Genetic Mechanism Controls Tumor Growth

Investigators have discovered a genetic process that controls cellular growth in the fruit fly Drosophila melanogaster, and think that a similar mechanism may be at work in normal and cancerous human cells.

The researchers, from Emory University School of Medicine (Atlanta, GA, USA) and the University of California, Berkeley (USA), have published their results in the November 2005 issue of the journal Developmental Cell. Ken Moberg, Ph.D., assistant professor of cell biology at Emory University School of Medicine, is the lead author of the study.

The Emory and Berkeley researchers have revealed important details about how mutational inactivation of the D melanogaster version of tumor susceptibility gene 101 (Tsg 101) causes cells to overgrow, leading to organ hypertrophy and tumor-like growths. Scientists first identified the human Tsg101 gene in the mid-1990s centering on its ability to control the growth of cells in a culture dish, but very little has been learned since then about how it does this. "The work that was done 10 years ago strongly implicated Tsg101 as a growth regulatory gene, but how it works has remained largely obscure,” Dr. Moberg stated. In the meantime, the Tsg101 gene has become better known for its role in "endosomal sorting,” the process by which proteins are moved to and from the cell surface, but scientists had little success connecting this characteristic to the gene's possible role in human cancer. "People didn't really understand how the two would fit together,” Dr. Moberg said.

Dr. Moberg's results demonstrate that there is a direct association between the "sorting” and growth regulatory roles of Tsg101. Dr. Moberg and coworkers determined that defective sorting of the Notch receptor, a protein that sends signals throughout the cell, is vital to the biology of Tsg101 mutant cells. Endosomal sorting is an important way in which cells control Notch activity, and when Tsg101 mutant cells are unable to properly sort Notch protein, it becomes hyperactivated, and causes excess tissue growth.

Furthermore, Dr. Moberg found that the process through which Tsg101 controls cell growth is non-cell-autonomous, meaning that mutated cells cause surrounding normal cells to overgrow, resulting in tumor-like growths made up of a heterogeneous mixture of
cells, some normal, some mutated.

Previously, most mutations that cause cancer have been found to act cell-autonomously, meaning the mutant cells themselves overgrow and form a genetically homogeneous tumor. For this reason, Dr. Moberg commented, "This is a very surprising and somewhat novel mechanism for a growth regulatory gene. These new findings suggest the possibility that, in fact, some as yet unidentified subset of human cancers might actually be composed of a mixture of normal cells and cells with mutations in genes like Tsg101.”

Whereas the study up to now has been limited to fruit flies, Dr. Moberg expects his research to initiate a renewed concentration on the role of the Tsg101 mutations in human cancers. "I'm hoping this will eventually translate into a better understanding of the role of the human version of the gene in disease.”

Furthermore, agents already available that target Notch may find new applications if human Tsg101 is found to control growth in a similar way to fruit fly Tsg101. "It may turn out that some of these drugs may actually be clinically useful in treating a hypothetical class of human cancers that harbor mutations in Tsg101,” stated Dr. Moberg.