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

Autor: Peter E. Schwartz, Sergio Pecorelli, Masoud Azodi, Emiliano Cocco, Joyce Varughese, Dan-Arin Silasi, Stefania Bellone, Natalia Buza, Michelle Glasgow, Luisa Carrara, Thomas J. Rutherford, Alessandro D. Santin, Marta Bellone, Paola Todeschini, Charles J. Lockwood
Jazyk: angličtina
Rok vydání: 2011
Předmět:
Keratinocytes
Cancer Research
Pathology
Immunoconjugates
medicine.medical_treatment
Messenger
Uterine Cervical Neoplasms
Drug Screening Assays
chemistry.chemical_compound
0302 clinical medicine
Immunologic
Molecular Targeted Therapy
RNA
Neoplasm
Cytotoxicity Tests
Cervical cancer
Human papillomavirus 16
0303 health sciences
Tumor
Human papillomavirus 18
Neovascularization
Pathologic
Factor VII
medicine.diagnostic_test
lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens
Neoplasm Proteins
3. Good health
Oncology
030220 oncology & carcinogenesis
Carcinoma
Squamous Cell
Adenocarcinoma
Immunohistochemistry
Female
Immunotherapy
Research Article
medicine.medical_specialty
Cell Line
Tumor
Complement System Proteins
Cytotoxicity Tests
Immunologic
Drug Screening Assays
Antitumor
Humans
Immunoglobulin G
Interleukin-2
Papillomavirus Infections
RNA
Messenger
Thromboplastin
lcsh:RC254-282
Cell Line
Flow cytometry
03 medical and health sciences
Tissue factor
Genetics
medicine
Carcinoma
Neovascularization
030304 developmental biology
Pathologic
business.industry
Antitumor
medicine.disease
Squamous Cell
chemistry
RNA
Neoplasm
business
Zdroj: BMC Cancer, Vol 11, Iss 1, p 263 (2011)
BMC Cancer
ISSN: 1471-2407
Popis: 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.
Databáze: OpenAIRE
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