Profiling microdissected epithelium and stroma to model genomic signatures for cervical carcinogenesis accommodating for covariates. Cancer Res 2007 Aug 01;67(15):7113-23
Date
08/03/2007Pubmed ID
17671178DOI
10.1158/0008-5472.CAN-07-0260Scopus ID
2-s2.0-34547637241 (requires institutional sign-in at Scopus site) 74 CitationsAbstract
This study is the first comprehensive, integrated approach to examine grade-specific changes in gene expression along the entire neoplastic spectrum of cervical intraepithelial neoplasia (CIN) in the process of cervical carcinogenesis. This was accomplished by identifying gene expression signatures of disease progression using cDNA microarrays to analyze RNA from laser-captured microdissected epithelium and underlying stroma from normal cervix, graded CINs, cancer, and patient-matched normal cervical tissues. A separate set of samples were subsequently validated using a linear mixed model that is ideal to control for interpatient gene expression profile variation, such as age and race. These validated genes were ultimately used to propose a genomically based model of the early events in cervical neoplastic transformation. In this model, the CIN 1 transition coincides with a proproliferative/immunosuppression gene signature in the epithelium that probably represents the epithelial response to human papillomavirus infection. The CIN 2 transition coincides with a proangiogenic signature, suggesting a cooperative signaling interaction between stroma and tumor cells. Finally, the CIN 3 and squamous cell carcinoma antigen transition coincide with a proinvasive gene signature that may be a response to epithelial tumor cell overcrowding. This work strongly suggests that premalignant cells experience a series of microenvironmental stresses at the epithelium/stroma cell interface that must be overcome to progress into a transformed phenotype and identifies the order of these events in vivo and their association with specific CIN transitions.
Author List
Gius D, Funk MC, Chuang EY, Feng S, Huettner PC, Nguyen L, Bradbury CM, Mishra M, Gao S, Buttin BM, Cohn DE, Powell MA, Horowitz NS, Whitcomb BP, Rader JSAuthor
Janet Sue Rader MD Chair, Professor in the Obstetrics and Gynecology department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
Biomarkers, TumorCarcinoma, Squamous Cell
Epithelium
Female
Gene Expression Profiling
Gene Expression Regulation, Neoplastic
Humans
Lasers
Microdissection
Neoplasm Invasiveness
Oligonucleotide Array Sequence Analysis
RNA, Neoplasm
Reverse Transcriptase Polymerase Chain Reaction
Stromal Cells
Transcriptional Activation
Uterine Cervical Dysplasia
Uterine Cervical Neoplasms