title: Tissue factor expression in ovarian cancer: implications for immunotherapy with hI-con1, a factor VII-IgGF(c) chimeric protein targeting tissue factor.
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 (51)chromium-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.
authors: Department of Obstetrics, Gynecology & Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06520-8063, USA.
authors: Emiliano
authors: E
authors: Cocco
authors: Joyce
authors: J
authors: Varughese
authors: Natalia
authors: N
authors: Buza
authors: Stefania
authors: S
authors: Bellone
authors: Ken-Yu
authors: KY
authors: Lin
authors: Marta
authors: M
authors: Bellone
authors: Paola
authors: P
authors: Todeschini
authors: Dan-Arin
authors: DA
authors: Silasi
authors: Masoud
authors: M
authors: Azodi
authors: Peter E
authors: PE
authors: Schwartz
authors: Thomas J
authors: TJ
authors: Rutherford
authors: Luisa
authors: L
authors: Carrara
authors: Renata
authors: R
authors: Tassi
authors: Sergio
authors: S
authors: Pecorelli
authors: Charles J
authors: CJ
authors: Lockwood
authors: Alessandro D
authors: AD
authors: Santin
mesh_terms: D045744:Cell Line, Tumor; D005167:Factor VII / Q000276:immunology / Q000378:metabolism / Q000627:therapeutic use; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D018796:Immunoconjugates / Q000276:immunology / Q000378:metabolism / Q000627:therapeutic use*; D007141:Immunoglobulin Fc Fragments / Q000276:immunology / Q000378:metabolism / Q000627:therapeutic use; D007167:Immunotherapy / Q000379:methods*; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D013925:Thromboplastin / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000627:therapeutic use*
chemical_list: D018796:Immunoconjugates; D007141:Immunoglobulin Fc Fragments; C562041:hI-con1; D005167:Factor VII; D013925:Thromboplastin