Scientists at Cincinnati Children’s Hospital Medical Center have identified a way to kill two types of cancer cells that maintain a constant flow of these dying, cell-free cells in a typical mouse model of leukemia. The team’s work could lead to new approaches for treating this difficult-to-treat condition, finding a useful broader approach that has the potential to be tested in clinical trials. The study was published online in the Journal of Controlled Release. Malignant melanoma, which accounts for about 70 percent of all cancer-associated deaths in the United States, is a deadly form of skin cancer with little treatment and little treatment is curative. Patients normally take chemotherapy or infusions of the hormone to protect themselves but the treatments can do little to stop or stabilize the tumor. “This disease has been treatable before, but the target consumer’s access to that medicine is taking a hit due to the drug resistance—the cells are able to evolve and become resistant to the treatment, and we just can’t find a good way to kill them as they’re very common,” says Rabia Ali, Ph.D., of the Julian and Carole Anderson Investigative Oncology Research Center at Cincinnati Children’s. Most patients with malignant melanoma are diagnosed with one of three drug-resistant tumors: high, medium and low-grade—the latter that typically emerges in blood or bone marrow. But since the cancer arises resistant to cytoplasmic cell infiltration, long-term treatment is not feasible for these patients. To reduce the underlying levels of cell resistance, Ali and colleagues wanted to see if targeting sites in the invading cells known as cancer stem cells, which are associated with resistance in the malignant cells, would improve the response to treatments. Using the mouse model that they developed for this study, the researchers discovered that in high-grade malignant melanoma, these cancer stem cells have increased activity that allows them to release cytokines trapped inside cancer cells. Impaired responses to this bombardment have resulted in high blood-cancer-causing amounts of T-cell infiltration. The researchers targeted these cancer stem cells by interfering with the flow of apoptotic cells (cells that have been killed). These pro-apoptotic cells release the immune system signaling extraceptosis to repopulate the tumor microenvironment to fight off any potential future attack. “Our goal was to learn if targeting cancer stem cells would improve the response to cytoplasmic cell infiltration and improve the odds for survival,” says Joshua R. Tabar, Ph.D., a co-first author of the study and a postdoctoral fellow in the Tabar Lab at Wyss Institute for Biologically Inspired Engineering. The researchers tracked the progression of 1 mouse model (three psoriatic disorders) with about 150 cancer stem cells. They first analyzed its blood and collected other information, including which tumors each had, whether their radiographic response was normal or not, along with post-translational stress. They found approximately 4 percent of patients receiving average IV treatment had “cytoplasmic infiltration,” the ability for cancer stem cells not to invade and promote tumor growth. “We saw perfect survival outcomes in the large majority of these patients, indicating that the aberrant recruitment of cells by cancer stem cells plays an important role in cancer survival,” Tabar says. The next step will be to determine whether these cancer stem cells are caused by aberrant recruitment, and contributes to the tumor’s control of tumor growth. “Lastly, we will need to determine if aberrant stem cell recruitment contributes to the treatment resistance that can occur in these patients,” Ali says. Co-first author Shwaroswami Kundu, Ph.D., a postdoctoral fellow in the Tabar Lab, directs the Lundbeck Laboratories at Wyss Institute for Biologically Inspired Engineering.
