Abstract
An organotypic model of endometrial carcinogenesis and chemoprevention was developed in which normal endometrial organotypic cultures exposed to the carcinogen, DMBA (7,12-dimethylbenz[a]anthracene), developed a cancerous phenotype in the absence, but not presence of subsequent treatment with a flexible heteroarotinoid (Flex-Het), called SHetA2. A discriminant function based on karyometric features of cellular nuclei and an agar clonogenic assay confirmed these histologic changes. Interpretation of microarray data using an internal standard approach identified major pathways associated with carcinogenesis and chemoprevention governed by c-myc, p53, TNFalpha and Jun genes. Cluster analysis of functional associations of hypervariable genes demonstrated that carcinogenesis is accompanied by a stimulating association between a module of genes that includes tumor necrosis factor alpha (TNFalpha), c-myc, and epidermal growth factor-receptor (EGF-R) and a module that includes insulin-like growth factor I-receptor (IGF-IR), p53, and Jun genes. Two secreted proteins involved in these systems, tenascin C and inhibin A, were validated at the protein level. Tenascin C is an EGF-R ligand, and therefore may contribute to the increased EGF-R involvement in carcinogenesis. The known roles of the identified molecular systems in DMBA and endometrial carcinogenesis and chemoprevention supports the validity of this model and the potential clinical utility of SHetA2 in chemoprevention.
Highlights
In comparison to classical approaches evaluating single molecules or pathways, a systems biology approach provides a broader perspective with the possibility of uncovering novel results in complex tissues, such as cancer of the uterine endometrium
Three key karyometric features of the nuclei showed dramatic and statistically significant increases in the cells in DMBA-treated cultures relative to untreated cultures. These three features and others were nearly identical in the cultures treated with DMBA + SHetA2 and control cultures treated with solvent only, consistent with SHetA2 chemoprevention activity
The results of the karyometric analysis demonstrate that DMBA increases the numerical value of the discriminant function scores causing a shift to the right, and that this shift is prevented by SHetA2 (Fig. 1A)
Summary
In comparison to classical approaches evaluating single molecules or pathways, a systems biology approach provides a broader perspective with the possibility of uncovering novel results in complex tissues, such as cancer of the uterine endometrium. To develop a model system that incorporated the complexity of the endometrial microenvironment, we cultured primary human endometrial cells inside and on top of collagen gels in filter inserts and demonstrated that hormonal treatments of these cultures induced tissue architecture reflective of different phases of the menstrual cycle (Kamelle et al 2002). Both single stromal cells and epithelial glands developed inside the collagen
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