Death receptors and ligands in cervical carcinogenesis: an immunohistochemical study.
OBJECTIVE
Increasing imbalance between proliferation and apoptosis is important in cervical carcinogenesis. The death ligands FasL and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induce apoptosis by binding to their cognate cell-surface death receptors Fas or death receptor (DR) 4 and DR5. This study aims to examine if changes in death ligand and death receptor expression during different stages of cervical carcinogenesis are related to an imbalance between proliferation and apoptosis.


METHODS
The immunohistochemical expression and localization of Fas/FasL and DR4/DR5/TRAIL were assessed in 11 normal cervices, 15 cervical intraepithelial neoplasia (CIN) grade I, 15 CIN II, 13 CIN III, and 25 (microinvasive) squamous cell cervical cancers. The number of apoptotic cells was determined by morphological criteria and the number of proliferating cells by counting Ki-67-positive cells.


RESULTS
A marked increase in proliferation as well as apoptosis percentage was found with increasing severity of neoplasia. In normal cervix and CIN I samples, FasL, DR4, DR5, and TRAIL staining was mainly observed in the basal/parabasal layer, whereas Fas staining was localized in the superficial, more differentiated epithelial layer. Frequency of Fas-positive staining decreased with increasing severity of CIN. In contrast, homogeneous FasL, DR4, DR5, and TRAIL expression throughout the lesions was more frequently observed in CIN III and cervical cancer. FasL, DR4, DR5, and TRAIL staining patterns were correlated, although TRAIL expression was more intense in low-grade lesions. No association was found between death receptor or ligand expression with the percentage of apoptosis or proliferation.


CONCLUSIONS
The loss of Fas and the deregulation of FasL, DR4, DR5, and TRAIL in the CIN-cervical cancer sequence suggest a possible functional role of these death ligands and receptors during cervical carcinogenesis. The frequent expression of DR4 and DR5 presents these receptors as promising targets for innovative therapy modalities in cervical cancer.
Reesink-Peters
N
N
Department of Gynecologic Oncology, University Hospital Groningen, PO Box 30001, 9700 RB, Groningen, The Netherlands.
Hougardy
B M T
BM
van den Heuvel
F A J
FA
Ten Hoor
K A
KA
Hollema
H
H
Boezen
H M
HM
de Vries
E G E
EG
de Jong
S
S
van der Zee
A G J
AG
D017209:Apoptosis / Q000502:physiology; D051017:Apoptosis Regulatory Proteins; D014408:Biomarkers, Tumor / Q000096:biosynthesis / Q000378:metabolism; D002294:Carcinoma, Squamous Cell / Q000378:metabolism* / Q000473:pathology; D048708:Cell Growth Processes / Q000502:physiology; D002584:Cervix Uteri / Q000378:metabolism; D053222:Fas Ligand Protein; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D019394:Ki-67 Antigen / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000096:biosynthesis / Q000378:metabolism*; D009367:Neoplasm Staging; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor / Q000096:biosynthesis / Q000378:metabolism*; D053221:TNF-Related Apoptosis-Inducing Ligand; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000378:metabolism; D002583:Uterine Cervical Neoplasms / Q000378:metabolism* / Q000473:pathology*; D019014:fas Receptor / Q000096:biosynthesis / Q000378:metabolism*; D002578:Uterine Cervical Dysplasia / Q000378:metabolism* / Q000473:pathology
D051017:Apoptosis Regulatory Proteins; D014408:Biomarkers, Tumor; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D019394:Ki-67 Antigen; D008562:Membrane Glycoproteins; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor; D053221:TNF-Related Apoptosis-Inducing Ligand; C105190:TNFRSF10A protein, human; C505639:TNFRSF10B protein, human; C505653:TNFSF10 protein, human; D014409:Tumor Necrosis Factor-alpha; D019014:fas Receptor