Epithelial ovarian carcinoma (EOC) is a leading cause of death from gynecologic malignancies. Peritoneal metastasis is an unsolved clinical problem in treatment of EOC. Currently used therapeutic approaches are not specific to EOC metastasis and are inefficient at keeping patients in remission. Thus, targeting the pro-metastatic pathways could provide improved opportunities to increase survival. In our approach to find new targets we searched among pathways that satisfy the following criteria: 1) play a major role in EOC progression;2) have proven to be effective targets for treatments of other diseases. Chemokine signaling is essential for cancer cell migration, proliferation, adhesion, and invasion, i.e., properties that are necessary for a successful development of metastasis. In this application we will characterize fractalkine pathway as crucial for the development of metastasis in EOC and determine potential usefulness of its main players, chemokine fractalkine (CX3CL1) and its receptor, fractalkine CX3CR1, as novel targets for future therapies aimed at prevention and retardation of metastatic spread. Our preliminary data show that primary and metastatic specimens of human EOC are highly positive for CX3CR1, while normal ovarian surface epithelium in non-diseased control subjects is CX3CR1-negative. Moreover, we show that EOC cells can migrate in CX3CR1-dependent manner to CX3CL1. Furthermore, in our pilot experiments increase of CX3CR1 expression in EOC cells led to formation of more tumors of larger size in a xenograft EOC mouse model. Chemokines are promising drug targets. Moreover, chemokine receptors are the G protein coupled receptors, a class of proteins that are effective drug targets covering an estimated 30% of FDA approved drugs. Such drugs have been proven to work in the clinic, and new drugs against CX3CL1 and CX3CR1 are currently under development. CX3CL1/CX3CR1 is a uniquely suitable drug target because the interaction between the chemokine and its receptor is very specific, and there are no other chemokine ligands activating CX3CR1, in contrast to other chemokine/receptor pairs that display high cross-reactivity. Thus, drugs directed at either CX3CR1 or CX3CL1 will likely to affect only the CX3CL1/CX3CR1 axis. Based on our preliminary data and published literature our hypothesis is that CX3CL1/CX3CR1 axis is required for homing metastatic EOC cells to the peritoneum and facilitation of metastatic spread by supporting cell adhesion and migration. To test this hypothesis we propose two aims.
In Aim 1 we will determine the requirement of CX3CL1/CX3CR1 in adhesion to peritoneal mesothelial cells and underlying extracellular matrix using cell culture models and previously developed by us EOC metastasis-specific culture conditions. Adhesion is one of the main initial steps of the metastatic colonization of the peritoneum.
In Aim 2 we will characterize the requirement for CX3CL1/CX3CR1 in development of EOC metastasis in vivo using a xenograft mouse model.
Epithelial ovarian carcinoma is the deadliest gynecologic malignancy mainly due to metastasis and is an unsolved problem in public health. In this proposal we will characterize the requirement for chemokine signaling in progression of ovarian carcinoma, because 1) according to our preliminary data it could play a major role in all stages of the ovarian carcinoma metastatic cascade, and 2) chemokines and their receptors are effective drug targets proven to work in the clinic in treatments of other diseases.
|Gurler Main, H; Xie, J; Muralidhar, G G et al. (2016) Emergent role of the fractalkine axis in dissemination of peritoneal metastasis from epithelial ovarian carcinoma. Oncogene :|
|Gurler, Hilal; Yu, Yi; Choi, Jacqueline et al. (2015) Three-dimensional collagen type I matrix up-regulates nuclear isoforms of the microtubule associated protein tau implicated in resistance to paclitaxel therapy in ovarian carcinoma. Int J Mol Sci 16:3419-33|
|Muralidhar, Goda G; Barbolina, Maria V (2013) Chemokine receptors in epithelial ovarian cancer. Int J Mol Sci 15:361-76|
|Kim, Mijung; Rooper, Lisa; Xie, Jia et al. (2012) Fractalkine receptor CX(3)CR1 is expressed in epithelial ovarian carcinoma cells and required for motility and adhesion to peritoneal mesothelial cells. Mol Cancer Res 10:11-24|