Involvement of the TGF-β and β-Catenin Pathways in Pelvic Lymph Node Metastasis in Early-Stage Cervical Cancer

Maartje G Noordhuis,Rudolf S.N Fehrmann,Perry D Moerland,Esther R Nijhuis,Emiel Ver Loren Van Themaat,Harry Hollema,Elisabeth G.E De Vries,Geertruida H De Bock,Klaske A Ten Hoor,Haukeline H Volders,G Bea A Wisman,Ate G.J Van Der Zee,Ed Schuuring,Mirjam Kok,Jelmer J Van Zanden

doi:10.1158/1078-0432.ccr-10-2320

Abstract

Presence of pelvic lymph node metastases is the main prognostic factor in early-stage cervical cancer patients, primarily treated with surgery. Aim of this study was to identify cellular tumor pathways associated with pelvic lymph node metastasis in early-stage cervical cancer. Gene expression profiles (Affymetrix U133 plus 2.0) of 20 patients with negative (N(0)) and 19 with positive lymph nodes (N(+)), were compared with gene sets that represent all 285 presently available pathway signatures. Validation immunostaining of tumors of 274 consecutive early-stage cervical cancer patients was performed for representatives of the identified pathways. Analysis of 285 pathways resulted in identification of five pathways (TGF-β, NFAT, ALK, BAD, and PAR1) that were dysregulated in the N(0), and two pathways (β-catenin and Glycosphingolipid Biosynthesis Neo Lactoseries) in the N(+) group. Class comparison analysis revealed that five of 149 genes that were most significantly differentially expressed between N(0) and N(+) tumors (P < 0.001) were involved in β-catenin signaling (TCF4, CTNNAL1, CTNND1/p120, DKK3, and WNT5a). Immunohistochemical validation of two well-known cellular tumor pathways (TGF-β and β-catenin) confirmed that the TGF-β pathway (positivity of Smad4) was related to N(0) (OR: 0.20, 95% CI: 0.06-0.66) and the β-catenin pathway (p120 positivity) to N(+) (OR: 1.79, 95%CI: 1.05-3.05). Our study provides new, validated insights in the molecular mechanism of lymph node metastasis in cervical cancer. Pathway analysis of the microarray expression profile suggested that the TGF-β and p120-associated noncanonical β-catenin pathways are important in pelvic lymph node metastasis in early-stage cervical cancer.

Highlights

Standard treatment of early-stage cervical cancer patients consists of radical hysterectomy and pelvic lym-Authors' Affiliations: Department of 1Gynecologic Oncology, 2Pathology, 3Medical Oncology, and 4Epidemiology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands; 5Bioinformatics Laboratory, Department of Clinical Epidemiology, Biostatistics, and Bioinformatics, Academic Medical Center, Amsterdam, The Netherlands; and 6Netherlands Bioinformatics Centre (NBIC), Nijmegen, The NetherlandsNote: Supplementary data for this article are available at Clinical Cancer Research Online.Note: Current address of Emiel Ver Loren van Themaat: Max-PlanckInstitute for Plant Breeding Research, Carl-von-Linne-Weg 10, 50829 Ko€ln, GermanyNote: M.G
Analysis of 285 pathways resulted in identification of five pathways (TGF-b, NFAT, ALK, BAD, and PAR1) that were dysregulated in the N0, and two pathways (b-catenin and Glycosphingolipid Biosynthesis Neo Lactoseries) in the Nþ group
Pathway analysis of the microarray expression profile suggested that the transforming growth factor b (TGF-b) and p120-associated noncanonical b-catenin pathways are important in pelvic lymph node metastasis in early-stage cervical cancer

Summary

Introduction

Standard treatment of early-stage cervical cancer patients consists of radical hysterectomy and pelvic lym-. Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/). For this group of patients, the presence of lymph node metastases is the most important prognostic factor [1]. Early-stage cervical cancer patients with negative lymph nodes have a 5-year survival of 90% versus only 65% in patients with lymph node metastases [2]. Patients with lymph node metastases are treated with adjuvant (chemo)radiation. The combination of surgery and (chemo)radiation is associated with severe morbidity [3]. If the presence of metastatic lymph nodes could be predicted prior to treatment, primary chemoradiation could be considered, which is effective, but associated with a different treatment-related morbidity pattern

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