Blood exosomes shown to contain tumor-specific genetic information for brain cancer

Nov 17 2008

Tiny vesicles called exosomes released into the bloodstream from aggressive brain tumors contain genetic signatures that may help guide future diagnosis and treatment of this deadly disease.

In their report in the December issue of Nature Cell Biology (DOI: 10.1038/ncb1800), Massachusetts General Hospital researchers describe finding tumor-associated gene messages in the blood samples of brain cancer patients, including the gene mutation known as EGFRvIII, which is specific for the aggressive form of brain cancer glioblastoma.

"The fact that we can harvest this important cancer signature from exosomes circulating in blood is a critical demonstration of Exosome's technology for advanced personalized medicine diagnostics", said James R. McCullough, chief executive officer of Exosome Diagnostics. "Exosomes offer us the possibility of diagnosing and monitoring a variety of cancers from blood draws, rather than solely by invasive tissue biopsies. In addition, because the effects of some anti-cancer drugs are enhanced or disabled by a tumor's genetic composition, it may be possible to manage treatment regimens by analyzing the genetic contents of patient exosomes."

Exosome Diagnostics is developing several tests using the non-invasive exosome technology to measure single genetic mutations such as those found in the EGFR, KRAS and BRAF genes for use in lung, colon, brain and melanoma cancers. The Company is also developing complex mutational profiles of cancer tumors for monitoring disease progression and mutational status. After the research described in the paper was completed, Exosome Diagnostics exclusively licensed Massachusetts General Hospital's provisional patent on the technology.

"We believe these results have broad implications for personalized medicine," said Johan Skog, Ph.D., director of genetics at Exosome Diagnostics. "Detecting mutational profiles through a noninvasive blood test could allow us to monitor how a tumor's genetic makeup changes in response to therapy, which may necessitate changes in treatment strategy." The lead author on the study, Dr. Skog, is also with the MGH Neuroscience Center.

Many types of cells release exosomes as part of normal cell-to-cell communication, and several types of tumor cells are known to shed exosomes containing proteins that can alter the cellular environment to favor tumor growth. The current investigation is believed to be the first to carefully analyze the contents of exosomes shed from glioblastoma cells and to characterize their genetic content.

"Because they contain virtually the entire transcriptome," said Dr. Skog, "exosomes may one day be used to conduct full tumor genetic profiling to help with early diagnosis and eligibility for personalized therapeutic treatment based on an individual's specific tumor."

The investigators first analyzed tumor cells from three glioblastomas and verified that the cells released exosomes containing RNA and protein molecules, sometimes at levels significantly different from that present in the tumor cells themselves. Some messenger RNAs related to activities such as cell proliferation and migration, angiogenesis or immune response were highly abundant in the exosomes but not in tumor cells from the same patient. When labeled glioblastoma exosomes were cultured with normal cells, tumor RNA was delivered into the normal cells and translated into proteins.

To study the potential of glioblastoma exosomes as markers of a tumor's genetic makeup, the research team analyzed tumor tissue and blood serum from 25 glioblastoma patients and were able both to find tumor exosomes and to identify, in some samples, a mutation in the epidermal growth factor receptor (EGFR) gene that characterizes a tumor subtype. In two patients, exosome analysis identified an EGFR mutation that did not appear in the sample of tumor tissue, reflecting how the often-chaotic diversity of cells within a tumor may cause a surgical biopsy to miss cells carrying critical information.

Xandra Breakefield, PhD, of the MGH Neuroscience Center is the senior and corresponding author of the Nature Cell Biology paper. She is also a member of the Exosome Diagnostics scientific advisory board. Additional co-authors are Tom Wurdinger, PhD, Sjoerd van Rijn, Dimphna Meijer, Laura Gainche, and Miguel Sena-Esteves, PhD, MGH Neuroscience Center; William Curry Jr, MD, and Robert Carter, MD, PhD., MGH Neurosurgery; and Anna Krichevsky, PhD, Brigham and Women's Hospital.