.69, however, that between TF and CA125 was 0.34. Using a cutoff of 246 pg/mL for VEGF in combination with TF, the sensitivity for differentiating cancer from benign disease was 85% and specificity improved slightly to 89.5%.
In order to determine the clinical value of serum TF levels in independent specimens, we conducted a validation study consisting of 39 women undergoing evaluation for adnexal masses. There were 34 cases of invasive epithelial ovarian carcinoma and five benign cases. In women with a diagnosis of ovarian carcinoma who had TF levels
To assess whether serum TF levels were associated with tumor TF expression, we performed TF immunohistochemistry on 12 representative tumor samples from patients with high and low serum TF levels (Fig 5). The high serum expressers tended to have a stronger tumoral staining intensity (n = 4 of 6) when compared with those with low serum TF levels (n = 1 out of 6). Although no statistical significance can be gathered from this small subset, the emerging pattern was that strong TF expression was mainly present in tumor cell islets. TF staining of the stromal cells was mostly weak in all samples.
The key findings from our study are that serum TF levels are significantly elevated in patients with ovarian carcinoma when compared to individuals with LMP tumors and benign ovarian disease. Elevated levels of TF 190 pg/mL are an independent prognostic factor for death from disease in patients with ovarian carcinoma. TF may be a useful diagnostic tool for invasive malignancy in a panel of biomarkers and merits further investigation. We examined the significance of TF in patients with ovarian carcinoma because of its emerging functions in tumor angiogenesis and progression. Multiple studies have established the role of procoagulant TF in the promotion of tumor angiogenesis by two distinct mechanisms: the clotting-dependent and the clotting-independent pathways.4,5,20-22 In the clotting-dependent pathway of TF induced angiogenesis, TF activates factor VII, and initiates the clotting cascade that generates thrombin, which in turn induces endothelial proliferation and stimulates the release of pro-angiogenic cytokines such as interleukin 8 (IL-8) and VEGF.3,20 In addition, the clotting cascade is responsible for the activation of platelets that releases stored VEGF and facilitates the extravasation of tumor emboli.4 One of the other end products of this coagulation pathway is fibrin that triggers more TF and cytokines while providing a solid structural matrix for new blood vessels by enabling endothelial cell adhesion and migration.4,5 In the clotting-independent pathway of TF-induced angiogenesis, cellular transcriptional changes occur as TF forms a complex with factor VII and factor X. Through the activation of the PARs, rapid downstream signaling achieves the upregulation of pro-angiogenic factors such as VEGF while downregulating antiangiogenic proteins such as thrombospondin.4,5,21,22 These phenomena that ultimately lead to overproduction of hypercoagulable factors and angiogenic cytokines have been demonstrated in ovarian carcinoma.23 Furthermore, transfection with TF in an ovarian cancer cell line increased invasive and metastatic properties in a murine model.24 In the current study, we demonstrated that preoperative TF levels for patients with invasive ovarian carcinoma were significantly higher than for those with either LMP tumors or benign adnexal disease. The median TF level was significantly higher in the benign group when compared to its LMP counterpart. There were two patients with benign disease who had significantly elevated serum TF levels: one was diagnosed with Meig's syndrome and another with ovarian torsion. It is possible that the development of ascites in Meig's syndrome may be a manifestation of elevated TF level, which yields upregulation of VEGF, a known inducer of vascular permeability.19 In the setting of ovarian torsion, hypoxia, an established initiator of both TF and VEGF, may have contributed to the elevated TF levels seen.19
Previous studies in solid tumors have revealed that high TF expression is predictive of poor outcome.7-10,12,13 In our study, TF levels Although our data set, with relatively small number of benign and early-staged cases, is not ideal to comment definitively on TF as an independent diagnostic tool, we attempted to further characterize the utility of preoperative serum TF levels by determining its predictive value in differentiating malignancy from benign disease. The sensitivity and specificity for malignancy using TF cutoff at 35 pg/mL were 89% and 83%, respectively, and when preoperative CA125 levels were added to the model, the sensitivity remained the same, whereas specificity improved to 86%. Recently, another glycoprotein, YKL-40, of the chitinase family, was investigated as a biomarker for the diagnosis of ovarian cancer. At a cutoff of 61 ng/mL, YKL-40 had a comparable sensitivity and specificity for the detection of ovarian malignancy of 72% and 90%, respectively.26 In a study that addressed the clinical value of preoperative VEGF levels in patients with ovarian masses, at a cutoff VEGF level of 246 pg/mL, the sensitivity was 74% and the specificity was 71% for predicting ovarian malignancy. However, when preoperative CA125 level was performed in this model, the sensitivity improved to 90%, whereas the specificity remained at 71%.19 The initial proteomics study reported a near 100% sensitivity and specificity for detecting early ovarian cancer27; nevertheless, these results remain to be validated in larger independent studies.28 Even though TF levels are known to be elevated in other malignancies as well as diseases such as sepsis that can cause coagulopathy, it is possible that a combination of circulating factors may yield even higher sensitivity and specificity. High TF expression has been established in various other cancers6-11; however, to the best of our knowledge, its prognostic and diagnostic values have yet to be elucidated in ovarian cancer. Although TF is a membrane-bound receptor, the plasma TF as determined by commercially available enzyme-linked immunosorbent assay (ELISA) assays is believed to be derived from tumor, stroma and damaged vascular endothelial cells.9,29 The exact process of tumor release of TF may be the shedding of microvesicles containing elements of cellular membrane.29 The correlation between serum TF levels and tissue TF is controversial: in breast cancer, there is significant correlation between the two9; however, another study suggests that this may not always be the case.29 TF immunohistochemistry of representative tumor tissue samples in this study revealed that the high serum TF expressers tended to have more intense tumoral staining, suggesting that circulating TF levels are at least in part reflective of tumor TF expression. Recently, there has been a growing interest in low molecular weight heparin (LMWH) as a treatment modality in cancer. One of the mechanisms of its action is speculated to be the de novo activation of the tissue factor pathway inhibitor (TFPI) and its properties in the favorable modification of tumor angiogenesis.1 Randomized clinical trials have demonstrated a survival benefit with LMWH in solid tumors that outlasts the active treatment period, supporting the postulation that LMWH may alter tumor angiogenesis at the cellular level.30-32 Furthermore, a direct inhibitor of TF, recombinant nematode anticoagulant protein c2 (RNAPc2) has been shown to impede both primary and metastatic tumor growth in mice, probably by blocking TF signaling through PAR1 and PAR2.33 Such agents may be particularly useful in individuals with high TF levels.
