A groundbreaking study has uncovered the origin of one of the most aggressive forms of ovarian cancer, called high-grade serous carcinoma, which primarily develops in the fallopian tube.
This discovery opens the door to new ways of diagnosing and potentially treating the disease, which is the sixth-leading cause of cancer death in women.
High-grade serous carcinoma is especially deadly because it has no clear symptoms and no reliable tools for early detection. Most patients are diagnosed too late for effective treatment, and many do not survive beyond five years.
Until now, scientists had limited knowledge about where exactly this type of cancer starts in the body. However, a new study published in Nature Communications has identified a specific type of cell in the fallopian tube that is especially prone to becoming cancerous.
These cancer-prone cells, called pre-ciliated tubal epithelial cells, are a transitional type of cell found in the fallopian tube.
They are an intermediate stage between stem cells and fully developed ciliated cells, which help move fluids and eggs through the tube. These pre-ciliated cells are now recognized as the origin of the cancer.
Dr. Alexander Nikitin, a professor at the College of Veterinary Medicine at Cornell University and the senior author of the study, emphasized the importance of the discovery:
“We not only identified the cells where the cancer originates, but we also uncovered mechanisms that could lead to new diagnostic tools and therapies.”
The research was conducted in mice, where the fallopian tube is known as the uterine tube. The team analyzed the cellular makeup of the uterine tube and found that high-grade serous carcinoma can develop in both the ovaries and this part of the fallopian tube.
While Nikitin’s previous work had linked the origins of this cancer to the ovaries, this new study is the first to pinpoint specific cells in the fallopian tube that are cancer-prone.
One of the key steps in the study was characterizing all the cell types present in the uterine tube. Researchers wanted to determine which types of cells might be most responsible for the development of ovarian cancer.
After identifying all the different types of cells, they focused on how certain genetic mutations could lead to cancer.
In human cases of high-grade serous carcinoma, mutations in two key genes are common: TP53 and RB1. These genes play a role in suppressing tumor growth when they function correctly.
In more than 96% of cases, the TP53 gene is mutated, while different components of the RB1 pathway are altered in over 60% of cases.
Previous research had already shown that these genes were involved in cancer development in the ovaries, but this new study explores their role in the fallopian tube.
Surprisingly, when the researchers inactivated TP53 and RB1 in stem cells of the fallopian tube, no cancer developed, even after a year. Instead, the stem cells died, suggesting that they were not the main source of the cancer.
However, when the same genes were inactivated in a group of pre-ciliated transitional cells, high-grade serous carcinoma rapidly developed in the mice.
The researchers used single-cell sequencing data to identify cells expressing a gene called Pax8, which is commonly associated with this type of cancer.
They found that pre-ciliated cells with Pax8 were particularly prone to becoming cancerous when both TP53 and RB1 were inactivated.
These cells, which are in an early stage of developing cilia (hair-like structures on the surface of cells), had specific gene expressions, including one called Krt5, that made them stand out.
Nikitin explained that the process of ciliogenesis, or the formation of cilia, is already well-studied in biology. This familiarity with how ciliated cells form could make it easier for researchers to identify potential diagnostic and therapeutic targets for ovarian cancer.
By understanding the specific cells and genetic pathways involved in the development of high-grade serous carcinoma, scientists now have a clearer path forward.
This discovery not only highlights the origins of the cancer but also offers hope for earlier detection and more effective treatments for a disease that has long been difficult to diagnose and treat.
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The research findings can be found in Nature Communications.
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