Mutations in Adjacent Cells Combine to Trigger Tumor Formation

Cancer researchers used a fruit fly (Drosophila melanogaster) model to show that cooperation at the molecular level between cells with different genetic mutations could trigger the development of malignant tumors.

Investigators at Yale University (New Haven, CT, USA) worked with two well-known Drosophila mutations RAS and scribble (scrib). RAS mutations are implicated in the development of more than 30% of cancers, and mutations in the tumor-suppressing gene scribble also contribute to tumor development. However, cells containing only mutated RAS or mutated scrib do not become cancerous.

Results published in the January 13, 2010, online edition of the journal Nature revealed that while both RAS and scrib mutations were required for cancer development, the two types of mutations did not have to be within the same cell. The investigators found that RAS and scrib mutations could cause tumors when they affected different adjacent epithelial cells. This interaction involved JNK (C-Jun N-terminal kinase) signaling.

JNK, by phosphorylation, modifies the activity of numerous proteins that reside at the mitochondria or act in the nucleus. Inflammatory signals, changes in levels of reactive oxygen species, ultraviolet radiation, protein synthesis inhibitors, and a variety of stress stimuli can activate JNK. In the current study, JNK activity was the driving force that stimulated RAS/scrib mutated tissues to develop into tumors in response to stress or injury.

"Better understanding of the underlying mechanism causing cancer always offers new tools to battle the disease," said senior author Dr. Tian Xu, professor of genetics at Yale University. "The bad news is that it is much easier for a tissue to accumulate mutations in different cells than in the same cell. A lot of different conditions can trigger stress signaling: physical stress, emotional stress, infections, inflammation - all these things.”

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