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

16 Citations (Scopus)

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

Fingerprint

Factor VII
Thromboplastin
Protein Transport
Ovarian Neoplasms
Immunotherapy
Neoplasms
Drug Therapy
Cell Line
Immunoglobulins
Histology
Immunohistochemistry
Ovarian Diseases
Polymerase Chain Reaction
Membranes
hI-con1
Therapeutics
Small Interfering RNA
Interleukin-2
Real-Time Polymerase Chain Reaction
Flow Cytometry

Keywords

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

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Tissue factor expression in ovarian cancer : Implications for immunotherapy with hI-con1, a factor VII-IgGF c chimeric protein targeting tissue factor. / Cocco, Emiliano; Varughese, Joyce; Buza, Natalia; Bellone, Stefania; Lin, Ken Yu; Bellone, Marta; Todeschini, Paola; Silasi, Dan Arin; Azodi, Masoud; Schwartz, Peter E.; Rutherford, Thomas J.; Carrara, Luisa; Tassi, Renata; Pecorelli, Sergio; Lockwood, Charles J.; Santin, Alessandro D.

In: Clinical and Experimental Metastasis, Vol. 28, No. 7, 01.10.2011, p. 689-700.

Research output: Contribution to journalArticle

Cocco, E, Varughese, J, Buza, N, Bellone, S, Lin, KY, Bellone, M, Todeschini, P, Silasi, DA, Azodi, M, Schwartz, PE, Rutherford, TJ, Carrara, L, Tassi, R, Pecorelli, S, Lockwood, CJ & Santin, AD 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, vol. 28, no. 7, pp. 689-700. https://doi.org/10.1007/s10585-011-9401-0
Cocco, Emiliano ; Varughese, Joyce ; Buza, Natalia ; Bellone, Stefania ; Lin, Ken Yu ; Bellone, Marta ; Todeschini, Paola ; Silasi, Dan Arin ; Azodi, Masoud ; Schwartz, Peter E. ; Rutherford, Thomas J. ; Carrara, Luisa ; Tassi, Renata ; Pecorelli, Sergio ; Lockwood, Charles J. ; Santin, Alessandro D. / Tissue factor expression in ovarian cancer : Implications for immunotherapy with hI-con1, a factor VII-IgGF c chimeric protein targeting tissue factor. In: Clinical and Experimental Metastasis. 2011 ; Vol. 28, No. 7. pp. 689-700.
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