A New Diagnostic Tool With the Potential to Predict Tumor Metastasis

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A recent discovery that microscopic particles once considered cellular trash are actually oncogenic exosomes may hold the key to diagnosing an individual’s type of cancer and determining its likelihood of future metastasis. A study published in the journal Nature Medicine in may 2012 was the first to show that measuring a melanoma patient’s exosome activity can predict survival. the findings grew out of earlier work by senior author David C. Lyden, m.D., Ph.D., of Weill Cornell medical College and memorial Sloan–Kettering Cancer in New york. “using confocal and electron microscopy, I noticed flecks that pathologists said were debris were actually homogeneous small particles at future sites of metastasis known as premetastatic niches where the metastatic process is initiated,” said Lyden. With metastatic melanoma exosomes the focus of the new research, the team examined exosomes in patients with metastatic disease. Because exosomes are found in all biofluids, they used stage IV melanoma plasma samples as a reference for exosome profiling. “We can perform a blood test to determine the exosome number and protein content [and] then correlate that to the stage of disease progression. this has helped validate the use of tumor exosomes as prognostic biomarkers,” explained Lyden. “For the first time, we have correlated circulating exosome profiles to melanoma metastasis and people are excited about its new role,” said hector Peinado, Ph.D., instructor of molecular biology in the department of pediatrics at Weill Cornell medical College and first author of the Nature Medicine study. “Like normal exosomes, tumor exosomes participate in cell signaling but with a more sinister result. they circulate to bone marrow progenitor cells and transfer information that promotes a prometastatic phenotype with a long-lasting memory. the cells are primed to promote cancer growth but can remain dormant only to metastasize years later.” Peinado says exosomal activity can now be measured and characterized. “every cancer type has its own exosome signature. our data show a fiveto 10-fold increase in protein content in tumor exosomes derived from stage III and stage IV melanoma patients compared to healthy people. this is the first study suggesting that circulating exosome signatures may determine which patients are at risk for metastasis and which ones do not need to be monitored.” Another new finding was “the first demonstration of a transfer and functional role of oncogenic information between tumor cells and noncancerous cells,” said Lyden. “exosomes are one of the most important mediators for the crosstalk between tumor cells and cells in the microenvironment.” Lyden sees exosome proteins as a potential target for drug development to reduce tumor growth and prevent metastasis. Lauren Pecorino, Ph.D., a cancer biologist at the university of Greenwich in London and author of Why Millions Survive Cancer, characterized their “landmark paper” as “the most far-reaching discovery in recent cancer research history.” In an e-mail, she wrote that it “elucidates a functional role of exosomes in metastasis, characterizes their use as a noninvasive prognostic indicator for melanoma patients, and demonstrates proof of principle for new molecular drug targets to inhibit metastasis.” Pecorino adds, “metastasis—the crux of treating cancer—may finally be within our grasp.” Co–corresponding author Jacqueline F. Bromberg, m.D., Ph.D., an oncologist and breast cancer scientist at memorial Sloan–Kettering Cancer Center, is optimistic that continued research of cancer-derived exosomes will change aspects of cancer treatment, leading to personalized medicine. “What I find interesting about these particles is their concentrated and stable protein/ rNA composition, which represents the cell of origin,” said Bromberg. “one could potentially follow the expression profile of exosomal molecules in response to therapies and monitoring exosomal activity throughout treatment to detect new mutations and protein expression patterns that alter the tumor’s phenotype and help understand the mechanisms responsible for drug resistance.” Further study may identify each tumor’s specific exosomal protein profile and subtype (e.g., er+, her2+, and er/Pr/ her2 for breast cancer), which would be useful for prognosis in predicting which patients could be at risk for future metastatic disease. Bromberg feels their research has substantial promise, but “using exosomes for cancer diagnosis and treatment is not yet ready for prime time.”