The Role of CDON in Ovarian Carcinoma
Abstract
Women with ovarian carcinoma are typically diagnosed when their disease has spread beyond the ovary. After diagnosis, patients have surgery and are treated with a combination of chemotherapy drugs. For most patients this works for a while, but the cancer usually comes back and drugs stop working. In spite of efforts to discover the cellular processes that drive tumor growth and clinical trials to test new therapeutic agents, there haven t been many successes, and therefore little improvement in outcome for patients over the past few decades. One of the reasons that ovarian cancers recur so often is because although chemotherapy drugs can kill most of the cancer cells, it may not kill all of them. The drug-resistant cells that are left behind are thought to behave aggressively and provide a reservoir for tumor re-growth and seeding of new tumors in the abdomen. With the goal of discovering new targets to exploit to treat or cure ovarian cancer, a central mission of the Ovarian Cancer Research Program, we looked for new targets in ovarian cancer cells that drive the re-growth and spread of this cancer. We recently began studying a protein called cell adhesion molecule (CAM)-related downregulated by oncogenes (CDON for short). CDON is expressed at the surface of cells, and as the name suggests, one of its functions is to help cells adhere to each other. CDON has another function, and that is as a receptor for hedgehog proteins, a family of growth factors that are secreted and released from cells to promote growth of other cells nearby. Under normal circumstances, hedgehog proteins are important for organ, limb, and brain development, in part by controlling the growth of normal stem cells. But hedgehog signaling can go awry in some cancers, promoting tumor growth and possibly the growth of cancer stem cells. Cancer stem cells are rare cells in tumors that have the ability to regenerate a tumor. These cells are often resistant to chemotherapy drugs, so after chemotherapy that kills most tumor cells, rare cancer stem cells may survive and cause re-growth or recurrence of the tumor. Abnormal hedgehog signaling is thought to be important in ovarian cancer and may be important for the growth and survival of ovarian cancer stem cells. Because CDON is a hedgehog receptor, we began to study it with the idea that it might have important functions in ovarian carcinoma cancer stem cells and promote the aggressive behavior of tumor cells. Our preliminary data show that the CDON gene is expressed highly in ovarian carcinoma cell lines, patient tumors, and patient-derived tumor models, where high levels of CDON messenger RNA are readily detectable, but surprisingly, very few cells in ovarian tumors express CDON protein. The low incidence of CDON protein expression in tumors is in line with the idea that this protein may be selectively expressed in and mark ovarian cancer stem cells. We have additional data that show that CDON protein is co-expressed with an ovarian cancer stem cell marker called ALDH1, and that the levels of both ALDH1 and CDON increase dramatically in cells grown under non-adherent conditions where they form small clusters of cells. These clusters of cells are much like free-floating aggressively behaving clusters of cells that are present in ascites or that may be left behind after chemotherapy. These observations have led us to hypothesize that CDON may mark and play an active role in ovarian cancer stem cells. We also hypothesize that expression of CDON contributes to drug resistance and the ability of tumor cells to adhere to one another and survive. To test these ideas, the aims of this proposal are to (1) use novel patient-derived tumor models and gold-standard tests to evaluate CDON as a candidate ovarian cancer stem cell marker; (2) compare the sensitivity of CDON positive and negative cells to chemotherapy drugs; and (3) to determine the role CDON plays in the formation of tumor cell aggregat
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610142
Entities
People
- Denise C. Connolly
Organizations
- United States Army