The Surgeon

Researchers report the fallopian tube fimbria rather than ovarian surface cells may be the site of origin for over 50 percent of sporadic and hereditary serous carcinoma, the most aggressive form of ovarian cancer. The new knowledge may enable earlier detection, better treatment and potential prevention of the most lethal gynecologic malignancy in Western countries.

“With the correct cell-of-origin in hand, we can now look for differences between the benign cells and the tumor that arises from them and develop early detection biomarkers. We can identify aberrations in signaling pathway and genetic alterations in serous cancers compared with the fallopian tube secretory epithelial cells (FTSECs), and propose new targeted therapies to tackle these pathways,” said lead researcher Keren Levanon, M.D., Ph.D. Levanon is a postdoctoral research fellow in the lab of Ronny I. Drapkin, M.D., Ph.D., at the Dana-Farber Cancer Institute in Boston.

The inner lining of the fallopian tube is composed of ciliated and secretory cells. Ciliated cells, which are characterized by distinctive hair-like structures, transport unfertilized egg and sperm cells toward each other and transport a fertilized egg toward the uterus. “We never find this type of cell in high-grade tumors of the ovary,” Levanon said.

Secretory cells, as their name suggests, secrete molecules essential to the maintenance of the egg and sperm and facilitate fertilization.

“This type of cell is uniquely represented in the precursor lesions leading to early and eventually invasive serous cancer,” Levanon said. Only a handful of biomarkers that distinguish secretory from ciliated cells have been reported: Bcl-2, HMFG2 and Pax-8.

Using a new model system to study these cells, Levanon finds that FTSECs appear to respond faster to DNA damage, adding that DNA repair mechanisms are more effective in FTSECs than in neighboring ciliated cells. The research team is investigating the potential implications of these differences in response rates and whether ovulation elicits a similar response.

“The identification of the FTSEC as a cell-of-origin has a number of translational implications,” Levanon said. “We are now at a unique position to start understanding the normal biology of the fallopian tube and how it is affected by hormonal and inflammatory insults throughout life. The understanding of risk factors at a molecular level may, in the future, evolve into recommendations for primary prevention.”

Levanon said the team’s findings would likely change how pathologists examine fallopian tubes after surgical removal, with a new emphasis on the fimbria to measure the incidence of precursors and early cancers among women who carry BRCA mutations. Future studies may explore connections between specific genetic or environmental modifiers and the incidence of precursor lesions in the fimbria.

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