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Open Access Research article

Expression of Tissue factor in Adenocarcinoma and Squamous Cell Carcinoma of the Uterine Cervix: Implications for immunotherapy with hI-con1, a factor VII-IgGFc chimeric protein targeting tissue factor

Emiliano Cocco1, Joyce Varughese1, Natalia Buza2, Stefania Bellone1, Michelle Glasgow1, Marta Bellone1, Paola Todeschini1, Luisa Carrara1, Dan-Arin Silasi1, Masoud Azodi1, Peter E Schwartz1, Thomas J Rutherford1, Sergio Pecorelli3, Charles J Lockwood1 and Alessandro D Santin1*

Author Affiliations

1 Department of Obstetrics, Gynecology & Reproductive Sciences, Yale University School of Medicine, 333 Cedar street, New Haven (06519), CT, USA

2 Department of Pathology, Yale University School of Medicine, 333 Cedar street, New Haven (06519), CT, USA

3 Division of Gynecologic Oncology, University of Brescia, 1 Spedali Civili (52100), Brescia, Italy

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BMC Cancer 2011, 11:263  doi:10.1186/1471-2407-11-263

Published: 22 June 2011

Abstract

Background

Cervical cancer continues to be an important worldwide health problem for women. Up to 35% of patients who are diagnosed with and appropriately treated for cervical cancer will recur and treatment results are poor for recurrent disease. Given these sobering statistics, development of novel therapies for cervical cancer remains a high priority. We evaluated the expression of Tissue Factor (TF) in cervical cancer and the potential of hI-con1, an antibody-like-molecule targeted against TF, as a novel form of immunotherapy against multiple primary cervical carcinoma cell lines with squamous- and adenocarcinoma histology.

Methods

Because TF is a transmembrane receptor for coagulation factor VII/VIIa (fVII), in this study we evaluated the in vitro expression of TF in cervical carcinoma cell lines by immunohistochemistry (IHC), real time-PCR (qRT-PCR) and flow cytometry. Sensitivity to hI-con1-dependent cell-mediated-cytotoxicity (IDCC) was evaluated in 5-hrs-51chromium-release-assays against cervical cancer cell lines in vitro.

Results

Cytoplasmic and/or membrane TF expression was observed in 8 out of 8 (100%) of the tumor tissues tested by IHC and in 100% (11 out of 11) of the cervical carcinoma cell lines tested by real-time-PCR and flow cytometry but not in normal cervical keratinocytes (p = 0.0023 qRT-PCR; p = 0.0042 flow cytometry). All primary cervical cancer cell lines tested overexpressing TF, regardless of their histology, were highly sensitive to IDCC (mean killing ± SD, 56.2% ± 15.9%, range, 32.4%-76.9%, p < 0.001), while negligible cytotoxicity was seen in the absence of hI-con1 or in the presence of rituximab-control-antibody. Low doses of interleukin-2 further increased the cytotoxic effect induced by hI-con1 (p = 0.025) while human serum did not significantly decrease IDCC against cervical cancer cell lines (p = 0.597).

Conclusions

TF is highly expressed in squamous and adenocarcinoma of the uterine cervix. hI-con1 induces strong cytotoxicity against primary cervical cancer cell lines overexpressing TF and may represent a novel therapeutic agent for the treatment of cervical cancer refractory to standard treatment modalities.