Stromal Drivers of Ovarian Cancer Initiation
Abstract
Ovarian cancer claims the life of one U.S. woman every 38 minutes. Ovarian cancer is a silent killer, causing only vague symptoms until the disease has widely spread, making it difficult to cure. When ovarian cancer is caught before it spreads, 90% of women are cured, while only 30% of women survive ovarian cancer once it has spread. Early diagnosis is the key to curing ovarian cancer. To date, there are no effective early diagnostic tests, and the only prevention strategy is surgical removal of the ovaries and fallopian tubes leading to loss of fertility and early-onset menopause. The development of effective early diagnostic tests is critically needed to save lives but is only possible by understanding how ovarian cancer starts. Our goal is to revolutionize the understanding of ovarian cancer initiation to develop effective early diagnostic strategies in ovarian cancer. The most common type of ovarian cancer, high grade serous ovarian cancer (HGSC), begins in the fallopian tube (FT) and quickly spreads to the ovary and the rest of the abdomen. Epithelial cells that line the inner wall of the FT are the cells which develop into ovarian cancer. Pre-cancerous changes occur in these FT epithelial cells which over time develop into cancer. However, not all pre-cancer cells progress to cancer. What makes these cells begin down the cancer-formation path or continue along that path is unknown. To date, research has been confined to studying these epithelial cells alone. However, cancer development is much more complex than this myopic focus will capture. Cancer cells are seeds that need fertile soil to take root and grow. To understand cancer initiation, we must fundamentally change our approach, studying both the seed and its supportive soil. We identified a unique cell type which is responsible for the development of this cancer supportive soil called carcinoma-associated mesenchymal stem cells (MSCs). These cells act like fertilizer, helping cancer cells survive, grow, and spread. We recently found that these cancer supportive MSCs exist within FTs and may actually predate the formation of cancer. In fact, our initial small study found 30% of normal FTs (without cancer or pre-cancer cells) from women at high risk for ovarian cancer due to a BRCA mutation, but only 3% of normal FTs from women without BRCA mutations contain these specialized cancer supportive MSCs that we call high-risk mesenchymal stem cells (hrMSCs). This mirrors the risk of developing ovarian cancer as women with BRCA mutations are at least 10 times more likely to get ovarian cancer than other women. Further, these hrMSCs cluster around pre-cancer cells as well as unique stretches of otherwise normal appearing epithelial cells. We propose a game-changing concept where the supportive soil precedes the formation of the cancer, helping to initiate the first ‘seeds’ of cancer. We propose to: 1. Calculate how often hrMSCs are present in FTs of women without cancer. 2. Establish if FT epithelial cells close to hrMSCs are more likely to turn into cancer. 3. Determine whether hrMSCs can promote the transformation of normal epithelial cells into ovarian cancer. These experiments will use tissues and cells derived from patient surgical samples to ensure our findings are directly relevant to ovarian cancer patients. Ultimately, the concept that supportive soil pre-dates the formation of cancer and drives the process of cancer initiation will completely change how we understand cancer formation. This information is critical to developing new ways to screen for ovarian cancer. If hrMSCs are present even before cancer starts, testing for markers of these unique cells may be critical to developing an early diagnosis test for ovarian cancer. The soil greatly outnumbers the initial seeds, therefore detecting the cancer supportive soil may be easier and more effective than detecting the seed.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2211101
Entities
People
- Lan Coffman
Organizations
- United States Army
- University of Pittsburgh