title: Overexpression of the alpha v beta 6 integrin in cervical squamous cell carcinoma is a prognostic factor for decreased survival.
abstract: Cervical squamous cell carcinomas are composed histologically of tumour cell islands surrounded by varying amounts of tumour stroma, the amount and composition of which are influenced by local TGF-beta(1). TGF-beta(1) is secreted in an inactive complex with latency-associated peptide (LAP). Both LAP and the extracellular matrix (ECM) protein fibronectin are important ligands for the integrin receptor alpha v beta 6. While alpha v beta 6 is only weakly expressed by normal epithelia, it is up-regulated in different carcinomas where it generally reflects a more aggressive phenotype. In cervical cancer, the expression of alpha v beta 6 has not thus far been investigated. Given the ability of alpha v beta 6 both to activate TGF-beta(1) and to interact with fibronectin, we studied correlations between the expression of these components and disease parameters in a large cohort of cervical cancer specimens. We analysed alpha v beta 6 expression using immunohistochemistry in primary cervical squamous carcinomas of FIGO stage IA to IIB patients and correlated the findings with formerly investigated fibronectin and TGF-beta(1) expression and clinico-pathological parameters. alpha v beta 6 expression was also examined in cervical intra-epithelial neoplasia (CIN) and lymph node metastases. alpha v beta 6 was only weakly expressed in normal epithelium but clearly up-regulated in CIN lesions. In carcinomas, strong expression of alpha v beta 6 in tumour cells correlated with different clinico-pathological parameters and with worse overall and disease-free survival. Furthermore, alpha v beta 6 expression correlated positively with TGF-beta(1) mRNA expression as well as with fibronectin expression. Overexpression of alpha v beta 6 in cervical squamous carcinomas is an unfavourable prognostic factor. This might reflect an increased capacity of alpha v beta 6-expressing tumour cells to migrate in a fibronectin-rich ECM and/or to activate TGF-beta(1) at the tumour/stroma interface, both of which processes may contribute to cervical cancer progression.
authors.affiliation: Department of Pathology, Leiden University Medical Centre, Leiden, The Netherlands.
authors.forename: S
authors.initials: S
authors.lastname: Hazelbag
authors.forename: G G
authors.initials: GG
authors.lastname: Kenter
authors.forename: A
authors.initials: A
authors.lastname: Gorter
authors.forename: E J
authors.initials: EJ
authors.lastname: Dreef
authors.forename: L A
authors.initials: LA
authors.lastname: Koopman
authors.forename: S M
authors.initials: SM
authors.lastname: Violette
authors.forename: P H
authors.initials: PH
authors.lastname: Weinreb
authors.forename: G J
authors.initials: GJ
authors.lastname: Fleuren
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000951:Antigens, Neoplasm / Q000032:analysis / Q000235:genetics*; D014408:Biomarkers, Tumor / Q000032:analysis / Q000235:genetics*; D002278:Carcinoma in Situ / Q000737:chemistry / Q000401:mortality / Q000473:pathology; D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D002584:Cervix Uteri / Q000737:chemistry / Q000473:pathology; D018450:Disease Progression; D005260:Female; D005353:Fibronectins / Q000032:analysis; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D017403:In Situ Hybridization / Q000379:methods; D016023:Integrins / Q000032:analysis / Q000235:genetics*; D008207:Lymphatic Metastasis; D008875:Middle Aged; D011379:Prognosis; D012333:RNA, Messenger / Q000032:analysis; D015996:Survival Rate; D016212:Transforming Growth Factor beta / Q000235:genetics; D002583:Uterine Cervical Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology
chemical_list: D000951:Antigens, Neoplasm; D014408:Biomarkers, Tumor; D005353:Fibronectins; D016023:Integrins; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; C073878:integrin alphavbeta6