Metastasis Requires Complex Trigger

Researchers using a Drosophila model system have found that a combination of a mutation in the RAS oncogene and the inactivation of any one of a number of genes affecting cell polarity are required to induce tumors to metastasize.

RAS is a family of genes that have many biologic functions but mainly control cell growth and development. Mutations in a RAS gene can lead to uncontrolled cell growth, and more than 30% of lung cancers, 90% of pancreatic cancers, and 50% of colon cancers are associated with mutations at a specific site in the gene K-RAS. Tumors arising from mutations in RAS do not generally metastasize in the fruit fly.

Investigators at Yale University (New Haven, CT, USA) designed a genetic screen to investigate what genes could stimulate RAS-generated tumors to spread. They reported in the October 9, 2003, online edition of Science that the trigger for metastasis required both the presence of a RAS mutation and the inactivation of any one of a number of genes affecting cell polarity. This combination leads to metastatic behavior, including basement membrane degradation, loss of E-cadherin expression, migration, invasion, and secondary tumor formation. Inactivation of these cell polarity genes cannot drive metastatic behavior alone or in combination with other tumor-initiating alterations.

Senior author Dr. Tian Xu, professor and vice chair of the department of genetics at Yale School of Medicine, explained, "By finding common sets of gene mutations that can make a tumor metastasize, this guides us to specific biological processes that can be targeted by drugs to inhibit metastases. It also implies that we may soon have a better ability to detect early on which tumors require the most intensive treatment to stop the progress of cancer.”




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