STANFORD, Calif.—Researchers from the Stanford University School of Medicine have discovered that lowering levels of a cancer signal under a specific threshold—much like a light dimmer switch—reverses tumor development in mice, according to a study published in the July 1 issue of Cancer Research.
The researchers identified a precise threshold level of Myc, a transcription factor that regulates gene expression, which determined the fate of tumor cells in a cancer of the immune system in mice. Above the threshold, high levels of Myc drove immune cells to grow too large and multiply uncontrollably. When the researchers lowered Myc levels below the threshold, the same cells shrank to normal size, stopped multiplying and began dying normally.
Although the findings do not represent a cure or even better treatments for cancer, the researchers say they could help target cancer chemotherapy to tumors while minimizing side effects for the body's healthy cells.
"Our findings suggest that the Myc switch can be shut off partially and this may be useful in the treatment of some cancers," says the study's senior author, Dr. Dean Felsher, an associate professor of medicine and oncology at Stanford. "We are partnering with companies interested in making drugs that target Myc."
Using mice that were genetically engineered to develop Myc-driven tumors in response to a chemical in their drinking water, the researchers slowly lowered Myc from an elevated, cancer-causing level to the precise point at which tumor cells returned to normal. Near the threshold, they examined many aspects of cell metabolism to obtain a detailed picture of how the cancer cells changed as Myc dropped. They measured changes in gene activity, protein levels, protein activation inside the cells and the appearance of cell-labeling proteins on the exterior surface of the cells.
A unique feature of the study was software developed by the scientists to help them see how these different types of data fit together into detailed metabolic pathways.
Identifying the threshold was important because Myc contributes to about 50 percent of human cancers, including malignancies of the immune system and lung, the researchers wrote.
"Our results show that there is a threshold level of Myc required to maintain a tumor phenotype," the authors wrote. "At this critical threshold level of Myc expression, there is a marked change in the global cellular program from cellular proliferation to proliferative arrest and apoptosis. Importantly, we performed both a gene expression–based analysis as well as a proteomic analysis to identify genes and proteins that may be useful as biomarkers for indicating tumor status."
From here, the researchers plan to investigate how different levels of Myc expression influence gene expression and outcome as well as whether this occurs because of different levels of promoter occupancy.
"Most importantly, we plan to investigate if human tumors also exhibit a threshold level of oncogene expression to maintain tumorigenesis. Our results provide a first glimpse, suggesting that, at least in some cases, partial suppression of the level of Myc overexpression may be sufficient to induce a clinical effect on a tumor," the researchers wrote.
The multidisciplinary research team that conducted the work included 14 scientists from seven different Stanford departments. The research was supported by grants from the National Cancer Institute, the National Cancer Institute Integrative Cancer Biology Program, the Leukemia and Lymphoma Society, the Damon Runyon Foundation, the Burroughs Wellcome Fund, a Weiland Family Fellowship and a Flight Attendant Medical Research Institute Young Clinical Scientist Award.
The researchers identified a precise threshold level of Myc, a transcription factor that regulates gene expression, which determined the fate of tumor cells in a cancer of the immune system in mice. Above the threshold, high levels of Myc drove immune cells to grow too large and multiply uncontrollably. When the researchers lowered Myc levels below the threshold, the same cells shrank to normal size, stopped multiplying and began dying normally.
Although the findings do not represent a cure or even better treatments for cancer, the researchers say they could help target cancer chemotherapy to tumors while minimizing side effects for the body's healthy cells.
"Our findings suggest that the Myc switch can be shut off partially and this may be useful in the treatment of some cancers," says the study's senior author, Dr. Dean Felsher, an associate professor of medicine and oncology at Stanford. "We are partnering with companies interested in making drugs that target Myc."
Using mice that were genetically engineered to develop Myc-driven tumors in response to a chemical in their drinking water, the researchers slowly lowered Myc from an elevated, cancer-causing level to the precise point at which tumor cells returned to normal. Near the threshold, they examined many aspects of cell metabolism to obtain a detailed picture of how the cancer cells changed as Myc dropped. They measured changes in gene activity, protein levels, protein activation inside the cells and the appearance of cell-labeling proteins on the exterior surface of the cells.
A unique feature of the study was software developed by the scientists to help them see how these different types of data fit together into detailed metabolic pathways.
Identifying the threshold was important because Myc contributes to about 50 percent of human cancers, including malignancies of the immune system and lung, the researchers wrote.
"Our results show that there is a threshold level of Myc required to maintain a tumor phenotype," the authors wrote. "At this critical threshold level of Myc expression, there is a marked change in the global cellular program from cellular proliferation to proliferative arrest and apoptosis. Importantly, we performed both a gene expression–based analysis as well as a proteomic analysis to identify genes and proteins that may be useful as biomarkers for indicating tumor status."
From here, the researchers plan to investigate how different levels of Myc expression influence gene expression and outcome as well as whether this occurs because of different levels of promoter occupancy.
"Most importantly, we plan to investigate if human tumors also exhibit a threshold level of oncogene expression to maintain tumorigenesis. Our results provide a first glimpse, suggesting that, at least in some cases, partial suppression of the level of Myc overexpression may be sufficient to induce a clinical effect on a tumor," the researchers wrote.
The multidisciplinary research team that conducted the work included 14 scientists from seven different Stanford departments. The research was supported by grants from the National Cancer Institute, the National Cancer Institute Integrative Cancer Biology Program, the Leukemia and Lymphoma Society, the Damon Runyon Foundation, the Burroughs Wellcome Fund, a Weiland Family Fellowship and a Flight Attendant Medical Research Institute Young Clinical Scientist Award.
