Tissue factor expression in ovarian cancer: Implications for immunotherapy with hI-con1, a factor VII-IgGF c chimeric protein targeting tissue factor

Emiliano Cocco, Joyce Varughese, Natalia Buza, Stefania Bellone, Ken Yu Lin, Marta Bellone, Paola Todeschini, Dan Arin Silasi, Masoud Azodi, Peter E. Schwartz, Thomas J. Rutherford, Luisa Carrara, Renata Tassi, Sergio Pecorelli, Charles J. Lockwood, Alessandro D. Santin

Research output: Contribution to journalArticle

17 Scopus citations

Abstract

We evaluated the expression of tissue factor (TF) in ovarian cancer (EOC) and the potential of hI-con1, an antibody-like molecule targeting TF, as a novel form of therapy against chemotherapy-resistant ovarian disease. We studied the expression of TF in 88 EOC by immunohistochemistry (IHC) and real-time-PCR (qRT-PCR) and the levels of membrane-bound-complement-regulatory-proteins CD46, CD55 and CD59 in primary EOC cell lines by flow-cytometry. Sensitivity to hI-con1-dependent-cell-mediated-cytotoxicity (IDCC), complement-dependent-cell- cytotoxicity and inhibition of IDCC by γ-immunoglobulin were evaluated in 5-h 51chromium-release-assays. Cytoplasmic and/or membrane TF expression was observed in 24 out of 25 (96%) of the EOC samples tested by IHC, but not in normal ovarian-tissue. EOC with clear cell histology significantly overexpress TF when compared to serous, endometrioid, or undifferentiated tumors by qRT-PCR. With a single exception, all primary EOC that overexpressed TF demonstrated high levels of CD46, CD55 and CD59 and regardless of their histology or resistance to chemotherapy, were highly sensitive to IDCC. The effect of complement and physiologic doses of γ-immunoglobulin on IDCC in ovarian cancer cell lines overexpressing TF was tumor specific and related to the overexpression of CD59 on tumor cells. Small-interfering-RNA-mediated knockdown of CD59 expression in ovarian tumors significantly increased hI-con1-mediated cytotoxic activity in vitro. Finally, low doses of interleukin-2 further increased the cytotoxic effect induced by hI-con1 (P < 0.01). hI-con1 molecule induces strong cytotoxicity against primary chemotherapy-resistant ovarian cancer cell lines overexpressing TF and may represent a novel therapeutic agent for the treatment of ovarian tumors refractory to standard treatment modalities.

Original languageEnglish (US)
Pages (from-to)689-700
Number of pages12
JournalClinical and Experimental Metastasis
Volume28
Issue number7
DOIs
StatePublished - Oct 1 2011
Externally publishedYes

Keywords

  • Cancer
  • Factor VII
  • Immunotherapy
  • Ovarian carcinoma
  • Tissue factor

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Fingerprint Dive into the research topics of 'Tissue factor expression in ovarian cancer: Implications for immunotherapy with hI-con1, a factor VII-IgGF <sub>c</sub> chimeric protein targeting tissue factor'. Together they form a unique fingerprint.

  • Cite this

    Cocco, E., Varughese, J., Buza, N., Bellone, S., Lin, K. Y., Bellone, M., Todeschini, P., Silasi, D. A., Azodi, M., Schwartz, P. E., Rutherford, T. J., Carrara, L., Tassi, R., Pecorelli, S., Lockwood, C. J., & Santin, A. D. (2011). Tissue factor expression in ovarian cancer: Implications for immunotherapy with hI-con1, a factor VII-IgGF c chimeric protein targeting tissue factor. Clinical and Experimental Metastasis, 28(7), 689-700. https://doi.org/10.1007/s10585-011-9401-0