High-grade serous ovarian cancer (HGSOC) is the most common and lethal type of ovarian cancer. It has become clear that this type of ovarian cancer can actually originate in the fallopian tube and then spread to the ovary. However, these tumors were diagnosed as ovarian because that is where large tumors always formed. This suggests that colonization of the ovary may be a key step in progression of this disease. This research project explores the role of the ovary in the spread of these tumors and identifies potential targets to prevent spread of tumors of the fallopian tube to the ovary.
We found that tumorigenic cells from the fallopian tube were unable to form tumors when injected into the peritoneum of mice but formed very aggressive tumors that spread throughout the peritoneum when injected in to ovarian microenviroment, suggesting that the ovary plays a key role in spread of these tumors. We show that an unknown protein secreted from the ovary stimulates migration of fallopian tube cells via the EGF receptor. We will identify this protein using proteomic techniques, thus identifying a novel chemotactic agents that stimulate migration of fallopian tube derived cells toward the ovary. Another reason fallopian tube-derived tumors may colonize the ovary is that during ovulation, tumor cells adhere to extracellular matrix exposed during rupture of the follicle. We show that ovulation mimetic treated ovaries (i.e. tearing the surface of the ovary without associated hormone changes) increases the ability of fallopian tube and HGSOC cells to attached to the surface of the ovary and fallopian tube cell preferentially adhere to ovarian stroma cells more than ovarian surface epithelial cells. While normal fallopian tube cells could adhere to the ovarian stroma, they were unable to thrive in this collagen rich microenviroment, but HGSOC cell lines could. Therefore, this research will also identify the genetic mutations that allow fallopian tube cells to grow and survive in the collagen reach microenvironment of the ovarian stroma and elucidate the signaling pathways responsible for increased remodeling of the extracellular matrix by HGSOC cells. Finally, we show that deletion of a single gene (PTEN) results in fallopian tube cells forming spheroids, small multiple-cell structures that might be important for metastasis of tumors. We will evaluate the ability of spheroids to attach to the surface of the ovary and identify the pathway downstream of PTEN that resulted in spheroid formation. Overall, this research will identify multiple steps in colonization of the ovary that may be targeted to develop new therapies for this deadly disease.
This grant was made possible in part by a donation from Jack Dubnicek, in memory of Jamison Manning.