For a disease that affects an estimated 6 to 10% of women, surprisingly little is known about endometriosis — a disorder that causes uterine tissue to grow outside the uterus. Endometriosis is a risk factor for propensity to some tumors of the reproductive system. However, endometriosis lesions are not cancerous but can result in both chronic and intense pain as well as infertility. The severity of the symptoms can vary greatly among women, and can also change throughout a woman’s lifetime. Currently, there is no cure for the disease; its management is often hit or miss, and sometimes includes multiple surgeries and hormonal treatment. Novel approaches employed by NIBIB-funded researchers have revealed a possible combination of proteins and signaling pathways associated with more severe symptoms of the disease and the likelihood that endometriosis results in infertility, opening the door for rational design of new therapies.
Linda Griffith, Ph.D., and her team at the Massachusetts Institute of Technology describe their results in a paper published in February in Science Translational Medicine. Griffith and her collaborators Doug Lauffenburger at MIT and Keith Isaacson at Newton Wellesley Hospital suspected that, similar to breast cancer, endometriosis may have molecular characteristics that transcend the number, size, shape, and locations of lesions and instead group together patients by the varied intensity and symptoms experienced by patients. So she and her team took an unbiased approach and looked broadly at networks of cellular proteins interacting and communicating with each other, knowing it would be unlikely to find a single culprit. The team identified some cytokines-- proteins that are released by one cell and trigger action in another—as key candidates
The team looked at peritoneal fluid samples from 57 premenopausal women diagnosed with endometriosis compared to controls without endometriosis. In about a third of the women, they found a specific signature of 13 cytokines that changed together, suggesting that they were all part of a communication network. Then, using data that had been published by others about which immune cells produce various cytokines, they “reverse engineered” the communication network. Tracing these cytokines back to their origin eventually led Griffith to the ‘garbage disposal’ of the immune system, the macrophage. Macrophages are large immune cells that ingest foreign cells that could do the body harm. Once triggered, these scavenger cells secrete some of the cytokines that cause inflammation, the body’s initial response to a harmful agent. It is the inflammation that causes much of the intense pain suffered by endometriosis patients. Since it has been previously shown that women with faulty immune systems tend to be more susceptible to endometriosis, Griffith’s team seemed to be on the right track. But much like “fever” is a generic symptom that can be treated with drugs; inflammation is a generalized response that can have different causes. The key to a cure is treating the underlying cause of the symptoms, which, in the case of the inflammation associated with endometriosis, has been unknown until now.
Altered levels of the inflammatory cytokines found by Griffith, such as IL-8 and RANTES, are linked to increased severity of the symptoms of endometriosis, and perhaps more importantly, were possibly indicative of particular intracellular signaling cellular pathways. When Griffith’s team tested patient cells in the lab they tried giving established and investigational drugs that inhibit kinase signaling pathways, some of which were successful in decreasing the amount of the cytokines secreted by the macrophages, and thus validating this approach. The breakthrough discovery is an example of using molecular systems biology (rather than just the number and morphology of lesions as discovered by surgery) to classify the disease more accurately and could significantly aid in diagnosis and perhaps guide development of future treatments to control endometriosis. Griffith hopes that by identifying this specific network of proteins, more researchers will begin to realize that endometriosis is a disease that can, and should, be approached with the molecular classification mechanisms in mind.
The research is in its early stages and will need to be reproduced with a larger sample of patients before the signature can be used as a diagnostic method or inform drug development, and such studies are already underway. “This is the first step in the realization of precision medicine for a complex disease that has, to date, been very difficult to classify and predict,” said NIBIB’s program director of Tissue Engineering and Regenerative Medicine, Rosemarie Hunziker, Ph.D. “It is a significant finding in a rarely studied and poorly understood disease that affects many, many women.”