New Delhi: Researchers at the University of Pittsburgh have discovered a group of high-risk cells in the fallopian tubes that may play a key role in the development of high-grade serous ovarian carcinoma (HGSOC), the most common and deadly form of ovarian cancer.
The study, published on March 14 in Cancer Discovery, highlights potential new ways to prevent and detect the disease, which kills over 12,000 women in the U.S. each year.
"Ovarian cancer is the leading cause of death from gynaecologic cancer in the Western world, but we currently have no way to detect it early and no prevention strategies apart from surgical castration, which is only indicated in high-risk women," said cosenior author Lan Coffman, Associate Professor of Medicine at the Pitt School of Medicine. "Understanding the underlying biology of how ovarian cancer forms is critical to improving outcomes for our patients."
HGSOC begins in the fallopian tubes when healthy epithelial cells turn into precursor lesions known as serous tubal intraepithelial carcinoma (STIC), which can later develop into tumours. However, researchers wanted to understand why these healthy cells become cancerous.
"Most researchers have been focused on the epithelial cells that turn into these STIC lesions and eventually into cancer," said Coffman. "Until now, no one has really looked at the surrounding stromal microenvironment of these lesions."
The study found that mesenchymal stem cells (MSCs), which usually help repair healthy tissue, become reprogrammed by tumour cells to support cancer growth. The team investigated when these cancer-associated MSCs form and how early they contribute to cancer initiation.
When profiling MSCs in the fallopian tubes of women without cancer, they found cells resembling cancer-associated MSCs in otherwise healthy women. These high-risk MSCs were more common in women at higher risk of ovarian cancer, such as older individuals or those with BRCA gene mutations, suggesting they could play a role in the early stages of the disease.
When the researchers introduced these high-risk MSCs into lab-grown mini-organs (organoids) derived from patient fallopian tube tissue, healthy epithelial cells turned into cancerous cells.
"High-risk MSCs promote DNA damage in epithelial cells and then help those mutated cells survive," explained Coffman. "It’s the perfect storm for cancer initiation."
The study also found that these high-risk MSCs helped tumour cells grow faster and increased their resistance to chemotherapy.
To understand why this happens, the researchers discovered that high-risk MSCs had lower levels of an antioxidant called AMP kinase. Reduced AMP kinase led to higher levels of a protein called WT1, which triggered the formation of compounds that cause DNA damage.
"This is the first report that stromal changes in the fallopian tube actually have a causative role in ovarian cancer initiation," said Coffman. "It also points to a path where we might be able to intervene."
The findings suggest that existing drugs that boost AMP kinase levels could potentially prevent or reverse early changes in the stroma that lead to ovarian cancer.
The study also opens possibilities for early detection. According to Coffman, compounds secreted by high-risk MSCs that circulate in the bloodstream could serve as biomarkers for early-stage ovarian cancer, aiding in detection before symptoms appear.
This research provides valuable insights into ovarian cancer’s early development and may lead to better prevention and detection strategies in the future.