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New Extracellular Particle Could Prove Useful for Cancer Diagnosis, Monitoring


NEW YORK (GenomeWeb) – A team led by researchers at Weill Cornell Medicine has identified two distinct populations of exosomes as well as a new class of extracellular particle that they have termed exomeres.

Described in a study published this week in Nature Cell Biology, the three particle populations appear to have distinct molecular characteristics and biological functions and, in the case of particles shed by cancer cells, could prove useful for diagnosing and monitoring disease, said David Lyden, a pediatric neuro-oncologist and professor at Weill Cornell and senior author on the paper.

Lyden and his colleagues isolated the different exosome and exomere populations using asymmetric flow field-flow fractionation (AF4), which uses the combination of forward laminar channel flow and variable crossflow positioned perpendicular to each other to separate particles based on their density and hydrodynamic properties.

The technique is used in areas like virus research and biopolymer development, said Haiying Zhang, an assistant professor at Weill Cornell and first author on the paper, but it has not typically been applied to exosome work.

The researchers became interested in the technique after an electron microscopy analysis of a population of tumor exosomes made clear that there was a population of particles present that was too small to be isolated by conventional exosome-separation approaches.

"When we did electron microscopy of the tumor exosome population, it was clear it was not a homogeneous population," Lyden said. "You could see large exosomes, small exosomes, and it was also obvious that there was a very predominant small particle present in the EM field. So, we thought, 'How are we going to really understand these distinct particle types?'"

AF4 offered the ability to separate exosomes with very high resolution, and, after optimizing the technique to work with these particles, the researchers found they could identify three distinct groups of extracellular bodies: large exosome vesicles (Exo-L), measuring between 90 and 120 nanometers; small exosome vesicles (Exo-S) measuring between 60 and 80 nm, and a previously unidentified population of particles around 35 nm in size, which they called exomeres.

Using mass spectrometry, the researchers analyzed the protein, glycoprotein, lipid content of Exo-L, Exo-S, and exomere particles shed by more than 20 different cancer types. They also looked at the genetic content of these particles, finding in all cases distinct molecular profiles.

They also observed clear differences in where in the body these particles localized, Lyden said, noting that Exo-Ls are found predominantly in lymph nodes, while Exo-Ss are typically found in distant organs, and exomeres are primarily taken up by hematopoietic tissues like spleen, bone marrow, and liver.

This finding, he said, points toward the potential functions of these different particles.

"The larger exosomes have more immunologic signaling proteins, and we find these larger exosomes in greater density in lymph nodes," he said. "So, are they communicating with the immune system? The smaller ones like to go to distant organs. Are they responsible for distant metastases? Liver is the number one organ where we find exomeres. What are they doing there?"

One possibility, which Lyden said he and his colleagues are exploring in another paper soon to be published, is that exomeres localizing to the liver are "inhibiting normal liver function, affecting clotting, coagulation, and the metabolism of the liver and its energy stores."

"We think that these exomeres are allowing more [liver] energy stores to be made available to the tumor, as opposed to being stored in the liver," he said.

Exosomes are of keen interest in cancer research and diagnostic work where they are seen as potential markers of disease. Companies like ExosomeDx have commercialized tests using exosomal markers to diagnose or guide treatment in diseases including prostate and lung cancer while other researchers are exploring the use of exosomes for testing in areas like pancreatic and breast cancer.

Lyden said that he and his colleagues have found that by using mass spec-based proteomic analysis of circulating exosomes they can identify early-stage cancer patients.

"We get plenty of tumor tissue and blood samples from patients who are, for instance, stage I lung cancer or pancreatic cancer, and in those blood sample we can [identify] that they have cancer based on the [exosome proteomics]," he said.

The identification of exomeres could further improve such analyses, Lyden said, particularly given that they appear the be more highly abundant than exosomes in most kinds of cancer.

Of the 20-plus cancer types the researchers looked at, "exomeres are by far the predominant particle secreted," in nearly all cases, he said. "We think they are critical, because obviously the exosome field is starting to take off, but exomeres, even though they are smaller, are actually quite numerous. There are billions of them being secreted into the bloodstream and lymphatic system. They have not been recognized [previously], but they really display biology behind a lot of the systemic effects of cancer."

The different proportions of exosomes and exomeres present in a patient could have important implications for the course of their cancer, Lyden suggested, noting that in past work he and his colleagues have demonstrated a role for tumor exosomes in preparing sites for potential metastases.

A patient where Exo-L particles predominate could be at particular risk of metastases in the lymph nodes, while a higher proportion of Exo-S particles could indicate a higher risk of distant metastases, he said.

A particularly high tumor exomere burden, meanwhile, might indicate the potential for systemic effects like liver shutdown that could affect a patient's ability to tolerate chemotherapy.

"If we see all three particles, it could be a bad sign for metastases and broad systemic effects," Lyden added.

Lyden said he had been contacted by a number of companies currently exploring cell-free DNA and circulating tumor cells for cancer testing about his work with exosomes and exomeres. He said he and his colleagues are also working on studies of exosome and exomere content in patients undergoing surgery for early-stage cancers including lung and pancreatic to further build evidence for these particles' diagnostic and monitoring potential.

The researchers are also exploring refinements of their AF4 system, he said, including possibly adding charge-based component to further improve separation of the three particle groups.