TY - JOUR
T1 - Profiling microdissected epithelium and stroma to model genomic signatures for cervical carcinogenesis accommodating for covariates
AU - Gius, David
AU - Funk, Margo C.
AU - Chuang, Eric Y.
AU - Feng, Sheng
AU - Huettner, Phyllis C.
AU - Nguyen, Loan
AU - Bradbury, C. Matthew
AU - Mishra, Mark
AU - Gao, Shuping
AU - Buttin, Barbara M.
AU - Cohn, David E.
AU - Powell, Matthew A.
AU - Horowitz, Neil S.
AU - Whitcomb, Bradford P.
AU - Rader, Janets
PY - 2007/8/1
Y1 - 2007/8/1
N2 - 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 patientmatched 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.
AB - 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 patientmatched 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.
UR - http://www.scopus.com/inward/record.url?scp=34547637241&partnerID=8YFLogxK
U2 - 10.1158/0008-5472.CAN-07-0260
DO - 10.1158/0008-5472.CAN-07-0260
M3 - Article
C2 - 17671178
AN - SCOPUS:34547637241
SN - 0008-5472
VL - 67
SP - 7113
EP - 7123
JO - Cancer research
JF - Cancer research
IS - 15
ER -