Abstract
Folate receptor alpha (FOLR1/FRA) is reported to be overexpressed in epithelial ovarian cancers (EOC), especially the serous histotype. Further, while dysregulation of the folate-dependent 1-carbon cycle has been implicated in tumorogenesis, little is known relative to the potential mechanism of action of FOLR1 expression in these processes. We therefore investigated the expression of FOLR1, other folate receptors, and genes within the 1-carbon cycle in samples of EOC, normal ovary and fallopian tube on a custom TaqMan Low Density Array. Also included on this array were known markers of EOC such as MSLN, MUC16 and HE4. While few differences were observed in the expression profiles of genes in the 1-carbon cycle, genes previously considered to be overexpressed in EOC (e.g., FOLR1, MSLN, MUC16 and HE4) showed significantly increased expression when comparing EOC to normal ovary. However, when the comparator was changed to normal fallopian tube, these differences were abolished, supporting the hypothesis that EOC derives from fallopian fimbriae and, further, that markers previously considered to be upregulated or overexpressed in EOC are most likely not of ovarian origin, but fallopian in derivation. Our findings therefore support the hypothesis that the cell of origin of EOC is tubal epithelium.
Highlights
Ovarian cancer causes more deaths than any other cancer of the female reproductive system, with more than 15,000 deaths expected in 2013 in the United States alone [1]
We found that the expression differences observed for FOLR1, other known epithelial ovarian cancer (EOC) markers (e.g., MSLN, MUC16), and genes involved in signal transduction in EOC were lost when the comparison was changed from normal ovary to normal fallopian tube
These included folate transporters/receptors, genes involved in 1-carbon cycle metabolism and folate homeostasis, known markers of ovarian cancer and genes involved in signal transduction (Table 1)
Summary
Ovarian cancer causes more deaths than any other cancer of the female reproductive system, with more than 15,000 deaths expected in 2013 in the United States alone [1]. We found that the expression differences observed for FOLR1, other known EOC markers (e.g., MSLN, MUC16), and genes involved in signal transduction in EOC were lost when the comparison was changed from normal ovary to normal fallopian tube These data confirm, or at the very least support the hypothesis that gene expression of EOC correlates well with that of fallopian normal tissue samples and further support the hypothesis that EOC derives from tubal fimbriae. These data suggest that genes/proteins commonly considered to be markers of EOC are not a priori overexpressed in EOC but, rather, their expression is retained from the cell of origin of EOC and should be considered passengers rather than drivers or a result of tumorogenesis per se These findings reveal how application of fallopian tube normal tissue as the tissue of origin may fundamentally change certain paradigms that exist in ovarian cancer gene expression profile studies and lead to the discovery of new potential therapeutic targets
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