In summary, preoperative serum TF levels are significantly elevated in patients with ovarian cancer compared with those with LMP tumors and benign disease. High TF levels,
The author or immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.
Dollar Amount Codes (A) < $10,000 (B) $10,000-99,999 (C)
IL-8 (interleukin 8): A proinflammatory cytokine structurally related to platelet factor 4, IL-8 is released by several cell types (eg, monocytes, macrophages, T cells, endothelial cells, tumor cells) in response to an inflammatory stimulus. It activates neutrophils and is a chemokine for neutrophils and T lymphocytes. It is also an angiogenic factor. MVD (microvessel density): A quantification technique used to assess the number of vessels in a particular tumor specimen using immunohistochemical stains for endothelial markers. High MVD has been found to be associated with poor prognosis in patients with solid tumors. PARs (protease-activated receptors): A family of seven transmembrane G protein–coupled receptors with four subtypes identified in humans, (PAR1-4). It is usually activated by thrombin (except PAR2). When the receptor ligand is cleaved, it initiates a cascade of intracellular signaling, which ultimately leads to increased angiogenic activity. RNAPc2 (recombinant nematode anticoagulant protein c2): An 85–amino acid protein originally isolated from a hematophagus hookworm with known inhibition of the factor VIIa/tissue factor complex. TFPI (tissue factor pathway inhibitor): A de novo regulator of coagulation activated by tissue factor, it contains protease inhibitor domains for the inhibition of factor Xa and VIIa/tissue factor complex. THBS (thrombospondin): Family of extracellular adhesive proteins with five members (THBS-1 through THBS-4, and cartilage oligomeric matrix protein [COMP]), THBSs play a role in several cellular processes, including platelet aggregation and angiogenesis. VEGF (vascular endothelial growth factor): VEGF is a cytokine that mediates numerous functions of endothelial cells including proliferation, migration, invasion, survival, and permeability. VEGF is also known as vascular permeability factor. VEGF naturally occurs as a glycoprotein and is critical for angiogenesis. Many tumors overexpress VEGF, which correlates to poor prognosis. VEGF-A, -B, -C, -D, and -E are members of the larger family of VEGF-related proteins. YKL-40: A member of the chitinase glycoprotein family, it has been reported to be involved in angiogenesis and matrix degradation. However, its exact function remains unknown.
Presented in part at the 36th Annual Meeting of the Society of Gynecologic Oncologists, Miami Beach, FL, March 19-23, 2005. Funded in part by The University of Texas at M.D. Anderson Cancer Center Specialized Programs of Research Excellence in ovarian cancer (Grant No. 1P50CA83639). Terms in blue are defined in the glossary, found at the end of this article and online at www.jco.org. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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Kakkar AK, Levine MN, Kadziola Z, et al: Low molecular weight heparin, therapy with Dalteparin, and survival in advanced cancer: The Fragmin advanced malignancy outcome study. J Clin Oncol 22:1944-1948, 2004 31. Klerk CP, Smorenburg SM, Otten HM, et al: The effect of low molecular weight heparin on survival in patients with advanced malignancy. J Clin Oncol 23:2130-2135, 2005 32. Lee AY, Rickles FR, Julian JA, et al: Randomized comparison of low molecular weight heparin and coumarin derivatives on the survival of patients with cancer and venous thromboembolism. J Clin Oncol 23:2123-2129, 2005 33. Hembrough TA, Swartz GM, Papathanassiu A, et al: Tissue factor/factor VIIa inhibitors block angiogenesis and tumor growth through a nonhemostatic mechanism. Cancer Res 63:2997-3000, 2003 Submitted June 2, 2005; accepted October 5, 2005. This article has been cited by other articles:
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Copyright © 2006 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
