Scouting for Metastasis: New Study Uncovers the Role of Exosomes in Cancer’s Spread

By Jim Stallard,

Monday, November 16, 2015

Electron microscope image of three exosomes, which appear as blue concave discs on light green background.

Certain types of tumors preferentially seek out and colonize specific organs through metastasis. New research shows that tumor cells send signals throughout the body to prepare these organs for the arrival of metastatic cells. The signals are transmitted through microscopic bubble-like compartments known as exosomes, which set the stage for cancer cells to take root and thrive.

  • Certain types of tumor cells preferentially seek out and colonize specific organs.
  • Research shows they send signals in advance to prepare the organs.
  • Microscopic compartments called exosomes carry the signals.
  • Without this advance work, cancer cells won’t take root and grow in distant sites.

Cancer becomes especially lethal when it metastasizes from a primary tumor to other organs. But this spread does not occur randomly — within a population of cancer cells, certain subgroups preferentially seek out and colonize specific organs.

New research from scientists at Memorial Sloan Kettering and Weill Cornell Medical College has found that tumor cells send signals throughout the body to prepare specific organs for the arrival of metastatic cells. These signals are transmitted through small vesicles — microscopic bubble-like compartments — known as exosomes, which act as location scouts to set the stage at distant sites where cancer cells can take root and thrive.

After being secreted by cancer cells, the exosomes circulate throughout the body and are taken up by other cells. At particular metastatic sites, they prime what is called the microenvironment — noncancerous cells, molecules, and blood vessels that will eventually surround the tumor — to be nurturing to cancer cells after they arrive.

“If the cancer cells are seeds, then the soil of the microenvironment needs to be appropriately fertilized for the seeds to grow,” says MSK medical oncologist Jacqueline Bromberg, who has led pioneering research into exosomes in collaboration with David Lyden of Weill-Cornell Medical College.  

The researchers sought to learn whether certain molecules in the exosomes were “addressing” them to specific organs.

“We know that patients with metastatic disease to one organ can shed millions of cancer cells into the circulation and yet all the other organs in the body can remain cancer free for a long time,” she explains. “The question we asked was whether cancer exosomes could selectively prepare their favorite organs before the seeds arrive.” 

Directed by Surface Proteins

Earlier research had suggested that exosomes play a role in metastasis, but the details were unclear. While exosomes can be taken up by a wide variety of cells, in most cases they are not retained, nor do they transmit signals to change their surroundings.

In the new study, led by Drs. Bromberg and Lyden and published online by the journal Nature, the researchers sought to learn whether certain molecules in the exosomes were “addressing” them to specific organs, which might shed light on why tumor cells later preferentially go to those same organs.

Schematic illustration showing progression from left to right of exosomes spreading from breast tumor through blood vessel to lungs and liver in human torsos on the right.

They discovered that exosomes display a variety of receptor proteins called integrins on their surface, and that the integrin type determines which organ the exosome will target. For example, an integrin called αvΒ5 directs exosomes to the liver, while the integrin α6Β4 causes them to home in on the lung.

The specific integrin makes it easier for the exosome to be taken in and prime a particular organ because the integrin binds to other proteins, called adhesion molecules, amid the organ’s cells.

“These integrins are like cellular Velcro, and they’re looking for the right sticky ‘hook’ to adhere to,” Dr. Bromberg says. “When they connect with the right adhesion molecule, it allows the exosome to start doing its work preparing the organ to accept and nurture the cancer cells.”  

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Powerful Effects on Organ Selection

The researchers also showed that when they blocked the expression of αvΒ5 or α6Β4 in cancer cells, the exosomes those cells shed were no longer able to educate their respective target organs — the liver and lung. In experiments with mice, cancer cells that usually take root and grow in these organs could not do so without the exosomes carrying out their advance work.

Another mouse study showed the exosomes can even redirect cancer cells to spread to organs they don’t usually target, further demonstrating their powerful effect.

“Remarkably, if we treated mice with lung-targeting exosomes, we could redirect breast cancer cells that would normally spread to the bone, causing them to spread to the lungs instead,” Dr. Bromberg says.

The researchers also found an important clue as to how the exosomes condition the target organs to be welcoming to cancer cells: They appear to stimulate the cells in the microenvironment to produce a protein group called S100, which are already known to precondition host cells for metastasis.   

“We think the exosome integrins not only help with adhesion to the microenvironment but also trigger key signaling pathways and inflammatory responses in target cells, resulting in the education of that organ to permit the growth of metastatic cells,” Dr. Bromberg explains.

