title: Prognostic relevance of TGF-beta1 and PAI-1 in cervical cancer.
abstract: Cervical carcinoma is a human papilloma virus (HPV)-related immunogenic type of malignancy, in which escape of the tumor from the hosts' immune response is thought to play an important role in carcinogenesis. The multifunctional cytokine transforming growth factor-beta(1) (TGF-beta(1)) is involved in immunosuppression, stroma and extracellular matrix formation and controlling (epithelial) cell growth. The plasminogen activating (PA) system plays a key role in the cascade of tumor-associated proteolysis leading to extracellular matrix degradation and stromal invasion. Changes in expression of components of this system, including plasminogen activator inhibitor-1 (PAI-1), have been associated with poor prognosis in a variety of solid tumors. The present study was undertaken to assess the role of both components on relapse, survival and other clinicopathologic parameters in cervical cancer. The expression of TGF-beta(1) mRNA in 108 paraffin-embedded cervical carcinomas was detected by mRNA in situ hybridization. Immunohistochemistry was used to investigate the expression of PAI-1 protein. The presence of cytoplasmatic TGF-beta(1) mRNA in tumor cells was not significantly correlated with the other clinicopathologic parameters investigated or with a worse (disease-free) survival. Expression of the PAI-1 protein in tumor cells was strongly correlated with worse overall and disease-free survival, in addition to well-known prognostic parameters such as lymph node metastasis, depth of tumor infiltration, tumor size and vasoinvasion. In the multivariate analysis, PAI-1 turned out to be a strong independent prognostic factor. In a subgroup of patients without lymph node metastases, PAI-1 was predictive for worse survival and relapse of disease, too. Our results show that the (enhanced) expression of PAI-1 by carcinoma cells is correlated with worse (overall and disease-free) survival of patients with cancer of the uterine cervix. The expression of TGF-beta(1) in itself is not associated with worse survival in these patients. Although simultaneous presence of the 2 factors was observed in all tumors, induction of PAI-1 by TGF-beta(1) could not be demonstrated in our group of cervical carcinomas.
authors.affiliation: Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands. hazelbag@planet.nl
authors.forename: Suzanne
authors.initials: S
authors.lastname: Hazelbag
authors.forename: Gemma G
authors.initials: GG
authors.lastname: Kenter
authors.forename: Arko
authors.initials: A
authors.lastname: Gorter
authors.forename: Gert Jan
authors.initials: GJ
authors.lastname: Fleuren
mesh_terms: D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000032:analysis* / Q000235:genetics; D002277:Carcinoma / Q000737:chemistry* / Q000473:pathology*; D016001:Confidence Intervals; D018572:Disease-Free Survival; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D008207:Lymphatic Metastasis; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D009364:Neoplasm Recurrence, Local / Q000737:chemistry / Q000473:pathology; D009367:Neoplasm Staging; D016017:Odds Ratio; D017395:Plasminogen Activator Inhibitor 1 / Q000032:analysis* / Q000235:genetics; D011237:Predictive Value of Tests; D011379:Prognosis; D016016:Proportional Hazards Models; D012333:RNA, Messenger / Q000032:analysis; D012334:RNA, Neoplasm / Q000032:analysis; D016019:Survival Analysis; D016212:Transforming Growth Factor beta / Q000032:analysis* / Q000235:genetics; D053773:Transforming Growth Factor beta1; D002583:Uterine Cervical Neoplasms / Q000737:chemistry* / Q000473:pathology*
chemical_list: D014408:Biomarkers, Tumor; D017395:Plasminogen Activator Inhibitor 1; D012333:RNA, Messenger; D012334:RNA, Neoplasm; C508960:TGFB1 protein, human; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1