Clear Cell and Endometrioid Carcinomas : are their differences attributable to distinct cells of origin?

Endometrial epithelium is the presumed tissue of origin for both eutopic and endometriosis-derived clear cell and endometrioid carcinomas. We had previously hypothesized that the morphological, biological and clinical differences between these cancers are due to subtype-restricted underlying mutations. Although some mutations and genomic landscape features are more likely to be found in one of these histotypes, we were not able to identify a single class of mutations that was exclusively present in one histotype and not the other. This lack of genomic differences led us to an alternative hypothesis that these cancers arise from distinct cells of origin within endometrial tissue, and it is the cellular context that accounts for their differences. In a proteomics screen, we have identified CTH as a marker for clear cell carcinoma differentiation, as it is expressed at high levels in clear cell carcinomas of the ovary and endometrium. We analyzed normal Müllerian tissues and found CTH was expressed in ciliated cells of endometrium (both eutopic endometrium and endometriosis) and fallopian tube. We have since determined that other ciliated cell markers are expressed in clear cell carcinomas whereas endometrial secretory cell markers are expressed in endometrioid carcinomas. To determine whether the ciliated endometrial cells are uterine derived we developed a 3D organoid culture system, which reliably produced both ciliated and secretory cells. Clear cell carcinoma is an IL-6 driven tumour and lineage experiments on bronchial epithelium have shown that IL-6 is an essential pathway in maintaining the population of ciliated cells. Taken together we hypothesize that endometrioid carcinomas are derived from cells of secretory cell lineage whereas clear cell carcinomas are derived from cells of endometrial origin that share features with a ciliated cell lineage.