Exosomes can even redirect cancer cells to spread to organs they don’t usually target, further demonstrating their powerful effect.

She says that the main short-term practical application of these findings might be to analyze exosomes, and the expression of integrins on their surface, to predict where a patient’s tumor is most likely to spread.

In the longer term, having earlier knowledge about the likely site of metastasis could someday help clinicians devise focused treatments that prevent the emergence of metastases at these sites.

“The next big challenge is to determine if this process is reversible — and if so, is there a step of no return?” Dr. Bromberg says. “Specifically, can we uneducate or reeducate these organs, rendering them inhospitable for metastasis?”

She explains that many have suggested using exosomes to deliver drugs or nucleic acids to cancers. “Identifying the integrin ‘zip codes’ that target specific cell types and tissues provides us with a unique opportunity to deliver such therapies to the organs that sustain the cancer,” she says.  “You could render future metastatic sites inhospitable so that cancer cells would not grow there.”

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do using disintegrins as a drug possibly prevent metastasis?
My group having a disintegrin isolated from snake venom showed previously to ameliorate fibrotic liver in CCL4 model mice

Thank you for your comment. We sent your question to Dr. Bromberg, who responds:

Yes they could depending on which integrin the “disintegrin” is blocking. this would be a very interesting approach to preventing cancer exosome education of specific organs.

does age have something to do with a" no further treatment can be done" attitude with an elderly metastatic breast cancer patient ?

Susan, we are unable to comment on individual cases, but a decision not to treat may have to do with a person's overall health more than his or her age. Many older cancer patients are able to continue treatment if they are otherwise in good health. Thank you for your comment.

This is very interesting research indeed.
How long would you suspect it would take to 1) map the zip codes, at least for a couple types of cancer 2) how long to test in lab with mice a targeted therapy to make zip code unfriendly to the cancer cell colonization?

Ed, thank you for reaching out. We sent your question to Dr. Bromberg, who responds:

1) To map the zip codes would take a few years.

2) Targeted therapies such as blocking antibodies or competing peptides are ongoing. It will take 2-3 years to test this using this model.

Are you doing anything at MSKCC to stop the exosomes other than chemo, surgery, radiation?
Thank you!

Thank you for your question. Research is ongoing into developing targeted therapies such as blocking antibodies or competing peptides that might block the effects of exosomes, but it is not possible to predict at this stage how effective such therapies would be or when they might become clinically available.

So, with these new understanding, can I suppose that in some way the biopsies procedures could do much more harm than good? I mean, that with the desruptive potencial that biopsies have, could throw into the circulation millons of these potencial methastatic prepared cells facilitating the dissemination process??

Mauricio, thank you for reaching out. Your concern is understandable, but experts think there is a very low likelihood that a biopsy will cause cancer to spread.

Here is a statement from the National Cancer Institute:

The chance that surgery will cause cancer to spread to other parts of the body is extremely low. Following standard procedures, surgeons use special methods and take many steps to prevent cancer cells from spreading during biopsies or surgery to remove tumors. For example, if they must remove tissue from more than one area of the body, they use different surgical tools for each area.

In addition, a recent study also dispelled the idea that biopsies cause cancer to spread:

Are you testing natural products that are known to stop the spread of cancer cells - like modified citrus pectin , I'm wonder whether these are suggested to patients after an initial diagnosis and treatment for a primary tumor ? Also other non toxic drugs and nutriceuticals like aspirin and turmeric, Q10 etc?

Thank you for reaching out. There is understandably a strong interest in "natural" cancer therapies, but these therapies should be regarded with great caution because most are unsupported by evidence. Many people offering testimonials to the effectiveness of such treatments may attribute benefits to them simply because their condition improved after using them — when the actual cause for the improvement is unrelated.

If you’re considering using a nontraditional cancer therapy, always check with a reputable source such as the National Cancer Institute or our About Herbs database, and always tell your doctor.

Some of the natural substances you mentioned are discussed in the About Herbs database, such as tumeric, citrus pectin, and Q10.

Here is a link to the About Herbs database:…

My brother in law has lung cancer. The Bellevue hospital is not sure. He doesn't have insurance. Can this hospital see without of insurance ?

Thank you for reaching out. Memorial Sloan Kettering does provide financial help to certain patients in need. If your brother does not have health insurance, we may be able to help. Go to this link to learn more:…

If your brother would like to make an appointment with a Memorial Sloan Kettering physician, he can call our Physician Referral Service at 800-525-2225 or go to­care/appointment. Thanks for your comment.

Great work. I'm surprised it didn't make your top 3 for the year.

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