Overexpression of epidermal growth factor type-1 receptor (EGF-R1) in cervical cancer: implications for Cetuximab-mediated therapy in recurrent/metastatic disease.
OBJECTIVE
To evaluate and compare epidermal growth factor type-1 receptor (EGF-R1) expression in short term and established cervical cancer cell lines generated from primary and metastatic/recurrent sites of disease. To evaluate the sensitivity of cervical cancer cell lines to treatment with a chimeric MAb against EGFR-1 (Cetuximab).


METHODS
EGFR-1 expression was evaluated by flow cytometry on 22 cervical cancer cell lines including 14 primary cervical cancer cell lines obtained from cervical biopsies (11 patients) and recurrent sites of disease (three patients) as well as eight established cell lines. Tumor cell lines were tested for sensitivity to Cetuximab-mediated complement-dependent cytotoxicity (CDC) and antibody-dependent cellular cytotoxicity (ADCC) in 51Cr release assays. Finally, Cetuximab-mediated inhibition of cell proliferation was also tested.


RESULTS
Fourteen out of fourteen (100%) primary tumors and seven out of eight (87.5%) established cervical cancer cell lines expressed EGFR-1 by flow cytometry. Cell lines from recurrent/metastatic sites of disease expressed higher levels of EGFR-1 when compared to those obtained from primary sites (p>0.05). Minimal CDC was detected in the majority of cervical cancer cell lines exposed to complement+/-Cetuximab in the absence of peripheral blood lymphocytes (PBL). In contrast, cervical tumor cell lines were found highly sensitive to Cetuximab-mediated ADCC when challenged with PBL from either healthy donors or cervical cancer patients. Importantly, ADCC was further increased in the presence of complement. Finally, tumor proliferation was significantly inhibited by Cetuximab in all cervical tumors tested.


CONCLUSIONS
EGFR-1 is highly expressed in primary and recurrent cervical tumors. Cetuximab might be a novel and attractive therapeutic strategy in patients harboring chemotherapy-resistant, recurrent, or metastatic cervical cancer.
Bellone
Stefania
S
Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, University of Arkansas for Medical Sciences, Little Rock, AR 72205-7199, USA.
Frera
Gianluca
G
Landolfi
Gianpiero
G
Romani
Chiara
C
Bandiera
Elisabetta
E
Tognon
Germana
G
Roman
Juan J
JJ
Burnett
Alexander F
AF
Pecorelli
Sergio
S
Santin
Alessandro D
AD
D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology*; D061067:Antibodies, Monoclonal, Humanized; D000920:Antibody-Dependent Cell Cytotoxicity / Q000187:drug effects; D000970:Antineoplastic Agents / Q000494:pharmacology; D045744:Cell Line, Tumor; D000068818:Cetuximab; D066246:ErbB Receptors / Q000096:biosynthesis* / Q000276:immunology; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D008213:Lymphocyte Activation / Q000187:drug effects; D008214:Lymphocytes / Q000187:drug effects / Q000276:immunology; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000201:enzymology* / Q000276:immunology / Q000628:therapy*; D002583:Uterine Cervical Neoplasms / Q000201:enzymology* / Q000276:immunology / Q000628:therapy*
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D066246:ErbB Receptors; D000068818:Cetuximab