When stressed cells go into survival mode and try repairing themselves, bad things can happen. One impact is a biological pathway that can support cancer and promote its progression. This is a story about one such pathway in multiple myeloma, the most devastating tumor-bone disease. It also is a story about how a dentist helped explain its pathological role in the malignant blood disorder, while identifying potential targets for treatments. When Hongjiao Ouyang received a $2 million National Institutes of Health grant recently, NIH officials expressed enthusiasm in their summary for her work “despite her clinical dentistry background.” They understand the rarity of a dentist landing an NIH grant to study cancer. The associate professor of dental medicine, with a doctoral degree in oral health sciences at the University of Pittsburgh School of Dental Medicine, is an endodontist, or root-canal specialist. Her research is what excited the NIH. “We’ve identified a novel pathway and the role of that pathway in modulating the bone-marrow environment on a microenvironment level in support of multiple myeloma,” Ms. Ouyang said, noting the role of her team and colleagues. It could be a universal pathway common to many cancers. Dentists who refer patients to hematologists due to jaw or skull pain unrelated to dental problems are responsible for about 30 percent of all myeloma diagnoses. About 24,050 adults —13,500 men and 10,550 women — will be diagnosed with the cancer this year, according to the American Society of Clinical Oncology’s website, Cancer.net. While the five-year survival rate is about 45 percent, a person’s age and overall health at the time of diagnosis are important factors in survival, with no way of predicting improvements in survival due to many new treatments with others in development. About 60 percent of patients with myeloma have bone fractures and bone pain, with 20 percent dying as a result of those fractures, Ms. Ouyang said. The cancerous impact on blood chemistry and proteins can affect the kidneys and immune system, leading to higher rates of infection, said Cyrus M. Khan, an Allegheny Health Network hematologist involved in treating multiple myeloma. “It is an incurable disease but it is best to go deep into remission. But we expect it to come back,” he said, noting there has been progress in turning a deadly cancer into a chronic disease. Healthy bone chemistry requires a balance in bone formation and destruction, with osteoblast cells building bone and osteoclast cells causing resorption, which is the breakdown of bone with resulting minerals released into the bloodstream. Myeloma causes devastating bone destruction by completely shutting down bone formation while simultaneously accelerating bone resorption. Here is how Ms. Ouyang explains the research she did with collaborators including hematologist G. David Roodman, now at Indiana University: One critical disease process involves how tumors progress by obtaining support from their neighboring environment. The Ouyang research team has identified a spliced version of the X-box-protein 1, or XBP1s, as a key player inside bone marrow cells that supports tumor growth and cancer-induced bone destruction. Normal levels of XBP1s are necessary for cells to control stress and generate the proper immune response. However, its overabundance can occur in the bone-marrow stromal cells in patients with multiple myeloma. Although the detailed mechanisms underlying this phenomenon remains unknown, she said, inflammation generated by the tumor is a possible reason for excessive amounts of  XBP1s. Those higher levels serve to help the cancer progress. At the same time, the tumor causes stress on a protein-folding factory (the endoplasmic reticulum) in the stromal cell, much the way too many holiday shoppers in a retail store can lead to mistakes or lack of service. Because chronic stress in the protein-folding factory can kill the cell, a repair process is initiated. An enzyme (IRE-1) is activated that results in the spliced version of XBP1s, which serves to increase the cell’s protein-folding capacity, while reducing reducing the number of excess proteins. However, XBP1s produces a pathological side effect by generating an inflammatory response in bone marrow stromal cells, beneficial to the tumor. In addition, too many of the proteins make osteoclasts overzealous in breaking down bone. Researchers still are working to determine how tumor cells also inhibit osteoblasts from rebuilding the bone. The net result is bone loss, which occurs in all cases of myeloma. In animal tests, an overabundance of XBP1s in the bone marrow stromal cells also enhanced tumor growth. In the cells of multiple myeloma patients in cell-culture dishes, reducing the proteins helped to suppress osteoclast formation. “We are investigating whether the deletion of XBP1 or XBP1s in bone marrow stromal cells through genetic or drug strategies, in the animal model, will prevent or minimize tumor growth and bone destruction,” Ms. Ouyang said, whose most recent study, with Guoshuang Xu as first author, was published in 2012 in the journal Blood. Maurizio Zanetti, a professor of medicine at the University of California, San Diego, is studying the same XBP1 pathway in prostate cancer and described Ms. Ouyang’s research as “an important piece of work.” “There has been only one other piece of work for backup, published in Nature last spring, that showed the XBP1 pathway in the progression of triple negative breast cancer,” Dr. Zanetti said, referring to a type of breast cancer that’s difficult to treat. “This, in my opinion, is the beginning of a lot of excitement in this particular arena of research.” Cells, he said, respond to endoplasmic reticulum stress by activating repairs and shutting down other biological functions. “In the process, though, several collateral damages are triggered. One is the activation of inflammatory processes, and the inflammation creates an environment conducive to cancer.” Now that the roles of the IRE-1 enzyme and the spliced XBP1 proteins have been explained in myeloma, the goal turns to discovering ways of targeting them for treatment. “It could be that pathway that is activated in breast cancer, prostate cancer and multiple myeloma,” but XBPI also is more active in many different cancers, Dr. Zanetti said. “This pathway also has been implicated in stress and cancer as a switch for survival that fuels the response and protects the tumor. ”Good luck to her,“ he said.