Researchers at Fox Chase Cancer Center have shown that a scaffolding protein previously known to be important in invasion and spread of tumors such as melanoma, neuroblastoma, and breast cancer, also has a role in metastases (growth and spread) of epithelial ovarian cancer. The research team is presenting their findings today at the American Association for Cancer Research (AACR) Annual Meeting 2014.
Scaffolding proteins function much like their name would suggest – they provide physical support to other proteins or molecules, to bring these molecules into close proximity so that they can interact with one another. The scaffolding protein featured in today’s presentation has already been shown to have a function in what are known as “oncogenic signaling pathways.”
In Biology, signaling pathways – also referred to as “signal transduction cascades” – are how cells pick up information from their environment and respond to changes. They often work by altering the expression pattern of their genes through a complex cascade of interactions that link cell signaling molecules – often receptors on the cell surface – to the genetic material in the nucleus of the cell. The cascades often include molecules such as phosphorylases or kinases (that remove or add phosphate groups to other proteins in the cascade, respectively), and scaffolding proteins that function as mentioned above.
The study reported today used mice models to study the ovarian cancer. Although studies performed in mouse models do not always translate directly into clinical studies for humans, in this particular study, some of the genes that were examined can also be found in human cancers. According to Rashid Gabbasov, a graduate researcher with the team, the scaffolding protein of interest (NEDD9 – for “Neural precursor cell Developmentally Down-regualted 9) has already been associated with metastasis of other tumor types; the researchers have now confirmed that its expression is important to the development of epithelial ovarian cancer. Because the protein is not an enzyme performing some catalytic activity, it may be difficult to target its function, although because it is a scaffolding protein, it may be possible to design a drug to disrupt its capacity to bring together the molecules it supports. Its presence or absence might also be used as a potential biomarker, for diagnosis of cancer. Epithelial ovarian cancer is number five on the list of cancer deaths; it kills 14,000 women every year. It is known as a “silent killer”: most symptoms are not specific and thus not much help in diagnosis; the disease has often already metastasized by the time of diagnosis; and advanced-stage ovarian cancer is usually fatal. For this reason, it is vital that an early biomarker be found.
The researchers who performed this study got interested in NEDD9 when they noticed that it was turning up in a lot of other cancers as part of a gene “signature.” To perform the study, the research team compared growth of tumors in two types of mice that had been bred specifically to develop ovarian tumors. One group of mice was genetically engineered to carry NEDD9; the other group did not express the protein. Growth of cancers in both groups was assessed with MRI scans (the same scans that are used to assess tumors in people). The mice that carried the NEDD9 molecule showed delayed development of tumors compared to the mice expressing NEDD9. When the tumor tissue from both groups was analyzed, the mice carrying NEDD9 were found to have more activity in numerous signaling pathways known to be oncogenic.
Next steps for the researchers include evaluating the genes that participated in the signaling pathways that were activated in the mice studies. Now that they have verified that the scaffolding protein is important in metastatic epithelial ovarian cancer, they hope to be able to translate the mouse research into useful information about human cancers.
By Laura Prendergast