Study Identifies Cells-of-origin of High-grade Serous Ovarian Cancer

Thoughtful young women suffering from ovarian cancer.
Young women suffering from ovarian cancer. Photo courtesy: 2019 Fotolia

The identity of the “cell-of-origin” in the development of many ovarian tumors, including high grade serous ovarian carcinoma (HGSOC) has been controversial. The disease generally presents as a large ovarian mass accompanied by widespread peritoneal metastasis. [1][2]

In the United States in 2018 approximately 22,240 new cases of ovarian cancer were diagnosed and 14,070 women died from the disease.

Fallopian tube epithelium (FTE) and ovarian surface epithelium (OSE) are both considered possible candidates, but scientists have often disagreed about which one may be the cause of the most lethal form of the disease which is rarely symptomatic until an advanced stage and causes ~70% of all ovarian cancer related deaths. [3]

Now, a new study, led by researchers from Perlmutter Cancer Center at NYU Langone Health, funded by the study Canadian Institutes of Health, the National Cancer Institute Center, the United States Department of Defense Ovarian Cancer Research Program, and the Ovarian Cancer Research Fund Alliance, finds that ovarian cancers may begin either in cells lining the outsides of ovaries or in cells on the surface of the adjacent fallopian tubes.

In addition, the “cell-of-origin” influences the growth rate of the resulting tumor, and the degree to which its responds to therapies, say the researchers.

The study’s findings were published online November 26, 2019 in Nature Communications.[4]

“Based on a better understanding of its origins, our study provides new insights into the biology and therapy of ovarian cancer,” noted the study’s first author Shuang Zhang, Ph.D, a postdoctoral fellow at Perlmutter Cancer Center.

Study
The researchers used genetically engineered mice in which the same cancer-causing genetic changes (mutations) were found either in fallopian tube or ovarian surface cells, as well as in “organoids,” 3-D cell cultures grown from tissue taken from the mice.

The results showed that both cell types gave rise to tumors, but the ones from the fallopian tube tended to spread more quickly and widely throughout the abdomen. The ovarian surface-derived tumors gave rise to larger overall collections of tumor cells. The researchers also found that the fallopian tube-derived tumors were considerably more sensitive to cis-platinum, the most active chemotherapeutic drug for the treatment of ovarian cancer for the last 4 decades.

Consistent with these findings, the researchers found that fallopian tube- and ovarian surface-derived tumors in mice expressed distinct sets of genes, many of which were expressed differently in the originating, normal cells. Cancer cells arise from normal cells in which disease-causing genetic changes have occurred.

Signature gene
By using these differentially expressed genes as a “signature” to compare to human ovarian cancer cells to each other, and to normal cells, the team found that some human tumors are more fallopian tube-like, while others more ovarian-like. Also, while many of the same genetic alterations could be found in both types of tumor, some abnormalities appeared to be more common in either fallopian- or ovarian-derived tumors.

“Our results suggest that high-grade cancer can originate in more than one cell type, and that the original cell type can significantly influence tumor behavior and therapy response,” explained enior study author Benjamin Neel, MD, Ph.D, director of the Perlmutter Cancer Center.

In the future, Neel said, physicians may need to consider the cell-of-origin, along with the specific genetic changes in the tumor, to optimize and personalize therapy.

Reference
[1] Klotz DM, Wimberger P. Cells of origin of ovarian cancer: ovarian surface epithelium or fallopian tube?. Arch Gynecol Obstet. 2017;296(6):1055–1062. doi:10.1007/s00404-017-4529-z
[2] Kurman RJ. Origin and molecular pathogenesis of ovarian high-grade serous carcinoma. Ann Oncol. 2013;24 Suppl 10:x16–x21. doi:10.1093/annonc/mdt463
[3] Köbel M, Kalloger SE, Huntsman DG, et al. Differences in tumor type in low-stage versus high-stage ovarian carcinomas. Int J Gynecol Pathol. 2010;29(3):203–211. doi:10.1097/PGP.0b013e3181c042b6
[4] Zhang S, Dolgalev I, Zhang T, Ran H, Levine DA, Neel BG. Both fallopian tube and ovarian surface epithelium are cells-of-origin for high-grade serous ovarian carcinoma. Nat Commun. 2019;10(1):5367. Published 2019 Nov 26. doi:10.1038/s41467-019-13116-2