Tumour microvesicles reveal detailed genetic information

The Massachusetts General Hospital (MGH) research team that first discovered tumour-associated RNA in tiny membrane-enclosed sacs released into the bloodstream by cancer cells has now found that these microvesicles also contain segments of tumour DNA, including retrotransposons - also called 'jumping genes' - that copy and insert themselves into other areas of the genome. The investigators' report, which has been published in Nature Communications, is the first to show that microvesicles are involved in transferring retrotransposons between cells.

'Retrotransposons' action of self-copying and reinserting themselves into the genome leads to genetic instability,' says Johan Skog, PhD, who led the current study while an investigator in the MGH Neurology Service. 'Many researchers have proposed this as a mechanism for genetic diversity and for evolution. Retrotransposons are known to be upregulated in cancer, and discovering them in microvesicles that can be found in all body fluids suggests they could be useful biomarkers to help understand tumour progression and monitor treatment response.'

Skog was lead author of a 2008 study that first identified tumour-associated RNA in microvesicles, also called exosomes, released by the deadly adult brain tumour glioblastoma. To further investigate the ability of microvesicles to reflect the genetic status of tumours, in the current study the MGH team analysed the nucleic acid contents of microvesicles from glioblastomas, from two types of paediatric brain tumours, and from malignant melanomas.

They found that the microvesicles contained tumour DNA as well as RNA and that microvesicles from one of the paediatric tumours studied had elevated levels of both DNA and RNA from the oncogene c-Myc, which correlated with the gene's expression in that tumour. 'We showed that amplification of c-Myc was present in microvesicles whenever it was present in the donor cell and that microvesicle analysis can reveal oncogene expression in the original tumour,' explains Leonora Balaj of MGH Neurology, the first author of the study.

High levels of retrotransposon-associated RNA sequences were also detected in tumour microvesicles, and the investigators found those microvesicles could transfer their contents into normal cells. 'One of the most important functions of tumour-derived microvesicles may be modification of normal cells in the microenvironment to make them more supportive of tumour growth,' says study co-author Xandra Breakefield, PhD, MGH Neurology and a professor of Neurology at Harvard Medical School.